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56Manual 2018 | Curso TeóriCo-PráTiCo de PuBERDaDE

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Bibliografia:

Chen M, eugster eA. Central Precocious Puberty: update on Diagnosis and Treatment. Paediatr Drugs. 2015;17(4):273-81.

Harrington J, Palmert M R. Definition, etiology, and evaluation of precocious puberty. en upToDate. Hoppin A G, Martin K, ed. 2018. Available at: http://www.upToDate.com/

Bereket A. A Critical Appraisal of the effect of Gonadotropin-Releasing Hormon Analog Treatment on Adult Height of Girls with Central Precocious Puberty. J Clin Res Pediatr endocrinol. 2017 30;9(Suppl 2):33-48.

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Central Precocious Puberty: Update on Diagnosis and Treatment

Melinda Chen1 and Erica A. Eugster1

1Section of Pediatric Endocrinology, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, 705 Riley Hospital Drive, Room # 5960, Indianapolis, IN 46202, USA

AbstractCentral precocious puberty (CPP) is characterized by the same biochemical and physical features as normally timed puberty but occurs at an abnormally early age. Most cases of CPP are seen in girls, in whom it is usually idiopathic. In contrast, ∼50 % of boys with CPP have an identifiable cause. The diagnosis of CPP relies on clinical, biochemical, and radiographic features. Untreated, CPP has the potential to result in early epiphyseal fusion and a significant compromise in adult height. Thus, the main goal of therapy is preservation of height potential. The gold-standard treatment for CPP is go-nadotropin-releasing hormone (GnRH) analogs (GnRHa). Numerous preparations with a range of delivery systems and durations of action are commercially available. While the outcomes of patients treated for CPP have generally been favorable, more research about the psychological aspects, optimal monitoring, and long-term effects of all forms of GnRHa treatment is needed. Several potential therapeutic alternatives to GnRHa exist and await additional investigation.

1 IntroductionCentral precocious puberty (CPP) refers to premature activation of the hypothalamic–pituitary–gonadal (HPG) axis, resulting in early development of secondary sexual characteristics. Although the exact threshold defining “normal” pubertal timing has been disputed, commonly used cutoffs to define CPP are 8 years of age for females (7.5 years for Hispanics and African Americans) and 9 years of age for males [1]. The earliest clinical manifestation of central puberty in girls is usually breast development (thelarche), followed by pubic hair (pub-arche). The pubertal growth spurt typically occurs during Tanner stage II–III, with the first menstrual period, known as menarche, usually occurring at Tanner stage IV. In boys, the initial clinical sign of central puberty is testicular enlargement and the pubertal growth spurt happens later than in girls [2, 3].

Although the precise mechanisms triggering the onset of puberty are unclear, the earliest known biochemical change during puberty is increased production of kisspeptin in the hypothalamus. While kisspeptin itself has several proposed stimulatory and inhibitory signals, which have not yet been clearly elucidated, it has been shown that increased

Correspondence to: Melinda Chen.Conflict of interest Dr. Chen has no conflicts of interest to disclose. Dr. Eugster participates in clinical trials investigating treatment of CPP, funded by Endo Pharmaceuticals. No sources of funding were used to support the writing of this article.

HHS Public AccessAuthor manuscriptPaediatr Drugs. Author manuscript; available in PMC 2018 March 27.

Published in final edited form as:Paediatr Drugs. 2015 August ; 17(4): 273–281. doi:10.1007/s40272-015-0130-8.

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kisspeptin production results in increased gonadotropin-releasing hormone (GnRH) release. Thus, a rise in kisspeptin is widely acknowledged as the seminal event that initiates HPG axis activation during puberty [2]. Inhibition of the GnRH pulse generator decreases first during sleep, resulting in an increase of nighttime luteinizing hormone (LH) pulse amplitude during early and mid-puberty. As puberty progresses, LH pulse amplitude increases during daytime hours as well, and estrogen and testosterone levels rise accordingly.

2 EtiologyCPP, for unknown reasons, is found predominantly in girls. In an observational study of the incidence of CPP in Spain, females were approximately ten times more likely to be affected than males [4], and other sources have cited a female-to-male ratio as high as 20:1 [5]. In addition, the etiology of CPP differs between the genders. While the majority of girls will have idiopathic CPP, boys are more likely to have a pathological source [1, 6]. Risk factors for CPP include a history of international adoption, as well as congenital or acquired central nervous system insults, such as hypothalamic hamartoma, septo-optic dysplasia, tumor, trauma, infection, or ischemia. Several genetic syndromes, including neurofibromatosis type 1, tuberous sclerosis, and Sturge–Weber syndrome, are associated with CPP [2]. Apart from recognized genetic syndromes, anywhere from 5.2 to 27.5 % of cases have been reported to be familial [7, 8].

Specific genetic causes of CPP have been described relatively recently. A substitution mutation in the G-protein coupled kisspeptin receptor gene KISS1R (formerly known as GPR54) was found in a patient with CPP and was associated with delayed degradation of the ligand–receptor complex within the cell membrane. This was further linked to an extended period of downstream signaling, postulated to result in increased amplitude of GnRH pulsatility [9]. An additional KISS1R polymorphism in the promoter region has been described in Chinese girls with CPP, though a detailed knowledge of whether or how this variant impacts the expression or function of the gene is as yet unknown [10].

A mutation in KISS1, encoding the ligand kisspeptin, has also been described within an amino-terminal sequence associated with protein degradation [11]. The mutated li-gand–receptor complex similarly demonstrates resistance to degradation. However, the low population frequency associated with this mutation suggests that it is a relatively uncommon cause of CPP.

More recently, ten separate heterozygous mutations in MKRN3, encoding makorin RING-finger protein 3, have been found in association with both sporadic and familial CPP [12–14]. MKRN3 is a paternally expressed imprinted gene located within the region typically affected in Prader–Willi syndrome. Although the exact function of MKRN3 in humans is as yet unknown, studies in mice have illustrated that mkrn3 mRNA is expressed in the hypothalamic arcuate nucleus, and that a decline in mkrn3 expression is temporally correlated with the rise in kiss1 expression. Other studies have postulated that down-regulation of MKRN3 is permissive for increased GnRH pulses during puberty [13]. Thus, deficiency of this protein would be expected to result in a loss of inhibition of HPG axis activation. These mutations are thought to result in loss of function of the abnormal gene

Chen and Eugster Page 2

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product. In familial cases, all affected subjects have inherited mutations from their fathers. Interestingly, there was an almost equal gender distribution of CPP among affected family members [12].

Other molecular defects have been identified with less clear or weaker associations. These include single nucleotide polymorphisms (SNPs) in the FSHB gene and the LHB gene, though the resulting molecular mechanisms that cause CPP have not been identified [15].Mutations in the Y1 subtype receptor for neuropeptide Y (NPY) could theoretically cause precocious puberty, as NPY is thought to be an inhibitor of pulsatile GnRH secretion. However, the only currently described mutation has not correlated well with an effect on function or with CPP [16]. Additional studies have investigated genes involved in hypothalamic hamartomas and have identified several with increased expression in patients with CPP [17]. LIN28B, which is postulated to have a role in determining the timing of pubertal development, has also been proposed as a genetic target in CPP. However, its exact role in humans is not yet clear. In addition, study findings have been contradictory, and no clinically significant mutations have yet been observed that cause a functional deficit at a molecular level [18, 19].

3 Diagnosis3.1 Clinical Features

On initial examination of the child with CPP, bilateral testicular enlargement (≥4 cc in volume) will be apparent in males, in contrast to patients with peripheral forms of precocious puberty. Girls usually present with both breast development and pubic hair, in contrast to nonpathological entities such as premature thelarche or premature adrenarche. Other signs of pathological precocious puberty include a rapid tempo of progression and linear growth acceleration. Bone age will typically be advanced, though this is certainly not exclusive to CPP and may be seen to a milder degree in numerous other conditions [2].

3.2 Biochemical FeaturesA GnRH stimulation test has long been considered the gold standard for the diagnosis of CPP. However, lack of availability of synthetic GnRH in the USA has led to the use of GnRH analogs (GnRHa) for this purpose instead. While precise cutoffs are difficult to establish, a peak stimulated LH of >∼8 mIU/mL after GnRH and >∼5 IU/L after GnRHa are considered indicative of CPP [2, 20]. An LH/FSH [luteinizing hormone/follicle-stimulating hormone] ratio of ≥2 is also consistent with CPP. However, the results should always be interpreted in light of the specific assay performed and the available sensitivity limits. An alternative diagnostic approach has been measurement of basal ultrasensitive LH, which is typically <0.3 IU/L in prepubertal children. However, basal ultrasensitive LH is often prepubertal in early CPP and thus may be falsely reassuring [1]. Measurement of basal or stimulated sex steroids, while never sufficient alone, can be helpful in evaluation of suspected CPP. This is particularly true of testosterone, whereas random estradiol levels are often unmeasurable even when advanced pubertal development is present. Even if the laboratory evaluation is unremarkable, patients should continue to be monitored over time and retested as indicated if clinical suspicion is high [1, 2, 20].



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4 ImagingPelvic ultrasound has been found to be a useful adjunct to support the diagnosis of CPP over other forms of puberty in girls, especially in equivocal situations. Uterine and ovarian dimensions have a stronger association with bone age than with chronological age and are correlated with CPP up to the age of 8 years [21]. While proposed cutoffs for uterine and ovarian volumes exist, these have been somewhat variable, and other studies have suggested a considerable overlap between patients with and without CPP, making reliable parameters difficult to establish. For those who present for evaluation after the age of 8 years, ultrasound parameters become even more difficult to interpret, as there is an even greater overlap in uterine and ovarian dimensions between prepubertal and early pubertal girls [21–24]. The finding of small ovarian follicles on a pelvic ultrasound is normal even in prepubertal girls [25]. Clinicians should further keep in mind that ultrasound results may be technician dependent.

The role of brain magnetic resonance imaging (MRI) in the evaluation of patients with CPP has been debated. Boys are more likely to have a pathological cause, making diagnostic imaging for intracranial pathology an essential tool in their evaluation [6]. However, controversy exists regarding recommendations in girls. When female CPP patients without neurological symptoms are screened with MRI, the incidence of positive findings is approximately 15 % [26, 27]. However, some of the abnormalities that are found may be incidental and unrelated to the CPP. In one study, 86 % of 182 girls had normal MRIs, 11 % had mild abnormalities believed to be unrelated to CPP, and 3 % had hamartomas, leading the authors to conclude that routine screening was not indicated in this population, particularly in girls older than 6 years [26]. This is in contrast to a prior study of 67 girls, in whom six of ten with MRI findings had hamartomas, while the remainder were diagnosed with an astrocytoma, teratoma, arachnoid cyst, and pineal cyst. Three of the ten had lesions requiring surgical intervention, leading the authors to conclude that MRI should be part of routine evaluation in CPP regardless of age [27]. Investigations into clinical and biochemical features of patients with intracranial pathology have suggested that younger age at onset, more rapid tempo, and higher levels of sex steroids or gonadotropins are predictive features. However, these overlap to such an extent that no specific cutoff has been identified that can be used to determine whether or not to obtain an MRI in any individual patient. For this reason, many institutions include a brain MRI as a universal part of the evaluation in all children diagnosed with CPP [26–29].

5 TreatmentThe primary goal of CPP treatment is to preserve final adult height. However, it should be recognized that some patients will have a nonprogressive or slowly progressive form of CPP, and these patients can achieve normal adult height without any intervention [20]. Therefore, a period of observation is usually appropriate prior to starting treatment. In patients who do show progression of CPP, there is significant variability in the degree of height gained after discontinuation of treatment, even among patients with the same bone age [30–32].Numerous studies have demonstrated that the greatest gain in final height is achieved in girls with onset of puberty before 6 years of age, although girls with onset between 6 and 8 years



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of age may still reap some benefit from treatment. In contrast, girls aged ≥8 years have not been found to benefit from intervention in terms of height. Thus, treatment in this age group is usually not indicated. An additional issue is that outcomes of treatment are typically defined as the difference between predicted adult height at baseline and the actual height achieved. Unfortunately, height prediction methods are notoriously flawed [33] and have often been found to overpredict height in the setting of early puberty. Therefore, it is impossible to predict the precise amount of additional height that will be gained by an individual patient as a result of putting puberty on hold. While preliminary evidence suggests that electronic methods of bone age assessment may be more accurate, there is minimal information available thus far about their use in precocious puberty [34]. Evidence regarding treatment benefit in males is more limited, as they comprise a relatively small proportion of patients with CPP. The existing data suggest a significant improvement in final height after treatment of CPP in boys [35], though the same measurement and prediction limitations exist.

Concerns about psychosocial functioning are often used as a justification for treatment of CPP. However, the existing data regarding the psychological aspects of CPP are limited and inconsistent. Insufficient controls and methodological problems render many studies difficult to interpret, compounded by the use of several different assessments, which make comparisons difficult. The current data do not consistently support problems in regard to body image, self-esteem, or sexual behavior in patients with CPP. Differences, where found, tend to be modest and suggest that patients with CPP may engage in psychosexual behaviors only slightly earlier than children with on-time puberty. The prevalence of psychopathology does not seem to differ from that in the general population [36]. Similarly, one study of girls with CPP and their mothers at the time of diagnosis found no difference in psychological distress as compared with girls who had early normal puberty, even prior to treatment [37].At this point, there is no consensus regarding whether CPP is associated with psychological distress and/or whether treatment ameliorates these problems, and more data in this area are needed [20].

GnRHa are well established as a standard of care for the treatment of CPP worldwide. While numerous delivery systems and routes of administration exist, depot intramuscular injections or sustained-release preparations have been most widely used. These drugs are believed to work by providing a steady concentration of GnRH activity instead of the pulsatile variation in levels characteristic of native GnRH release, which results in paradoxical down-regulation and suppression of the HPG axis. Monthly depot leuprolide acetate has been the most common form of injection therapy used in the USA. Although extended-release 3-monthly depot leuprolide preparations have been available in Europe and elsewhere for many years, they have been approved by the US Food and Drug Administration (FDA) only recently and are available in 11.25 and 30 mg dosage forms. Although patients on 11.25 mg 3-monthly injections have consistently been shown to have higher stimulated LH and FSH levels than patients receiving 7.5 mg monthly injections or 22.5 mg 3-monthly injections, this has not been accompanied by significant differences in sex steroid levels or clinical parameters [38,39]. Additional information about these preparations has been derived from a phase III open-label study involving patients receiving 3-monthly depot leuprolide acetate at 11.25 and 30 mg doses for 36 months [40]. Of 72 patients, only two discontinued therapy prior to 36



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months because of treatment failure, while 20 discontinued therapy to undergo age-appropriate puberty and 24 continued to receive 3-monthly depot leuprolide for the full study period. As in previous studies, LH escape was seen in a minority of patients on stimulation testing, but this did not correlate with clinical features suggesting lack of suppression. Thus, 3-monthly depot leuprolide seems to be both safe and effective for long-term use [38–40].

Adverse effects are similar for 1- and 3-monthly depot injections and include local reactions and pain at the injection site. Sterile abscess formation has been reported after administration of long-acting injection formulations. Although children who experience sterile abscess formation from long-acting preparations have subsequently been treated successfully with daily leuprolide, there are reported cases in the adult literature of resistance to GnRHa following sterile abscesses [41].

A popular alternative approach to depot GnRHa injections is the histrelin implant, which was approved by the FDA in 2007. This nonbiodegradable implant is made of a flexible hydrogel containing 50 mg of the potent GnRHa histrelin and is placed subcutaneously, usually in the inner aspect of the upper arm. The initial histrelin implant was first developed for treatment of metastatic prostate cancer, where it was found to successfully suppress LH and testosterone levels for up to 1 year. The implant was later reformulated to release histrelin at a higher dose of 65 lg/day for use in children with CPP. An initial pilot study in 11 girls previously treated with depot triptorelin showed satisfactory maintenance of LH and FSH suppression on stimulation tests. This was accompanied by clinical evidence of pubertal suppression, including regression of breast development, a decrease in growth velocity, and a decline in bone age advancement over 15 months. In addition to satisfactory clinical benefit, parents reported less discomfort and lifestyle interference overall than with monthly injections [42]. Following this initial report, a phase III study in 36 patients with CPP demonstrated profound suppression of the HPG axis within 1 month of implantation whether subjects were naïve or previously treated with a GnRHa [43]. The long-term extension phase of this study has now been completed and demonstrated significant improvements in predicted adult height after up to 6 years of sequential annual histrelin implants [44]. Reassuringly, body mass index (BMI) z-scores remained normal throughout the treatment interval.

A significant refinement of the histrelin implant as a therapeutic option has been the recognition that a single implant lasts at least 2 years. Given the known rate of release of 65 mcg of histrelin per day, a 50 mg implant should theoretically last 2 years. That this is indeed the case was demonstrated in a prospective study in 33 children with CPP in whom a single implant was left in place for 2 years. Peak stimulated LH levels at 12 and 24 months were equivalent, and clinical indices of CPP improved progressively. Use of a single implant for 2 years has the potential to significantly decrease costs and numbers of surgical procedures in children treated with this modality [45].

The most common adverse event associated with the histrelin implant is breakage and/or difficulty with localization of the device. These events occur only during explantation and have been noted to take place in 15–39 % of procedures, with a higher likelihood of



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breakage when the implant is left in place for 2 years [44–47]. Additional reported adverse events include local reactions, which are, for the most part, minor and self-limited. Sterile abscess formation [41], keloids [44], site infection [45], and implant extrusion [42] have rarely been reported. Placement and removal of the implant requires a minor surgical procedure. This is typically accomplished in an outpatient setting, using local anesthesia with the addition of conscious sedation if necessary [47]. In rare cases of difficulty with implant localization, ultrasound has proved to be a useful modality. Characteristics of the most frequently used GnRHa are summarized in Table 1.

6 Adjunctive Treatments6.1 Nonaromatizable Anabolic Steroids

Oxandrolone has been used to improve growth in patients for other indications. The exact mechanism has not been elucidated, but a stimulatory effect on the growth plate has been postulated. A small nonrandomized study of ten patients receiving oxandrolone in addition to GnRHa for severe deceleration of growth velocity during treatment for CPP suggested that this combination might improve adult height, compared with GnRHa alone. However, larger randomized studies have not been performed [48].

6.2 Growth HormoneSmall and nonrandomized studies have demonstrated a significant improvement in final adult height over pre-treated predicted adult height in patients treated with GnRHa and growth hormone (GH) as compared with patients treated with GnRHa alone. However, larger randomized studies are currently lacking, and routine use of GH in this setting is not recommended [49].

6.3 Aromatase InhibitorsAromatase inhibitors have the potential to attenuate estrogenic effects on skeletal maturation and to delay epiphyseal fusion. A small randomized study suggested slower bone age advancement and improved adult height in Chinese boys with CPP receiving letrozole [50].However, in general, the experience with these compounds in CPP has been very limited.

7 MonitoringChildren who are being treated for CPP should receive regular follow-up during which pubertal progression or suppression can be followed and documented. Tanner staging, determination of growth velocity, and assessment of skeletal maturation via bone age radiographs are all important indices of suppression. Whether laboratory testing should be routinely included during follow-up is controversial. While several different strategies for biochemical testing exist, no gold standard for how best to monitor children undergoing treatment for CPP has been established. A GnRH- or leuprolide-stimulated peak LH should be <4 IU/L in adequately suppressed children, and random serum gonadotropin levels should theoretically be in the prepubertal range (ultrasensitive LH <0.3 IU/L). However, random ultrasensitive LH levels have been noted to be elevated above prepubertal levels in children who are well suppressed on GnRHa therapy across all forms of treatment, including



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the histrelin implant [51, 52]. Therefore, the utility of measuring random LH levels in children undergoing treatment for CPP is highly questionable.

8 Resumption of the Native Hypothalamic–Pituitary–Gonadal AxisIn studies following patients beyond discontinuation of treatment, the mean time from cessation of injectable depot GnRHa to menses has been found to be 1.5 ± 0.5 years. Some studies have found a slightly shorter time to menses in girls who experienced menarche before treatment than in those who did not. Although less is known about boys, the existing data suggest that clinicians can expect advancement of the Tanner stage within 6 months of discontinuation of treatment [52].

Because use of the histrelin implant is more recent, the data are somewhat more limited but thus far seem to indicate similar results, with the average time from explantation to menarche being 12.75 (95 % confidence interval 9.6–15.9) months, with a range of 2–36 months. Likewise, in males, resumption of pubertal progression was seen on examination within 1 year. A negative trend has been noted between the total duration of GnRHa therapy and the time to menarche, whereas the age at explantation and the time to menarche were significantly inversely correlated [53].

9 OutcomesGirls with CPP have been found to have a higher BMI than their peers at diagnosis. However, this observation is confounded by the natural increase in BMI during puberty. Indeed, some authors have found that while BMI increases in general during treatment, the overall BMI standard deviation score (SDS) does not change. When BMI is evaluated after GnRHa treatment has been completed, there does not appear to be an adverse effect of treatment on BMI in girls with CPP, nor does there appear to be a large impact of CPP itself on BMI at adult height [31, 54, 55].

Results regarding the incidence of polycystic ovary syndrome (PCOS) in GnRHa-treated patients have been quite variable and contradictory, with some authors finding markedly increased rates of PCOS and other authors finding little or no difference. These results are even more difficult to interpret, as multiple criteria for the diagnosis of PCOS exist. Currently, no consensus exists on whether CPP or treatment with GnRHa results in an increased risk of PCOS [2, 54, 56].

Although bone mineral density (BMD) has been seen to be slightly reduced during treatment in girls, these changes do not appear to be sustained. This decrease is thought to be secondary to suppression of ovarian function. However, after treatment is discontinued and ovarian activity resumes, BMD is regained, and so girls are not significantly different from their peers without CPP, according to evaluation at adult height [31].

10 Reproductive Function and FertilityLimited information exists regarding the long-term effects of treatment for CPP on endocrine and reproductive function. In one study of 49 females receiving monthly depot



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leuprolide, 20 were followed to adulthood (age 18–26 years). Of these, 80 % reported regular menstrual cycles. Seven of 20 women reported a total of 12 pregnancies, with six live births, five spontaneous or elective terminations, one ongoing pregnancy, and no reports of stillbirth [52]. Though achievement of short-term treatment goals and resumption of puberty seem to be similar in girls treated with 3-monthly leuprolide and the histrelin implant, it remains to be seen whether similar long-term results can be expected. In addition, long-term data are notably lacking for all forms of treatment with regard to fertility and endocrine function beyond the third decade, as well as the timing of menopause.

11 Future DirectionsAlthough multiple preparations now exist for GnRHa treatment of CPP, further options are under investigation or may be considered. A 6-month formulation of triptorelin, for example, is currently under investigation, providing the potential for even less frequent dosing for those who do not wish to undergo a procedure for the histrelin implant [57].

Other targets for therapy could also be considered. Because GnRH agonists work by stimulation of receptors, leading to desensitization, there is an initial period of increased stimulation, leading to an LH flare, which sometimes precipitates vaginal bleeding in girls with advanced pubertal development before suppression takes place. A GnRH antagonist, however, would theoretically forego this initial phase by disrupting LH pulsatility without an initial flare. Kisspeptin agonists and antagonists, by acting upstream of GnRH, would be expected to have effects similar to those of GnRH agonist and antagonist therapies, respectively. However, since kisspeptin analogs would not work directly at the gonadotropin receptor, they would have the additional theoretical benefit of interrupting pulsatile GnRH and gonadotropin secretion without lowering gonadotropin release below basal secretory levels. Therefore, sex steroid levels under treatment with these agents could be expected to more closely mimic normal physiology [58]. Though use of kisspeptin antagonists in humans has not yet been studied, animal studies have suggested that kisspeptin analogs are able to cross the blood–brain barrier and suppress puberty [58].

Because existing biochemical markers can be unreliable, monitoring of treatment is also a worthwhile area of research. Markers under investigation include free alpha-subunit (FAS), which rises with suppression of the HPG axis. Though GnRHa levels decrease gradually with discontinuation of depot intramuscular injections, FAS levels are seen to acutely decrease within days of histrelin implant removal, preceding LH, FSH, and estradiol rises by weeks. In one case, elevated FAS levels beyond the expected time period were attributable to retained histrelin implant fragments and fell only after all fragments had been removed, highlighting the utility of FAS as a target for relatively rapid assessment of HPG axis recovery. A short “rebound” elevation in FAS can be seen in patients 3–8 weeks after histrelin implant removal. This effect is short lived and self limited, although the reasons for it are unclear [59].



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12 ConclusionCPP is seen most often in girls and is associated with a multitude of conditions. A substantial proportion (over a quarter) of cases are familial, and genetic causes have begun to be elucidated. The diagnosis is based on a combination of clinical and biochemical factors. Treatment with a GnRHa provides the greatest potential benefit for patients who are younger at the time of onset of CPP. Multiple treatment options are available, and more recent options have the benefit of less frequent dosing, with potential for improved compliance. Though several adjunctive treatments have been proposed, evidence supporting these treatments is generally sparse in CPP, and thus they cannot be recommended for routine use. Biochemical markers, bone age, and growth velocity should be followed during treatment to ensure efficacy. The available evidence shows that GnRHa are safe and effective, and long-term data suggest that reproductive function is satisfactory after discontinuation of treatment. However, long-term data, particularly regarding the newer formulations, are still lacking. Continued pharmacological and molecular genetic investigation and rigorously conducted prospective studies will continue to enhance knowledge and optimize treatment in children with CPP.

AcknowledgmentsNone.

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29. Mogensen SS, Aksglaede L, Mouritsen A, Sorensen K, Main KM, Gideon P, et al. Pathological and incidental findings on brain MRI in a single-center study of 229 consecutive girls with early or precocious puberty. PloS One. 2012; 7(1):e29829.doi: 10.1371/journal.pone.0029829 [PubMed: 22253792]

30. Carel JC, Roger M, Ispas S, Tondu F, Lahlou N, Blumberg J, et al. Final height after long-term treatment with triptorelin slow release for central precocious puberty: importance of statural growth after interruption of treatment. French Study Group of Decapeptyl in Precocious Puberty. J Clin Endocrinol Metab. 1999; 84(6):1973–8. DOI: 10.1210/jcem.84.6.5647 [PubMed: 10372696]

31. Pasquino AM, Pucarelli I, Accardo F, Demiraj V, Segni M, Di Nardo R. Long-term observation of 87 girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogs: impact on adult height, body mass index, bone mineral content, and reproductive function. J Clin Endocrinol Metab. 2008; 93(1):190–5. DOI: 10.1210/jc.2007-1216 [PubMed: 17940112]

32. Lazar L, Padoa A, Phillip M. Growth pattern and final height after cessation of gonadotropin-suppressive therapy in girls with central sexual precocity. J Clin Endocrinol Metab. 2007; 92(9):3483–9. DOI: 10.1210/jc.2007-0321 [PubMed: 17579199]

33. Carel JC, Lahlou N, Roger M, Chaussain JL. Precocious puberty and statural growth. Hum Reprod Update. 2004; 10(2):135–47. DOI: 10.1093/humupd/dmh012 [PubMed: 15073143]

34. Thodberg HH. Clinical review: an automated method for determination of bone age. J Clin Endocrinol Metab. 2009; 94(7):2239–44. DOI: 10.1210/jc.2008-2474 [PubMed: 19401365]

35. Mul D, Bertelloni S, Carel JC, Saggese G, Chaussain JL, Oostdijk W. Effect of gonadotropin-releasing hormone agonist treatment in boys with central precocious puberty: final height results. Horm Res. 2002; 58(1):1–7. DOI: 10.1159/000063209

36. Walvoord EC, Mazur T. Behavioral problems and idiopathic central precocious puberty: fact or fiction? Pediatr Endocrinol Rev. 2007; 4(S3):306–12.

37. Schoelwer MJ, Donahue KL, Bryk K, Didrick P, Berenbaum SA, Eugster EA. Psychological assessment of mothers and their daughters at the time of diagnosis of precocious puberty. Int J Pediatr Endocrinol. 2015; 2015(1):5.doi: 10.1186/s13633-015-0001-7 [PubMed: 25780366]

38. Badaru A, Wilson DM, Bachrach LK, Fechner P, Gandrud LM, Durham E, et al. Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty. J Clin Endocrinol Metab. 2006; 91(5):1862–7. DOI: 10.1210/jc.2005-1500 [PubMed: 16449344]

39. Fuld K, Chi C, Neely EK. A randomized trial of 1- and 3-month depot leuprolide doses in the treatment of central precocious puberty. J Pediatr. 2011; 159(6):982–7.e1. doi:10.1016/j.jpeds. 2011.05.036. [PubMed: 21798557]

40. Lee PA, Klein K, Mauras N, Lev-Vaisler T, Bacher P. 36-month treatment experience of two doses of leuprolide acetate 3-month depot for children with central precocious puberty. J Clin En-docrinol Metab. 2014; 99(9):3153–9. DOI: 10.1210/jc.2013-4471

41. Miller BS, Shukla AR. Sterile abscess formation in response to two separate branded long-acting gonadotropin-releasing hormone agonists. Clin Ther. 2010; 32(10):1749–51. DOI: 10.1016/j.clinthera.2010.09.009 [PubMed: 21194598]

42. Hirsch HJ, Gillis D, Strich D, Chertin B, Farkas A, Lindenberg T, et al. The histrelin implant: a novel treatment for central precocious puberty. Pediatrics. 2005; 116(6):e798–802. DOI: 10.1542/peds.2005-0538 [PubMed: 16322137]

43. Eugster EA, Clarke W, Kletter GB, Lee PA, Neely EK, Reiter EO, et al. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. J Clin En-docrinol Metab. 2007; 92(5):1697–704. DOI: 10.1210/jc.2006-2479



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44. Silverman, LA., Neely, EK., Kletter, GB., Lewis, K., Chitra, S., Terleckyj, O., Eugster, EA. J Clin Endocrinol Metab. Long-term continuous suppression with once-yearly histrelin subcutaneous implants for the treatment of central precocious puberty: a final report of a phase 3 multicenter trial. Epub 2015 Mar 24

45. Lewis KA, Goldyn AK, West KW, Eugster EA. A single histrelin implant is effective for 2 years for treatment of central precocious puberty. J Pediatr. 2013; 163(4):1214–6. DOI: 10.1016/j.jpeds.2013.05.033 [PubMed: 23809043]

46. Rahhal S, Clarke WL, Kletter GB, Lee PA, Neely EK, Reiter EO, et al. Results of a second year of therapy with the 12-month histrelin implant for the treatment of central precocious puberty. Int J Pediatr Endocrinol. 2009; 2009:812517.doi: 10.1155/2009/812517 [PubMed: 19956699]

47. Davis JS, Alkhoury F, Burnweit C. Surgical and anesthetic considerations in histrelin capsule implantation for the treatment of precocious puberty. J Pediatr Surg. 2014; 49(5):807–10. DOI: 10.1016/j.jpedsurg.2014.02.067 [PubMed: 24851775]

48. Vottero A, Pedori S, Verna M, Pagano B, Cappa M, Loche S, et al. Final height in girls with central idiopathic precocious puberty treated with gonadotropin-releasing hormone analog and oxandrolone. J Clin Endocrinol Metab. 2006; 91(4):1284–7. DOI: 10.1210/jc.2005-1693 [PubMed: 16449342]

49. Pucarelli I, Segni M, Ortore M, Arcadi E, Pasquino AM. Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution. J Pediatr Endocrinol Metab. 2003; 16(7):1005–10. [PubMed: 14513877]

50. Zhao X, Zhang Q. Clinical efficacy of letrozole in boys with idiopathic central precocious puberty. Chin J Contemp Pediatr. 2014; 16(4):397–400. DOI: 10.7499/j.issn.1008-8830.2014.04.018

51. Lewis KA, Eugster EA. Random luteinizing hormone often remains pubertal in children treated with the histrelin implant for central precocious puberty. J Pediatr. 2013; 162(3):562–5. DOI: 10.1016/j.jpeds.2012.08.038 [PubMed: 23040793]

52. Neely EK, Lee PA, Bloch CA, Larsen L, Yang D, Mattia-Goldberg C, et al. Leuprolide acetate 1-month depot for central precocious puberty: hormonal suppression and recovery. Int J Pediatr Endocrinol. 2010; 2010:398639.doi: 10.1155/2010/398639 [PubMed: 21437000]

53. Fisher MM, Lemay D, Eugster EA. Resumption of puberty in girls and boys following removal of the histrelin implant. J Pediatr. 2014; 164(4):912–6.e1. DOI: 10.1016/j.jpeds.2013.12.009 [PubMed: 24433825]

54. Magiakou MA, Manousaki D, Papadaki M, Hadjidakis D, Le-vidou G, Vakaki M, et al. The efficacy and safety of go-nadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study. J Clin Endocrinol Metab. 2010; 95(1):109–17. DOI: 10.1210/jc.2009-0793 [PubMed: 19897682]

55. Poomthavorn P, Suphasit R, Mahachoklertwattana P. Adult height, body mass index and time of menarche of girls with id-iopathic central precocious puberty after gonadotropin-releasing hormone analogue treatment. Gynecol Endocrinol. 2011; 27(8):524–8. DOI: 10.3109/09513590.2010.507289 [PubMed: 21501002]

56. Franceschi R, Gaudino R, Marcolongo A, Gallo MC, Rossi L, Antoniazzi F, et al. Prevalence of polycystic ovary syndrome in young women who had idiopathic central precocious puberty. Fertil Steril. 2010; 93(4):1185–91. DOI: 10.1016/j.fertnstert.2008.11.016 [PubMed: 19135667]

57. Dajani, T., Reiner, B., Salem, G., Shea, H., Rappaport, M., Alzohaili, O., Van Meter, Q., Domek, D., Bethin, K., Kaplowitz, P., Klein, K., Merritt, D., Rose, S., Kletter, G., Aisenberg, J., Brenner, D., Rogers, D., Silverman, L., Lee, P., Gomez, R., Cassorla, F., Yang, J., Eugster, E., Flores, O., Wright, N. ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD): 2014. Efficacy, safety, and pharmacokinetics (PK) of triptorelin 6-month formulation in patients with central precocious puberty. https://clinicaltrials.gov/ct2/show/NCT01467882

58. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012; 92(3):1235–316. DOI: 10.1152/physrev.00037.2010 [PubMed: 22811428]

59. Hirsch HJ, Lahlou N, Gillis D, Strich D, Rosenberg-Hagen B, Chertin B, et al. Free alpha-subunit is the most sensitive marker of gonadotropin recovery after treatment of central precocious puberty with the histrelin implant. J Clin Endocrinol Metab. 2010; 95(6):2841–4. DOI: 10.1210/jc.2009-2078 [PubMed: 20339028]



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Key Points

Molecular genetic etiologies of central precocious puberty (CPP) are beginning to be elucidated.

Evaluation of CPP should be based on a combination of clinical and biochemical factors, as each parameter has specific limitations.

The gold-standard treatment for CPP is gonadotropin-releasing hormone (GnRH) analogs (GnRHa).

GnRHa provide sustained high concentrations of GnRH, resulting in downregulation of the hypothalamic–pituitary–gonadal axis.

Multiple formulations of GnRHa exist. Although minor differences in gonadotropin levels are observed, all available GnRHa appear to be equally effective in terms of clinical parameters.

Long-term outcomes of children treated with GnRHa for CPP are reassuring with regard to fertility, body mass index, and bone mineral density.



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9/11/2018 Definition, etiology, and evaluation of precocious puberty - UpToDate

https://www.uptodate.com/contents/definition-etiology-and-evaluation-of-precocious-puberty/print 1/33

Official reprint from UpToDate

www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Definition, etiology, and evaluation of precocious puberty

Authors: Jennifer Harrington, MBBS, PhD, Mark R Palmert, MD, PhD

Section Editors: Peter J Snyder, MD, William F Crowley, Jr, MD, Mitchell E Geffner, MD

Deputy Editors: Alison G Hoppin, MD, Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2018. | This topic last updated: Sep 04, 2018.

INTRODUCTION — Precocious puberty is the onset of pubertal development at an age that is 2 to 2.5 standard deviations (SD)

earlier than population norms. The cause of precocious puberty may range from a variant of normal development (eg, isolated

premature adrenarche or isolated premature thelarche) to pathologic conditions with significant risk of morbidity and even death (eg,

malignant germ-cell tumor and astrocytoma).

The clinician faced with a child who presents with early development of secondary sexual characteristics should consider the following

questions:

The definition of precocious puberty and its causes and evaluation will be reviewed here. The treatment of precocious puberty is

discussed separately. (See "Treatment of precocious puberty".)

DEFINITION — Precocious puberty is traditionally defined as the onset of secondary sexual characteristics before the age of eight

years in girls and nine years in boys [1]. These limits are chosen to be 2 to 2.5 standard deviations (SD) below the mean age of onset

of puberty. In most populations, attainment of pubertal milestones approximates a normal distribution, with a mean age of onset of

puberty of about 10.5 years in girls and 11.5 years in boys (figure 1A-B) and an SD of approximately one year [1-9].

NORMAL PUBERTAL DEVELOPMENT — The hypothalamic-pituitary-gonadal axis is biologically active in utero and briefly during the

first week of life. It then becomes more active again during infancy, with peak activity between one and three months of age [10]. This

state yields sex steroid levels comparable with those seen in early-to-mid puberty, but without peripheral effects. In boys,

gonadotropin concentrations then decrease to prepubertal levels by six to nine months of age. In girls, luteinizing hormone (LH) levels

decrease at approximately the same time as in boys, but the follicle-stimulating hormone (FSH) concentrations can remain elevated

into the second year of life. This hypothalamic-pituitary-gonadal activity during infancy is known as the "mini puberty of infancy"; its

biological relevance is unknown.

The neonatal stage is followed by a long period of pre-puberty, which is a state of active suppression of the hypothalamic-pituitary-

gonadal axis. Puberty occurs when there is reactivation of the hypothalamic-pituitary-gonadal axis. The physiologic and genetic

mechanisms that affect timing of pubertal maturation are discussed separately. (See "Normal puberty", section on 'Sequence of

pubertal maturation'.)

In 1969 and 1970, Marshall and Tanner defined the standards of normal pubertal development in children and adolescents, known as

sexual maturity ratings or "Tanner stages" (picture 1A-C) [2,3]. These studies reported that the first sign of puberty in English girls

was breast development at an average age of 11 years (thelarche), followed by pubic hair growth (pubarche), and then menarche. In

English boys, the first sign was testicular enlargement at an average age of 11.5 years followed by penile growth and pubic hair

growth. (See "Normal puberty".)

Since these reports by Marshall and Tanner, several studies in the United States and other countries suggest that children, especially

overweight children, are entering puberty at a younger age than previously [4-9,11]. In addition, there are racial differences, with

puberty occurring earlier in African-American children compared with non-Hispanic Caucasian and Hispanic children. These data and

the proposed explanations for the trends are discussed separately. (See "Normal puberty", section on 'Trends in pubertal timing'.)

EPIDEMIOLOGY — Using the traditional definition of precocious puberty as the development of secondary sexual characteristics

®

Is the child too young to have reached the pubertal milestone in question? – To answer this question, the clinician needs to know

the normal ages for pubertal milestones and how to separate normal from abnormal development.

●

What is causing the early development? – To answer this question, the physician ascertains whether the development of

secondary sexual characteristics is attributable to androgen and/or estrogen effects, and whether the source of sex hormone is

centrally mediated through the hypothalamic-pituitary-gonadal axis, from an autonomous peripheral origin, or has an exogenous

basis.

●

Is therapy indicated, and, if so, what therapy?●



73



before age eight in girls and nine in boys (2 to 2.5 standard deviations [SD] below the average age of pubertal onset in healthy

children), one would expect that the prevalence rate should be around 2 percent, or 2 in every 100 children. However, population

studies looking at the prevalence rates of precocious puberty yield markedly different rates depending on the population studied:

These observations suggest that the definition of precocious puberty is problematic, at least in girls, and that selection of children for

evaluation should not only depend on age but also clinical features, race/ethnicity, and presence/absence of obesity [13]. (See

'Definition' above and 'Threshold for evaluation' below.)

There is a strong female predominance of children with precocious puberty. In a retrospective review of 104 consecutive children

referred for evaluation of precocious puberty, 87 percent were female [14].

THRESHOLD FOR EVALUATION — We suggest careful evaluation of children presenting with signs of secondary sexual

development younger than the age of eight years in girls or nine years in boys. The level of concern and extent of evaluation should

increase with younger age at presentation. Given the trend towards earlier pubertal development, in girls who are between the ages

of seven and eight, a comprehensive history and physical examination and clinical follow-up may be sufficient if the clinical evaluation

does not raise any additional concerns [15]. (See 'Epidemiology' above and 'Evaluation' below.)

A more controversial approach was suggested in 1999 by the Lawson Wilkins Pediatric Endocrine Society (LWPES), which

recommended that evaluation for a pathologic cause of precocious puberty be reserved for Caucasian girls who have breast and/or

pubic hair development before seven years of age and for African-American girls who have these findings before six years of age

[16]. This recommendation was based on a study describing the first signs of pubertal development among approximately 18,000 girls

in the United States and Puerto Rico, among whom development occurred at a younger age than had been previously reported

(figure 2) [11]. The study did not distinguish between girls with isolated thelarche or adrenarche from those with true precocious

puberty. This same study reported an average age at menarche of approximately 12.5 years, which was not substantially earlier than

had been reported in the 1940s [17].

This LWPES recommendation is controversial because of concerns that lowering the age threshold for evaluation of precocious

puberty will result in failure to identify some children with pathologic disease [18,19]. As an example, a retrospective review of 223

girls referred to a tertiary center for evaluation of pubertal development before eight years of age found that utilization of the LWPES

guidelines would have resulted in failure to identify a substantial number of patients with treatable disease [19]. Twelve percent of

these girls were ultimately diagnosed with an endocrinopathy that was amenable to early intervention, including congenital adrenal

hyperplasia, McCune-Albright syndrome, pituitary adenoma, and neurofibromatosis.

CLASSIFICATION — Precocious puberty can be classified based upon the underlying pathologic process (algorithm 1).

In a population-based United States study, breast and/or pubic hair development was present at age eight in 48 percent of

African-American girls and 15 percent of White girls [11]. At seven years of age, the proportions were 27 percent and 7 percent,

respectively.

●

In a population-based study of data from Danish national registries from 1993 to 2001, the incidence of precocious puberty was

20 per 10,000 girls and less than 5 per 10,000 boys [12]. The diagnostic age limit utilized in this study was eight years for girls

and nine for boys. About half the patients had central precocious puberty (CPP) and the remainder were isolated premature

thelarche or adrenarche, or early normal pubertal development. (See "Premature adrenarche".)

●

Central precocious puberty – Central precocious puberty (CPP, also known as gonadotropin-dependent precocious puberty

or true precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. CPP is characterized by

sequential maturation of breasts and pubic hair in girls, and of testicular and penile enlargement and pubic hair in boys. In these

patients, the sexual characteristics are appropriate for the child's gender (isosexual). CPP is pathologic in up to 40 to 75 percent

of cases in boys [20,21], compared with 10 to 20 percent in girls [22-24] (table 1) (See 'Causes of central precocious puberty

(CPP)' below.)

●

Peripheral precocity – Peripheral precocity (also known as peripheral precocious puberty, gonadotropin-independent

precocious puberty) is caused by excess secretion of sex hormones (estrogens or androgens) from the gonads or adrenal

glands, exogenous sources of sex steroids, or ectopic production of gonadotropin from a germ cell tumor (eg, human chorionic

gonadotropin, hCG) (table 2). The term precocity is used instead of puberty here because true puberty requires activation of the

hypothalamic-pituitary-gonadal (HPG) axis, as occurs in CPP. Peripheral precocity may be appropriate for the child's gender

(isosexual) or inappropriate, with virilization of girls and feminization of boys (contrasexual). (See 'Causes of peripheral precocity'

below.)

●

Benign or non-progressive pubertal variants – Benign pubertal variants include isolated breast development in girls

(premature thelarche), or isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and

apocrine odor) in boys or girls that result from early activation of the hypothalamic pituitary adrenal axis as confirmed by mildly

elevated levels of dehydroepiandrosterone sulfate (DHEAS) for age (premature adrenarche) (table 3). Both of these disorders

can be a variant of normal puberty. However, repeat evaluations are warranted in these children to be certain that the diagnosis

is correct. (See 'Types of benign or non-progressive pubertal variants' below.)

●



74



CAUSES OF CENTRAL PRECOCIOUS PUBERTY (CPP) — Central precocious puberty (CPP, also known as gonadotropin-

dependent precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. Although the onset is early,

the pattern and timing of pubertal events is usually normal. These children have accelerated linear growth for age, advanced bone

age, and pubertal levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

CPP can be treated with a gonadotropin-releasing hormone (GnRH) agonist, which leads to downregulation of the pituitary response

to endogenous GnRH, produces a prepubertal hormonal state, and stops the progression of secondary sexual development,

accelerated growth, and undue bone age advancement. (See "Treatment of precocious puberty", section on 'Treatment for CPP'.)

Idiopathic — CPP is idiopathic in 80 to 90 percent of cases of girls, but in only 25 to 60 percent of boys [20-24].

CNS lesions — Although CPP is idiopathic in up to 90 percent of girls and 60 percent of boys, some cases are caused by lesions of

the central nervous system (CNS), a condition often referred to as neurogenic CPP (table 1). Contrast-enhanced magnetic

resonance imaging (MRI) is therefore recommended, even in the absence of clinically evident neurologic abnormalities [20,22,24].

The low prevalence of CNS lesions in girls with the onset of puberty that begins after age six years raises the question if all girls in

this age group need imaging [23].

Many different types of intracranial disturbances can cause precocious puberty, including the following:

Genetics — Specific genetic mutations have been associated with CPP, although each appears to be present in only a minority of

cases:

Previous excess sex steroid exposure — Children who have been exposed to high serum levels of sex steroid (eg, those with

McCune Albright Syndrome and poorly controlled congenital adrenal hyperplasia) may sometimes develop superimposed CPP, either

from the priming effect of the peripheral precocity-derived sex steroid on the hypothalamus, or in response to the sudden lowering of

the sex steroid levels following improved control of the sexual precocity [38-40]. (See "Treatment of classic congenital adrenal

hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Monitoring and dose adjustment' and 'McCune-

Albright syndrome' below.)

Pituitary gonadotropin-secreting tumors — These tumors are extremely rare in children and are associated with elevated levels

of LH and/or follicle-stimulating hormone (FSH) [41,42].

Hamartomas – Hamartomas of the tuber cinereum are benign tumors that can be associated with gelastic (laughing or crying)

and other types of seizures [25]. They are the most frequent type of CNS tumor to cause precocious puberty in very young

children, although in most cases, the mechanism by which these tumors lead to CPP is unknown.

●

Other CNS tumors – Other CNS tumors associated with precocious puberty include astrocytomas [26], ependymomas,

pinealomas, and optic and hypothalamic gliomas [22]. Sexual precocity in patients with neurofibromatosis is usually, but not

always, associated with an optic glioma [27]. (See "Clinical manifestations and diagnosis of central nervous system tumors in

children".)

●

CNS irradiation – Precocious puberty caused by CNS irradiation is commonly associated with growth hormone (GH) deficiency

[28]. In this setting, regardless of height velocity, the GH axis should be evaluated. If testing shows GH deficiency, such patients

should be treated with GH combined with GnRH agonist therapy. (See "Endocrinopathies in cancer survivors and others exposed

to cytotoxic therapies during childhood", section on 'Growth hormone (GH) deficiency'.)

●

Other CNS lesions – Precocious puberty has been associated with hydrocephalus, cysts, trauma, CNS inflammatory disease, and

congenital midline defects, such as optic nerve hypoplasia. (See "Congenital anomalies and acquired abnormalities of the optic

nerve", section on 'Hypoplasia'.)

●

Gain-of-function mutations in the Kisspeptin 1 gene (KISS1) [29] and its G protein-coupled receptor KISS1R (formerly known as

GPR54) [30] have been implicated in the pathogenesis of some cases of CPP, while loss-of function mutations in KISS1R can

cause hypogonadotropic hypogonadism. These observations suggest that KISS1/KISS1R is essential for gonadotropin-releasing

hormone physiology and for initiation of puberty [31].

●

CPP also can be caused by loss-of-function mutations in MKRN3 (makorin ring finger protein 3), an imprinted gene in the

Prader-Willi syndrome critical region (15q11-q13). The decline of hypothalamic MKRN3 gene expression in mice [32] and serum

protein levels in girls prior to the onset of puberty [33] suggest that MKRN3 is one of the factors involved in repressing pubertal

initiation. Thus, loss of function mutations in this gene would lead to diminished inhibition and early onset of puberty. Paternally-

inherited loss of function mutations in MKRN3 have been demonstrated to be associated with up to 46 percent of familial cases

of CPP [32,34,35].

●

A loss-of-function mutation in another gene, DLK1 (Delta-like 1 homolog), leads to undetectable serum concentrations of the

DLK1 protein and has been associated with isolated CPP in five members of one family [36]. DLK1 is a paternally expressed

gene, mostly in adrenal, pituitary, and ovarian tissue. No definitive mechanistic link between DLK1 function and pubertal

development has been determined to date, but polymorphisms in this gene as well as in MKRN3 are associated with variation in

the age of menarche in large genome-wide association studies providing further evidence of a mechanistic link [37].

●



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CAUSES OF PERIPHERAL PRECOCITY — Peripheral precocity (also known as peripheral precocious puberty or gonadotropin-

independent precocious puberty) is caused by excess secretion of sex hormones (estrogens and/or androgens) derived either from

the gonads or adrenal glands, or from exogenous sources (table 2). Further characterization is based upon whether the sexual

characteristics are appropriate for the child's gender (isosexual) or inappropriate, with virilization of girls and feminization of boys

(contrasexual). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are suppressed (in the prepubertal range) and

do not increase substantially with gonadotropin-releasing hormone (GnRH) stimulation.

The approach to treatment for peripheral precocity depends on the cause. GnRH agonist therapy is ineffective, in contrast to patients

with central precocious puberty (CPP). (See "Treatment of precocious puberty", section on 'Treatment for peripheral precocity'.)

In the following discussion, the causes of peripheral precocity are described based upon sex.

Girls

Ovarian cysts — A large functioning follicular cyst of the ovaries is the most common cause of peripheral precocity in girls [43].

Affected patients often present with breast development, followed by an episode of vaginal bleeding, which occurs due to estrogen

withdrawal once the cyst has regressed. These cysts may appear and regress spontaneously, so conservative management is

usually appropriate [44]. Large cysts may predispose to ovarian torsion.

Ovarian tumors — Ovarian tumors are a rare cause of peripheral precocity in girls. Granulosa cell tumors, the most common

type, typically present as isosexual precocity; Sertoli/Leydig cell tumors (arrhenoblastoma), pure Leydig cell tumors, and

gonadoblastoma may make androgens and cause contrasexual precocity [45-47]. (See "Sex cord-stromal tumors of the ovary:

Granulosa-stromal cell tumors", section on 'Granulosa cell tumor'.)

Boys

Leydig cell tumors — Leydig cell tumor should be considered in any boy with asymmetric testicular enlargement. Even if a

distinct mass cannot be palpated and none is evident on ultrasonography, the larger testis should be biopsied if it enlarges during

follow-up. These testosterone-secreting tumors are almost always benign and are readily cured by surgical removal [48]. Radical

orchiectomy is the most common procedure; however, successful treatment by direct enucleation of the tumor with sparing of the

remainder of the testis has been reported [49]. (See "Testicular sex cord stromal tumors", section on 'Leydig cell tumors'.)

Human chorionic gonadotropin (hCG)-secreting germ cell tumors — Germ-cell tumors secrete hCG, which in boys activates

LH receptors on the Leydig cells, resulting in increased testosterone production [50]. The increase in testicular size (usually only to

an early pubertal size) is less than expected for the serum testosterone concentration and degree of pubertal development. This is

because most of the testis is made up of tubular elements whose maturation depends upon FSH. In girls, hCG-secreting tumors do

not lead to precocious puberty because activation of both FSH and LH receptors is needed for estrogen biosynthesis.

These tumors occur in the gonads, brain (usually in the pineal region), liver, retroperitoneum, and anterior mediastinum, reflecting

sites of embryonic germ cells before their coalescence in the gonadal ridge [50]. The histology of hCG-secreting tumors ranges from

dysgerminoma, which respond readily to therapy, to the more malignant embryonal cell carcinoma and choriocarcinoma. All males

with anterior mediastinal germinomas should have a karyotype because these tumors may be associated with Klinefelter syndrome.

(See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Pathology of mediastinal tumors", section on

'Germ cell tumors'.)

Familial male-limited precocious puberty — This rare disorder (also known as testotoxicosis) is caused by an activating

mutation in the LH receptor gene, which results in premature Leydig cell maturation and testosterone secretion [51]. Although

inherited as an autosomal dominant disorder, girls are not affected clinically because (similar to hCG-secreting germ tumors)

activation of both the LH and FSH receptors is required for estrogen biosynthesis [52]. Also similar to hCG-secreting tumors, the

increase in testicular size is usually only to an early pubertal size. Affected boys typically present between one to four years of age.

Treatment of this disorder is discussed separately. (See "Treatment of precocious puberty", section on 'Familial male-limited

precocious puberty'.)

Both girls and boys — The following causes of peripheral precocity can occur in either girls or boys. Physical changes either may

be isosexual or contrasexual depending on the sex of the child and the type of sex hormone produced. Excess estrogen will cause

feminization, while excess androgen will result in virilization.

Primary hypothyroidism — Children with severe, long-standing primary hypothyroidism occasionally present with precocious

puberty. In girls, findings include early breast development, galactorrhea, and recurrent vaginal bleeding, while affected boys present

with premature testicular enlargement [53-55]. Historically this has been referred to as the "overlap" or Van Wyk-Grumbach syndrome

[56]. The signs of pubertal development regress with thyroxine therapy. (See "Acquired hypothyroidism in childhood and

adolescence".)

A proposed mechanism is cross-reactivity and stimulation of the FSH receptor by high serum thyrotropin (TSH) concentrations, given

that both TSH and FSH share a common alpha subunit [57].



76



Exogenous sex steroids — Feminization, including gynecomastia in boys, has been attributed to excess estrogen exposure

from creams, ointments, and sprays. Caretakers using these topical estrogens to treat menopausal symptoms may inadvertently

expose children to the hormones [58,59]. Other possible sources of estrogen exposure include contamination of food with hormones,

phytoestrogens (eg, in soy), and folk remedies such as lavender oil and tea tree oil [60,61]. A food source was suspected for local

"epidemics" of early thelarche in Italy and Puerto Rico during the 1980s, but no single causative substance was found in food

samples [62-64]. Similarly, virilization of young children has been described following inadvertent exposure to androgen-containing

creams [65,66].

Adrenal pathology — Adrenal causes of excess androgen production include androgen-secreting tumors and enzymatic defects

in adrenal steroid biosynthesis (congenital adrenal hyperplasia). Boys who have an adrenal cause for their precocity will not have

testicular enlargement (testes will be <4 mL testicular volume or <2.5 cm in diameter). (See "Genetics and clinical presentation of

nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Premature pubarche may be the presenting feature of an inherited disorder of adrenal steroid metabolism, including 21-hydroxylase

deficiency, 11-beta hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase type 2 deficiency, hexose-6-phosphate

dehydrogenase deficiency, and PAPSS2 deficiency. (See "Uncommon congenital adrenal hyperplasias".)

Adrenal estrogen-secreting tumors can lead to feminization. Rarely, adrenal tumors may produce androgen and estrogen, the latter

because of intra-adrenal aromatization of androgen (or production of enough androgen that is peripherally aromatized to estrogen),

causing both male and female pubertal changes [67]. (See "Clinical presentation and evaluation of adrenocortical tumors".)

McCune-Albright syndrome — McCune-Albright Syndrome (MAS) is a rare disorder defined as the triad of peripheral

precocious puberty, irregular café-au-lait ("Coast of Maine") skin pigmentation (picture 2), and fibrous dysplasia of bone (image 1)

[68]. MAS should be considered in girls with recurrent formation of follicular cysts and cyclic menses [69]. The skin manifestations and

bone lesions may increase over time. In girls presenting with vaginal bleeding, the ovarian enlargement has often been mistaken for

an ovarian tumor, leading to unnecessary oophorectomy [70]. Girls presenting with premature vaginal bleeding should therefore be

evaluated for features of McCune-Albright syndrome to avoid this potential mistake.

The clinical phenotype varies markedly, depending on which tissues are affected by the mutation, but precocious puberty is the most

commonly reported manifestation [71]. As in other forms of peripheral precocity, the sequence of pubertal progression may be

abnormal, in that vaginal bleeding often precedes significant breast development [72]. Prolonged exposure to elevated levels of sex

steroids may cause accelerated growth, advanced skeletal maturation, and compromised adult height. Although the precocious

puberty is typically peripheral precocity, a secondary component of CPP may develop because of sex steroid withdrawal leading to

activation of the hypothalamic-pituitary-gonadal axis [73] (see 'Previous excess sex steroid exposure' above). In boys with MAS, while

sexual precocity is less common, there is a high prevalence of testicular pathology on ultrasound, including hyper-and hypoechoic

lesions (most likely representing areas of Leydig cell hyperplasia), microlithiasis, and focal calcifications [74].

Patients with MAS have a somatic (postzygotic) mutation of the alpha subunit of the Gs protein that activates adenylyl cyclase [75-77].

This mutation leads to continued stimulation of endocrine function (eg, precocious puberty, thyrotoxicosis, gigantism or acromegaly,

Cushing syndrome, and hypophosphatemic rickets) in various combinations. Mutations can be found in other non-endocrine organs

(liver and heart) resulting in cholestasis and/or hepatitis, intestinal polyps, and cardiac arrhythmias, respectively. A heightened risk of

malignancy has also been reported [78]. Germline occurrences of this mutation would presumably be lethal [75,77,79,80].

Treatment of MAS is described in a separate topic review. (See "Treatment of precocious puberty", section on 'McCune-Albright

syndrome'.)

TYPES OF BENIGN OR NON-PROGRESSIVE PUBERTAL VARIANTS — Early pubertal development fits into this category when the

early development of secondary sexual characteristics does not herald underlying pathology and is not followed by progressive

development (table 3). However, monitoring for evidence of pubertal progression is important, as some children presenting with an

apparent benign pubertal variant will instead turn out to have a different disorder. As examples, thelarche may be the initial

presenting feature of central precocious puberty (CPP), or progressive pubic hair development may herald a form of peripheral

precocity.

Premature thelarche — Most cases of premature thelarche are idiopathic and present under two years of age (and may even start

at birth). Many cases will remit spontaneously, and most others do not progress. However, follow-up is warranted because premature

thelarche can represent the initial presentation of true CPP in 10 to 20 percent of children referred to pediatric endocrine units [81-

83].

Key features of premature thelarche are:

Isolated breast development, either unilateral or bilateral – Typically not developing beyond Tanner stage 3●

Absence of other secondary sexual characteristics●

Normal height velocity for age (not accelerated)●

Normal or near-normal bone age●



77



Serum luteinizing hormone (LH) and estradiol concentrations are typically in the prepubertal range, but one should be cautious in

interpreting these levels in children under the age of two years because elevations can be seen as part of the normal transient "mini-

puberty of infancy," and CPP can be diagnosed inappropriately (See 'Normal pubertal development' above.)

Toddlers and children — Premature thelarche occurs in two peaks: one during the first two years of life and the other at six to

eight years of age [83], with potentially different underlying pathophysiology accountable for each of these peaks. Postulated

mechanisms include transient activation of the hypothalamic-pituitary-gonadal axis with excess follicle-stimulating hormone (FSH)

secretion [84]. In infants, soy-based formulas have been implicated, although the evidence is weak and may represent only a slower

waning of breast tissue during infancy [85-87]. Use of lavender oil, tea tree oil, or hair care products that contain placental extract has

also been implicated in some cases of premature thelarche [60]. In most instances, no cause can be found.

In most cases, premature thelarche requires only reassurance. However, the patient should be examined for other signs of pubertal

development, and growth data should be plotted; an accelerated height velocity may be indicative of progressive puberty and

requires further evaluation. To identify patients with progressive puberty, patients should be monitored for several months for

evidence of pubertal progression. (See 'Evaluation' below.)

Neonates — Breast hypertrophy can occur in neonates of both sexes, and is sometimes quite prominent. It is caused by

stimulation from maternal hormones and usually resolves spontaneously within a few weeks or months. The breast development may

also be associated with galactorrhea ("witch's milk"), which also resolves spontaneously [88]. While in most cases neonatal thelarche

disappears over the first months of life, failure to do so almost never has any pathologic significance. (See "Breast masses in children

and adolescents", section on 'Neonates and infants'.).

Premature adrenarche — Premature adrenarche is characterized by the appearance of pubic and/or axillary hair (pubarche) prior

to the age of eight years in girls and nine years in boys, in conjunction with a mild elevation in serum dehydroepiandrosterone sulfate

(DHEAS) for age. It is more common in girls, African-American and Hispanic females, and individuals with obesity and insulin

resistance [15]. Premature adrenarche is considered a variant of normal development, but may be a risk factor for later development

of polycystic ovary disease in girls. (See "Premature adrenarche" and "Definition, clinical features and differential diagnosis of

polycystic ovary syndrome in adolescents".)

In the child presenting with isolated adrenarche, monitoring for the development of other secondary sexual characteristics (breast or

testicular enlargement) is important to ensure that the child's presentation is not the first feature of CPP or a form of peripheral

precocity. Premature adrenarche can be associated with mild growth acceleration and advance in bone age. In children with

progressive virilization or with a more advanced bone age (>2 standard deviations [SD] beyond chronological age), further

investigation for other causes of early pubertal development should be considered. (See "Premature adrenarche", section on

'Evaluation of premature pubarche'.)

Pubic hair of infancy — Pubic hair of infancy is usually a benign condition where infants present with isolated genital hair, usually

finer in texture than typical pubic hair and located along the labia or over the scrotum (rather than on the pubic symphysis) [89-91].

The steroid profile of these infants demonstrates normal or mildly elevated DHEAS concentrations for age. Unlike premature

adrenarche, the condition is transient and the hair typically disappears within 6 to 24 months [92]. In the absence of progressive

development of further genital hair or other secondary sexual characteristics during follow-up, extensive evaluation is not needed.

Benign prepubertal vaginal bleeding — Benign prepubertal vaginal bleeding is characterized by the presence of isolated, self-

limited vaginal bleeding in the absence of other secondary sexual characteristics [93]. The underlying etiology is unknown but

potential mechanisms include increased endometrial sensitivity to circulating estrogens or transient stimulation of the HPG axis [94].

Pelvic ultrasonography is normal and gonadotropins are pre-pubertal. Genital or vaginal trauma, infection, and sexual abuse should

be excluded. In girls with recurrent episodes of vaginal bleeding, other diagnoses such as recurrent functional ovarian cysts or

McCune Albright Syndrome should be considered. (See 'McCune-Albright syndrome' above.)

Non-progressive or intermittently progressive precocious puberty — A subgroup of patients presenting with what clinically

appears to be CPP (often with evidence of both gonadarche and pubarche) will either have stabilization or very slow progression in

their pubertal signs [95]. The bone age is typically not as advanced compared with children with true CPP, and serum LH

concentrations are within the pre- or early-pubertal range, indicating that the hypothalamic-pituitary-gonadal axis is not fully activated

and a FSH-predominant response is typically seen if gonadotropin-releasing hormone agonist (GnRHa) stimulation testing is

performed. Monitoring for evidence of pubertal progression is important to distinguish these children from those with true CPP. In

children with non-progressive precocious puberty, treatment with a GnRHa is not needed because their adult height is not affected

(ie, their final height untreated is concordant with their midparental height) [95,96].

EVALUATION

Guiding principles — The evaluation for precocious puberty focuses on answering the following questions:

Who should be evaluated? – Evaluation is warranted in children presenting with signs of secondary sexual development

younger than the age of eight (girls) or nine (boys) years. The concern and extent of evaluation should increase with decreasing

age at presentation. In girls who are between the ages of seven and eight, a comprehensive history and physical examination

may be sufficient if this examination does not raise any additional concerns.

●



78



Initial evaluation — The evaluation of a patient suspected to have precocious puberty begins with a history and physical

examination. In most cases, radiographic measurement of bone age is performed to determine whether there is a corresponding

increase in epiphysial maturation.

Initial laboratory evaluation — If there is evidence of progressive development of secondary sexual characteristics, further

evaluation is needed to determine its cause, whether therapy is needed, and, if so, which treatment is appropriate.

Is the cause of precocity central or peripheral? – The sequence of pubertal development in children with central precocious

puberty (CPP) recapitulates normal pubertal development but at an earlier age (figure 1A-B). By contrast, individuals with

peripheral precocity have a peripheral source of gonadal hormones and are more likely to display deviations from the normal

sequence and/or pace of puberty. As an example, a girl who progresses to menstrual bleeding within one year of the onset of

breast development is more likely to have ovarian pathology (a cause of peripheral precocity) rather than CPP [97,98].

●

How quickly is the puberty progressing? – The pace of pubertal development reflects the degree and duration of sex steroid

action.

●

A rapid rate of linear growth and skeletal maturation (measured as advanced bone age) suggests either CPP or peripheral

precocity with high concentrations of sex steroids (table 4). Pubertal progression would be considered slow if there is

minimal or no change in stage of breast, pubic hair, or genital development during six or more months of observation. Height

velocity is considered accelerated if it is more than the 95 percentile for age (figure 3A-B).

•

th

By contrast, a child with normal linear growth and skeletal maturation (bone age normal or minimally advanced) suggests a

benign pubertal variant with low concentrations of sex steroids, rather than true CPP or peripheral precocity.

•

Is the precocity because of excess androgen or estrogen? – Are the secondary sexual characteristics virilizing or

feminizing? Isolated contrasexual development (isolated virilization in girls or isolated feminization in boys) excludes central

etiologies. While in girls the most common cause of virilization is due to excess adrenal androgens, a rare ovarian cause of

virilization is ovarian arrhenoblastoma (Sertoli-Leydig cell tumor) [99]. Conversely, a rare testicular cause of feminization is a

feminizing Sertoli cell tumor, which may be associated with Peutz-Jeghers syndrome [100]. (See "Sex cord-stromal tumors of the

ovary: Sertoli-stromal cell tumors", section on 'Clinical features' and "Testicular sex cord stromal tumors", section on 'Sertoli cell

tumors'.)

●

Medical history – The history focuses on when the initial pubertal changes were first noted, as well as the timing of pubertal

onset in the parents and siblings. In addition, other questions are directed toward evidence of linear growth acceleration,

headaches, changes in behavior or vision, seizures, or abdominal pain (indicative of either a central nervous system [CNS] or

ovarian process) and previous history of CNS disease or trauma. The possibility of exposure to exogenous sex steroids

(medicinal or cosmetic sources) or compounds with sex-steroid-like properties should always be explored [58].

●

Physical examination – This includes height, weight, and height velocity (cm/year). Children with benign forms of precocious

puberty do not usually display the early growth acceleration pattern that is seen among those with progressive forms of

precocious puberty [101]. The physical examination should include assessment of visual fields (a defect suggests the possibility

of a CNS mass) and examination for café-au-lait spots (which would suggest neurofibromatosis or McCune-Albright syndrome)

(picture 2). (See 'McCune-Albright syndrome' above.)

●

Pubertal staging – Secondary sexual development should be assessed to determine the sexual maturity rating (Tanner stage)

of pubertal development. This means staging breast development in girls (picture 1A), genital development in boys, and pubic

hair development in both sexes (picture 1B-C). In girls, the diameter of glandular breast tissue (by direct palpation including

compression to differentiate from adipose tissue when warranted) and the nipple-areolar complex should be assessed. In boys,

measurements are made of the testicular volume (figure 4) [102]. Penile size (stretched length of the non-erect penis, measuring

from the pubic bone to tip of glans, excluding the foreskin) is rarely used for monitoring of pubertal progress because penile

growth is not an early event in puberty, accurate measurement is difficult and may be awkward for the adolescent boy, and the

"pubertal threshold" for penile-stretched length is not as clear as it is for testicular volume. Accurate measurements of testicular

volume are critical to determine whether further radiologic or laboratory testing is necessary. (See "Normal puberty", section on

'Sexual maturity rating (Tanner stages)' and "Normal puberty", section on 'Sequence of pubertal maturation'.)

●

Bone age – In patients with early development of secondary sexual characteristics confirmed by physical examination,

evaluation of skeletal maturation by radiographic assessment of bone age can help with both the differential diagnosis and

assessment of whether there may be an impact on final height. However, in patients presenting with typical features indicative of

either isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for

pubertal progression is likely sufficient.

●

A significant advance in the bone age (greater than approximately 2 standard deviations [SD] beyond chronological age) is more

likely to be indicative of either CPP or peripheral precocity, rather than a benign pubertal variant. A significantly advanced bone

age does not, however, exclude a diagnosis of a benign pubertal variant. As an example, up to 30 percent of children with benign

premature adrenarche have bone ages more than two years in advance of their chronological age [103]. (See 'Types of benign

or non-progressive pubertal variants' above.)



79



The first step is to measure basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and either estradiol and/or

testosterone concentrations. The results are used to differentiate between CPP and peripheral precocity, which then guides

additional testing (algorithm 1 and table 4).

Basal serum LH — A good initial screening test to identify activation of the hypothalamic-pituitary-gonadal axis is measurement of

basal LH concentration (ideally in the morning), using sensitive immunochemiluminescence assays with a lower limit of detection of

≤0.1 mIU/mL (where mIU = milli-International Units) [104]. Results are interpreted as follows:

Care should be used in the interpretation of LH levels in girls under the age of two years, as gonadotropin concentrations may be

elevated at this age in association with the "mini-puberty of infancy" and CPP can be misdiagnosed during this phase of development

[10,107].

An emerging approach is to identify cases of progressive CPP using first-morning urinary gonadotropin levels. These early results

need further validation, but this could be an important alternative diagnostic strategy in the future [108,109].

Basal serum FSH — Basal FSH concentrations have limited diagnostic utility in distinguishing children with CPP from those with

benign pubertal variants. FSH concentrations are often higher in children with CPP compared with benign pubertal variants, but there

is substantial overlap between these groups of children [104,105]. Like LH, FSH concentrations are typically suppressed in children

with peripheral precocity.

Serum estradiol — Very high concentrations of estradiol, with associated suppression of gonadotropins, are generally indicative

of peripheral precocity, such as from an ovarian tumor or cyst. Most estradiol immunoassays, however, have poor ability to

discriminate at the lower limits of the assay between prepubertal and early pubertal concentrations [110]. More sensitive methods of

estimating estradiol concentrations, such as tandem mass spectrometry, distinguish better between pre-pubertal and pubertal

estradiol concentrations [111], and should be ordered exclusively. However, further studies are still needed to clarify threshold

concentrations.

Serum testosterone — Elevated testosterone concentrations are indicative of testicular testosterone production in boys, or of

adrenal testosterone production or exogenous exposure in both sexes. Very high concentrations, with associated suppression of

gonadotropins, are generally indicative of peripheral precocity. Measurement of other adrenal steroids (eg, dehydroepiandrosterone

sulfate [DHEAS]) may be necessary to help discriminate between adrenal and testicular sources of the androgens. In children with

CPP, testosterone immunoassays cannot always distinguish between prepubertal and early pubertal testosterone concentrations, but

tandem mass spectroscopy methods are more discriminative [112] (similar to the estradiol assays discussed above), so these should

be ordered whenever available.

Subsequent laboratory testing — Subsequent laboratory testing depends on the results of the tests outlined above (basal LH,

FSH, and estrogen or testosterone), and on the patient's clinical characteristics:

Serum LH concentrations after GnRH agonist stimulation — In children in whom the clinical picture is discordant with the

initial baseline investigations (ie, ongoing pubertal progression with basal LH level <0.3 mIU/mL), a gonadotropin-releasing hormone

(GnRH) stimulation test may help differentiate those with CPP from those with a benign pubertal variant. This test consists of

measurement of serum LH concentrations before and after administration of GnRH. GnRH is not available in the United States; a

GnRH agonist may be used instead because of the initial stimulatory effect on the hypothalamic-pituitary-gonadal (HPG) axis following

a single dose of a GnRH agonist.

A common protocol is as follows:

The results are interpreted as follows:

LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal

variant such as premature thelarche.

●

LH concentrations greater than 0.2 to 0.3 mIU/mL (the threshold depends on the assay used) can identify children with

progressive CPP with high sensitivity and specificity [105,106].

●

LH concentrations are less informative in the evaluation of children with non-progressive or intermittently progressive precocious

puberty. While such children typically have basal LH concentrations <0.2 to 0.3 mIU/mL, levels can be in the early pubertal range

in some children. Additional clinical characteristics such as lack of progression in secondary sexual characteristics or low LH/FSH

ratio post-gonadotropin stimulation test can help to differentiate these children from those with progressive CPP. (See 'Serum LH

concentrations after GnRH agonist stimulation' below.)

●

Blood is sampled at baseline for LH, FSH, and either estradiol in girls or testosterone in boys.●

The child is then given a single dose of GnRH at a dose of 100 mcg or the GnRH agonist leuprolide acetate at a dose of 20

mcg/kg.

●

LH is measured at 30 to 40 minutes post-GnRH or 60 minutes post-GnRH agonist [113-115]. Other protocols employ sampling

every 30 minutes for up to two hours [113,116] or testing of estradiol or testosterone 24 hours later [117,118].

●



80



As with basal LH levels, care must be taken in interpreting the results of GnRH stimulation test in girls under the age of two years, as

both basal and stimulated LH levels can be elevated as part of the normal hormonal changes associated with the mini-puberty of

infancy [107].

Serum adrenal steroids — In children with precocious pubarche, measurement of adrenal steroids may be necessary to help

distinguish between peripheral precocity and benign premature adrenarche. Children with premature adrenarche can have mild

elevation in adrenal hormones, with DHEAS concentrations of 40 to 135 mcg/dL (1.1 to 3.7 micromol/L), and testosterone levels ≤35

ng/dL (1.2 nmol/L) [121]. (See "Premature adrenarche", section on 'Hormonal measurements at baseline'.)

Concentrations above these thresholds warrant further investigation for causes of peripheral precocity, such as non-classical

congenital adrenal hyperplasia and virilizing adrenal tumors. In children with suspected non-classical congenital adrenal hyperplasia

(CAH) secondary to 21- hydroxylase deficiency who have an early morning 17-hydroxyprogesterone (17-OHP) concentration between

82 ng/dL (2.5 nmol/L) and 200 ng/dL (6 nmol/L), follow-up adrenocorticotropic hormone (ACTH) stimulation testing should be

performed. A 17-OHP value >200 ng/dL has a high sensitivity and specificity for non-classical CAH [122,123], although an ACTH

stimulation test may still be needed to confirm the diagnosis. (See "Diagnosis and treatment of nonclassic (late-onset) congenital

adrenal hyperplasia due to 21-hydroxylase deficiency".)

Other biochemical tests — In boys, human chorionic gonadotropin (hCG) should be measured to evaluate for the possibility of

an hCG-secreting tumor. If a tumor is found in the anterior mediastinum, a karyotype should be performed to evaluate for Klinefelter

syndrome because of its association with mediastinal germinoma [50]. A thyroid-stimulating hormone (TSH) concentration should be

measured if chronic primary hypothyroidism is suspected as the underlying cause for the sexual precocity.

Imaging

Peak stimulated LH – The optimal cutoff value of peak stimulated LH for identifying children with CPP has not been established,

and varies somewhat among assays. For most LH assays, a value of 3.3 to 5 mIU/mL defines the upper limit of normal for

stimulated LH values in prepubertal children [113,119]. Stimulated LH concentrations above this normal range suggest CPP.

●

Peak stimulated LH/FSH ratio – Children with progressive CPP tend to have a more prominent LH increase post-stimulation, and

higher peak LH/FSH ratios, compared with those with non- or intermittently progressive precocious puberty [117,120]. While a

definite diagnostic threshold has not been well defined, a peak LH/FSH ratio >0.66 is typically seen with CPP, whereas a ratio

<0.66 suggests non-progressive precocious puberty [120].

●

Stimulated estradiol / testosterone – Children with progressive CPP tend to have higher stimulated serum estradiol and

testosterone concentrations when measured 24 hours after administration of GnRH or GnRH agonist [117,118]. However, the

disadvantage of requiring venipunctures on two consecutive days as well as the lack of consistent published diagnostic

thresholds limits the clinical utility of these measurements.

●

Central precocious puberty ●

Brain magnetic resonance imaging (MRI) – We recommend performing a contrast-enhanced brain MRI for all boys with

CPP, and for girls with onset of secondary sexual characteristics before six years of age, because of higher rates of CNS

abnormalities in these groups of patients (see 'CNS lesions' above). In our practice, we usually do not perform MRI for girls

with CPP onset between seven and eight years of age if there is no clinical evidence of CNS pathology and if there is a

family history of earlier pubertal onset, or if the child has an increased body mass index (BMI).

•

In girls with CPP onset after their sixth birthday, there is ongoing debate about the utility of brain imaging in this age group

because of conflicting data about the risk for CNS pathology: In a meta-analysis, the prevalence of intracranial lesions was 3

percent among girls presenting with CPP after six years of age, compared with 25 percent among those presenting before

six years [124]. These findings are in contrast to a study of girls with precocious puberty that was not included in this part of

the meta-analysis, in which 13 of 208 girls (6.3 percent) had related MRI brain abnormalities, all of whom had onset of CPP

after the age of six years [22]. A younger age of onset of pubertal signs and higher basal LH and estradiol concentrations

have been proposed as predictive features for intracranial pathology [22,23,125]. Because these features and clinical

suspicion have been shown to have variable sensitivity to detect girls with abnormal brain MRIs, some have recommended

imaging for all girls with CPP [22,24].

Pelvic ultrasound – Pelvic ultrasonography may be a useful adjunct investigation to help differentiate between CPP and

benign pubertal variants, especially when the evaluation remains equivocal. Girls with CPP have greater uterine and ovarian

volumes compared with girls who are prepubertal or those with premature thelarche [126-129]. Diagnostic thresholds for

uterine and ovarian volumes have been proposed; however, these are variable and some studies have suggested that there

is considerable overlap between patients with and without CPP [126,127].

•

Peripheral precocity ●

In girls with progressive peripheral precocity, a pelvic ultrasound can be performed to help identify the presence of an

ovarian cyst or tumor. For suspected adrenal pathology, for example when there is rapid virilization, an adrenal ultrasound

should be strongly considered.

•



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SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around

the world are provided separately. (See "Society guideline links: Normal puberty and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."

The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or

five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and

who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more

detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and

are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your

patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of

interest.)

SUMMARY

Ultrasound examination of the testes can be performed in boys with peripheral precocity to evaluate for the possibility of a

Leydig-cell tumor.

•

In children where an adrenal tumor is suspected (due to evidence of progressive virilization and elevated serum adrenal

androgens, eg, DHEAS), an abdominal ultrasound and/or computerized tomography (CT) abdomen should be performed.

•

th th

th th

Basics topic (see "Patient education: Early puberty (The Basics)")●

Precocious puberty is defined as the onset of pubertal development more than 2 to 2.5 standard deviations (SD) earlier than the

average age (figure 1A-B). (See 'Definition' above.)

●

Because of the trend of earlier pubertal development, there is controversy about the lower age limit for normal pubertal

development. Nonetheless, we recommend evaluation in children presenting with secondary sexual development younger than

eight years in girls or nine years in boys (figure 2). (See 'Definition' above and 'Evaluation' above.)

●

The etiology of precocious puberty is classified by the underlying pathogenesis into three categories (see 'Classification' above):●

Central precocious puberty (CPP) is caused by an early activation of the hypothalamic-pituitary-gonadal axis. CPP is

pathologic in up to 40 to 75 percent of boys and 10 to 20 percent of girls (table 1). (See 'Causes of central precocious

puberty (CPP)' above.)

•

Peripheral precocity is caused by secretion of sex hormones either from the gonads or adrenal glands, ectopic human

chorionic gonadotropin (hCG) production by a germ cell tumor, or by exogenous sources of sex steroids, and is independent

from the hypothalamic-pituitary-gonadal axis (table 2). (See 'Causes of peripheral precocity' above.)

•

Benign pubertal variants include isolated breast development (premature thelarche), isolated pubic hair development

(premature pubarche/adrenarche), benign pre-pubertal vaginal bleeding, and non-progressive precocious puberty (table 3).

These patterns are usually a variant of normal puberty and require no intervention. If the finding is isolated breast

development or isolated pubarche, and there is no evidence of pubertal progression or accelerated growth, laboratory

evaluation may not be necessary. However, close follow-up is recommended because some of these patients will turn out to

have progressive precocity. (See 'Types of benign or non-progressive pubertal variants' above.)

•

The first step in the laboratory evaluation of progressive development of precocious secondary sexual characteristics is to

measure basal luteinizing hormone (LH), follicle stimulating hormone (FSH), and either estradiol or testosterone concentrations.

The results are used to differentiate between CPP and peripheral precocity, which then guides additional testing (algorithm 1 and

table 4). A good initial screening test to distinguish CPP from benign pubertal variants is measurement of a basal LH

concentration (see 'Basal serum LH' above):

●

In CPP, basal LH levels are often elevated into the pubertal range (greater than 0.2 to 0.3 mIU/mL, depending on the

assay).

•

LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign

pubertal variant such as premature thelarche.

•

If the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression with basal LH level <0.3

mIU/mL), a gonadotropin-releasing hormone (GnRH) stimulation test can be performed to help distinguish CPP from a benign

pubertal variant. Children with CPP have a pubertal (heightened) LH response to GnRH stimulation (table 4). (See 'Serum LH

concentrations after GnRH agonist stimulation' above.)

●

Recommendations for imaging depends on the type of precocious puberty (see 'Imaging' above):●

All boys with CPP should have brain imaging because of the high prevalence of central nervous system (CNS) lesions in this•



82



ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Paul Saenger, MD, MACE, who contributed to an

earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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the calculation of standard deviation scores. Acta Paediatr 2015; 104:e271.

103. DeSalvo DJ, Mehra R, Vaidyanathan P, Kaplowitz PB. In children with premature adrenarche, bone age advancement by 2 or

more years is common and generally benign. J Pediatr Endocrinol Metab 2013; 26:215.

104. Neely EK, Hintz RL, Wilson DM, et al. Normal ranges for immunochemiluminometric gonadotropin assays. J Pediatr 1995;

127:40.

105. Harrington J, Palmert MR, Hamilton J. Use of local data to enhance uptake of published recommendations: an example from the

diagnostic evaluation of precocious puberty. Arch Dis Child 2014; 99:15.

106. Houk CP, Kunselman AR, Lee PA. Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious



86



puberty in girls. Pediatrics 2009; 123:e1059.

107. Bizzarri C, Spadoni GL, Bottaro G, et al. The response to gonadotropin releasing hormone (GnRH) stimulation test does not

predict the progression to true precocious puberty in girls with onset of premature thelarche in the first three years of life. J Clin


108. Zung A, Burundukov E, Ulman M, et al. The diagnostic value of first-voided urinary LH compared with GNRH-stimulated

gonadotropins in differentiating slowly progressive from rapidly progressive precocious puberty in girls. Eur J Endocrinol 2014;

170:749.

109. Lucaccioni L, McNeilly J, Mason A, et al. The measurement of urinary gonadotropins for assessment and management of

pubertal disorder. Hormones (Athens) 2016; 15:377.

110. Bay K, Andersson AM, Skakkebaek NE. Estradiol levels in prepubertal boys and girls--analytical challenges. Int J Androl 2004;

27:266.

111. Rosenfield RL, Bordini B, Yu C. Comparison of detection of normal puberty in girls by a hormonal sleep test and a

gonadotropin-releasing hormone agonist test. J Clin Endocrinol Metab 2013; 98:1591.

112. Lee PA, Gollenberg AL, Hediger ML, et al. Luteinizing hormone, testosterone and inhibin B levels in the peripubertal period and

racial/ethnic differences among boys aged 6-11 years: analyses from NHANES III, 1988-1994. Clin Endocrinol (Oxf) 2010;

73:744.

113. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children.

Pediatrics 2009; 123:e752.

114. Houk CP, Kunselman AR, Lee PA. The diagnostic value of a brief GnRH analogue stimulation test in girls with central precocious

puberty: a single 30-minute post-stimulation LH sample is adequate. J Pediatr Endocrinol Metab 2008; 21:1113.

115. Kandemir N, Demirbilek H, Özön ZA, et al. GnRH stimulation test in precocious puberty: single sample is adequate for diagnosis

and dose adjustment. J Clin Res Pediatr Endocrinol 2011; 3:12.

116. Chi CH, Durham E, Neely EK. Pharmacodynamics of aqueous leuprolide acetate stimulation testing in girls: correlation between

clinical diagnosis and time of peak luteinizing hormone level. J Pediatr 2012; 161:757.

117. Carretto F, Salinas-Vert I, Granada-Yvern ML, et al. The usefulness of the leuprolide stimulation test as a diagnostic method of

idiopathic central precocious puberty in girls. Horm Metab Res 2014; 46:959.

118. Sathasivam A, Garibaldi L, Shapiro S, et al. Leuprolide stimulation testing for the evaluation of early female sexual maturation.

Clin Endocrinol (Oxf) 2010; 73:375.

119. Resende EA, Lara BH, Reis JD, et al. Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by

immunochemiluminometric and immunofluorometric assays in normal children. J Clin Endocrinol Metab 2007; 92:1424.

120. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin


121. Rosenfield RL. Clinical review: Identifying children at risk for polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92:787.

122. Livadas S, Dracopoulou M, Dastamani A, et al. The spectrum of clinical, hormonal and molecular findings in 280 individuals with

nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clin Endocrinol (Oxf) 2015; 82:543.

123. Armengaud JB, Charkaluk ML, Trivin C, et al. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia

from premature adrenarche. J Clin Endocrinol Metab 2009; 94:2835.

124. Cantas-Orsdemir S, Garb JL, Allen HF. Prevalence of cranial MRI findings in girls with central precocious puberty: a systematic

review and meta-analysis. J Pediatr Endocrinol Metab 2018; 31:701.

125. Chalumeau M, Chemaitilly W, Trivin C, et al. Central precocious puberty in girls: an evidence-based diagnosis tree to predict

central nervous system abnormalities. Pediatrics 2002; 109:61.

126. Eksioglu AS, Yilmaz S, Cetinkaya S, et al. Value of pelvic sonography in the diagnosis of various forms of precocious puberty in

girls. J Clin Ultrasound 2013; 41:84.

127. Sathasivam A, Rosenberg HK, Shapiro S, et al. Pelvic ultrasonography in the evaluation of central precocious puberty:

comparison with leuprolide stimulation test. J Pediatr 2011; 159:490.

128. de Vries L, Horev G, Schwartz M, Phillip M. Ultrasonographic and clinical parameters for early differentiation between precocious

puberty and premature thelarche. Eur J Endocrinol 2006; 154:891.

129. Badouraki M, Christoforidis A, Economou I, et al. Evaluation of pelvic ultrasonography in the diagnosis and differentiation of

various forms of sexual precocity in girls. Ultrasound Obstet Gynecol 2008; 32:819.

Topic 5812 Version 31.0



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GRAPHICS

Sequence of puberty in girls

Sequence of events in girls w ith average timing of pubertal development in the United States. The

median age for achieving each milestone is younger for African American girls (dashed vertical line)

compared with Caucasian girls (dotted vertical line). The median length of time between the onset

of puberty (breast Tanner stage 2) and menarche is 2.6 years, and the 95 percentile is 4.5 years.

SMR: sexual maturity rating (also known as Tanner stage).

Data from: Biro FM, Huang B, Lucky AW, et al. Pubertal correlates in black and white US girls. J Pediatr 2006;

148:234, and from: Tanner JM, Davies PS. J Pediatr 1985; 107:317.

Graphic 52047 Version 9.0

th



88



Sequence of puberty in boys

Sequence of pubertal events in boys w ith average timing of pubertal

development in the United States.

Data from:

1. Biro FM et al, Pubertal staging in boys. J Pediatr 1995; 127:100.

2. Karpati AM et al, Stature and pubertal stage assessment in American boys:

the 1988-1994 Third National Health and Nutrition Examination Survey. J

Adolesc Health 2002; 30:205-12.

3. Dore E et al. Gender differences in peak muscle performance during

growth. Int J Sports Med 2005; 26:274.

4. Neu CM et al. Influence of puberty on muscle development at the forearm.

Amer J Physiol Endocrin Metab 2002; 283:E103.

5. Tanner et al. Clinical longitudinal standards for height and height velocity

for North American children. J Pediatr 1985; 107:317.




89



Sexual maturity rating (Tanner staging) of breast

development in girls

Stages in breast development in girls.

Stage 1: Prepubertal, w ith no palpable breast tissue.

Stage 2: Development of a breast bud, w ith elevation of the papilla and

enlargement of the areolar diameter.

Stage 3: Enlargement of the breast, w ithout separation of areolar contour

from the breast.

Stage 4: The areola and papilla project above the breast, forming a

secondary mound.

Stage 5: Recession of the areo la to match the contour of the breast; the

papilla projects beyond the contour of the areola and breast.

Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands

third nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with

permission from the author.




90



Sexual maturity rating (Tanner staging) of pubic hair and

external genitalia development in boys

Stages of pubic hair development in boys:

Stage 1: Prepubertal, w ith no pubic hair.

Stage 2: Sparse, straight pubic hair along the base of the penis.

Stage 3: Hair is darker, coarser, and curlier, extending over the mid-

pubis.

Stage 4: Hair is adult-like in appearance, but does not extend to thighs.

Stage 5: Hair is adult in appearance, extending from thigh to thigh.

Stages of external genitalia development in boys:

Stage 1: Prepubertal.

Stage 2: Enlargement of testes and scrotum; scrotal skin reddens and

changes in texture.

Stage 3: Enlargement of penis (length at first); further growth of testes.

Stage 4: Increased size of penis w ith growth in breadth and

development of glans; testes and scrotum larger, scrotal skin darker.

Stage 5: Adult genitalia.

Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands third

nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with





91



Sexual maturity rating (Tanner staging) of pubic hair

development in girls

Stages of development in pubic hair in girls.

Stage 1: Prepubertal w ith no pubic hair.

Stage 2: Sparse, straight hair along the lateral vulva.

Stage 3: Hair is darker, coarser, and curlier, extending over the mid-pubis.

Stage 4: Hair is adult-like in appearance, but does not extend to the

thighs.

Stage 5: Hair is adult in appearance, extending from thigh to thigh.

Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands

third nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with





92



Timing of puberty in Caucasian and African American girls

in the United States

In this study, the first signs of puberty occurred at a younger age than

had been previously reported; the mean age of onset was earlier for

African American versus Caucasian girls.

Data from Herman-Giddens, ME, Slora, EJ, Wasserman, RC, et al, Pediatrics 1997;

99:505.




93



Etiology and mechanisms of precocious puberty

GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone.

From: Harrington J, Palmert MR, Hamilton J. Use of local data to enhance uptake of published recommendations: an example from the diagnostic

evaluation of precocious puberty. Arch Dis Child 2014; 99:15. Reproduced with permission from BMJ Publishing Group Ltd. Copyright © 2014.




94



Central (gonadotropin-dependent) precocious puberty

Etiology Clinical features Bone age Additional evaluation

Idiopathic

(80 to 90% of girls with CPP,

and 25 to 60% of boys with

CPP)

Early progressive pubertal

development, but proceeds in normal

sequence.

↑↑ Increased ovarian and uterine

volumes on ultrasound may help

differentiate girls with CPP from those

with premature thelarche.

Contrast enhanced MRI to rule out

CNS abnormality.Secondary to CNS lesions

(eg, hypothalamic hamartomas,

other CNS tumors and lesions,

cranial radiation)

Early progressive pubertal

development, but proceeds in normal

sequence.

Central precocious puberty secondary

to a CNS lesion occurs more

commonly in boys and younger

children.

↑↑

Post early exposure to sex

steroids

(after treatment for peripheral

precocity)

History of treatment of peripheral

precocity.

Progressive pubertal development with

breast development in girls and

testicular enlargement in boys.

↑↑ Basal and stimulated LH concentrations

are pubertal.

Central precocious puberty is characterized by basal LH concentrations >0.2 to 0.3 mIU/L, and/or stimulated LH concentration

post GnRH or GnRHa of >3.3 to 5.0 mIU/L.

↑↑: significantly advanced for chronological age (eg, ≥ 2 standard deviations); CPP: central precocious puberty; CNS: central nervous

system; LH: luteinizing hormone; MRI: magnetic resonance imaging; GnRH: gonadotropin-releasing hormone; GnRHa: gonadotropin-

releasing hormone agonist.

Courtesy of Drs. Jennifer Harrington and Mark Palmert.




95



Peripheral precocity (gonadotropin-independent precocious puberty)

Etiology Clinical featuresBone

ageAdditional evaluation

Girls only

Ovarian cysts Breast development and/or vaginal bleeding.

Occasionally presents with ovarian torsion

and abdominal pain.

↑ to ↑↑ Pelvic ultrasound may visualize the cyst,

although in some cases the cyst may have

involuted by the time of the study. Vaginal

bleeding is indicative of estrogen withdrawal.

Recurrent ovarian cysts suggest McCune

Albright Syndrome.

Ovarian tumor Development of either isosexual or

contrasexual sexual precocity, depending of

tumor type.

↑↑ Pelvic ultrasound

Boys only

Leydig cell tumor Asymmetrical enlargement of the testes. ↑↑ Pubertal testosterone concentrations.

Testicular ultrasound aids in diagnosis.

hCG-secreting germ

cell tumors

Symmetric testicular enlargement to an early

pubertal size, but testes remain smaller than

expected for degree of pubertal development.

Peripheral precocity is seen only in boys,

because hCG only activates LH receptors

(estrogen biosynthesis in the ovaries requires

both FSH and LH receptor activation).

↑↑ These tumors may occur in gonads, brain,

liver, retroperitoneum, or mediastinum.

When a tumor is identified in the anterior

mediastinum, a karyotype must be performed

because of an association of this finding with

Klinefelter syndrome.

Familial male-limited

precocious puberty



expected for degree of pubertal

development; spermatogenesis may occur.

Familial: Male-limited autosomal dominant

trait.


because there is only activation of the LH

receptors (ovarian estrogen biosynthesis

requires both FSH and LH receptor

activation).

↑↑ Genetic testing for mutations of the LH

receptor gene (LHCGR).

Girls and boys

Exogenous sex

steroids (estradiol and

testosterone creams)

Estrogen preparations cause feminization,

while topical androgens cause virilization in

both sexes.

↑ to ↑↑ Clinical history explores use of exogenous

sex steroids and folk remedies by caretakers.

McCune-Albright

syndrome

(girls>boys)

In girls, may present with recurrent episodes

of breast development, regression and

vaginal bleeding. In boys, sexual precocity

less common.

Skin: Multiple irregular-edged café-au-lait

spots.

Bone: Polyostotic fibrous dysplasia.

↑ to ↑↑ Ultrasound: Ovaries enlarged, with follicular

cysts. In boys, testicular ultrasound can

demonstrate hyper-and hypoechoic lesions

(most likely representing areas of leydig cell

hyperplasia), microlithiasis and focal

calcifications.

May have other hyperactive endocrine

disorders: ie, thyrotoxicosis, glucocorticoid

excess and/or gigantism.

Primary

hypothyroidism

Girls: vaginal bleeding, breast development

and galactorrhea.

Boys: testicular enlargement.

Other clinical features of hypothyroidism such

as short stature.

↓ Elevated TSH

Congenital adrenal

hyperplasia

(untreated)

Boys have prepubertal testes with enlarged

phallus and pubic hair development. Girls with

"nonclassic" CAH may present with early

pubic and/or axillary hair, and other signs of

androgen excess.

↑↑ Sex hormone levels vary depending on the

adrenal enzyme block. An early morning 17-

OHP >200 ng/dL (6 nmol/L) has a high

sensitivity and specificity for congenital

adrenal hyperplasia secondary to 21

hydroxylase deficiency. ACTH stimulation test

is recommended to confirm the diagnosis of

CAH if the 17-OHP level is intermediate (eg,

between 200 and 1500 ng/dL). After therapy

with glucocorticoids, CPP may develop.

Virilizing adrenal

tumor

Boys: pubic and/or axillary hair and penile

growth with pre-pubertal testes.

Girls: pubic and/or axillary hair, other

significant signs of androgen excess (acne

and clitoromegaly).

↑↑ High DHEA or DHEAS, androstenedione and

testosterone.

CT and/or ultrasound of adrenal glands to

locate tumor.



96



May present with signs of glucocorticoid

excess.

May be associated with hereditary cancer

syndromes.

Peripheral precocity is characterized by low or suppressed gonadotropin concentrations w ith elevated sex hormone levels.

Pubertal status should be monitored for six months after treatment, because treatment of peripheral precocity can trigger

central precocious puberty (CPP).

↑: advanced for chronological age; ↓: delayed for chronological age; hCG: human chorionic gonadotropin; LH: luteinizing hormone; FSH:

follicle-stimulating hormone; LHCGR: luteinizing hormone/choriogonadotropin receptor; CPP: central precocious puberty; TSH: thyroid-

stimulating hormone; CAH: congenital adrenal hyperplasia; 17-OHP: 17-hydroxyprogesterone; ACTH: adrenocorticotropic hormone; DHEA:

dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; CT: computed tomography.





97



Types of benign pubertal variants

Etiology Clinical Features Bone Age Additional Evaluation

Premature

adrenarche

(boys or girls)

Isolated pubarche. Gonads are prepubertal

in size and there is no breast development in

girls. Typical age of onset four to eight

years.

Seen more commonly in African-American

and Hispanic girls and in children with obesity

and insulin resistance.

↑ to ↑↑* Further investigations needed only if there is

significant progressive virilization, to help

exclude peripheral precocity.

Mild elevation in DHEAS for chronological age

(but appropriate for bone age).

Prepubertal concentrations of 17-

hydroxyprogesterone and testosterone.

Premature thelarche

(girls)

Isolated breast development with normal

growth velocity.

Most commonly seen in girls less than three

years of age.

Normal

(prepubertal)

No further evaluation needed in most cases,

unless evidence of pubertal progression.

Basal LH concentrations typically <0.2 to 0.3

mIU/L.

Non-progressive or

intermittently

progressive

precocious puberty

(boys or girls)

Development of gonadarche (breast or

testicular enlargement) with pubarche (pubic

and/or axillary hair), with either no

progression or intermittent slow progression

in clinical pubertal signs.

Normal to ↑ Basal LH concentrations typically <0.2 to 0.3

mIU/L, although can be in early pubertal

range in some children.

Lower stimulated LH/FSH ratio compared with

children with progressive central precocious

puberty.

Patients with non-progressive precocious

puberty do not need treatment with GnRH

agonist, because final height untreated is

concordant with mid-parental height.

If further evaluation is needed and performed, patients w ith benign pubertal variants typically have pre-pubertal basal LH

concentrations (<0.2 to 0.3 mIU/L) and/or stimulated LH concentration post GnRHa of <3.3 to 5.0 mIU/L.

↑: elevated for chronological age; DHEAS: dehydroepiandrosterone sulfate; LH: luteinizing hormone; FSH: follicle-stimulating hormone;

GnRH: gonadotropin-releasing hormone.

* Up to 30% of children with premature adrenarche can have a bone age more than two years advanced than their chronological age.

¶ Interpretation of basal LH and stimulated LH concentrations can be difficult in girls younger than two years of age because normal

gonadotropin concentrations can be elevated as part of the mini-puberty of infancy.[2]

Δ A peak LH/FSH ratio <0.66 suggests non-progressive precocious puberty, whereas a ratio >0.66 is typically seen with central precocious

puberty.

1. DeSalvo, DJ, Mehra R, Vaidyanathan P, Kaplowitz PB. In children with premature adrenarche, bone age advancement by 2 or more

years is common and generally benign. J Pediatr Endocrinolo Metab 2013; 26: 215.

2. Bizzarri C, Spadoni G, Bottaro G et al. The response to gonadotropin releasing hormone (GnRH) stimulation test does not predict the

progression to true precocious puberty in girls with onset of premature thelarche in the first three years of life. JCEM 2014; 99:433.

3. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol

Metab 1990; 71:1251.


¶

Δ

[1]

[3]



98



Café-au-lait spots in McCune-Albright syndrome

(A) A typical lesion on the face, chest, and arm of a five-year-old girl w ith

McCune-Albright syndrome, which demonstrates jagged "coast of Maine"

borders and the tendency for the lesions to both respect the midline and

follow the developmental lines of Blaschko (a configuration of skin lesions

characterized by arcs on the upper chest, S shapes on the abdomen, and

V shapes over the posterior midline, caused by patterns of X-chromosome

inactivation).

(B) Typical lesions that are often found on the nape of the neck and

crease of the buttocks are shown (arrows).

Reproduced from: Dumitrescu CE, Collins MT. McCune-Albright syndrome.

Orphanet J Rare Dis 2008; 3:12. Copyright ©2008 BioMed Central Ltd.




99



Radiographic appearance of fibrous dysplasia in McCune-Albright

syndrome

A) A proximal femur w ith typical ground glass appearance and shepherd's crook

deformity characteristic of fibrous dysplasia (FD) in a 10-year-old child. B) The

appearance of FD in the femur of an untreated 40-year-old man demonstrates the

tendency for FD to appear more sclerotic w ith time. C) The typical ground glass

appearance of FD in the craniofacial region on a CT image of a 10-year-old child is

shown. The white arrows indicate the optic nerves, which are typically encased

with FD. D) A CT image in a 40-year-old woman demonstrates the typical

appearance of craniofacial FD in an older person, w ith mixed solid and "cystic"

lesions. The Hounsfield Unit measurements of "cystic" lesions are quite useful in

distinguishing soft tissue "cystic" lesions from true fluid-filled cysts, which are much

more uncommon and tend to behave aggressively w ith rapid expansion and

compression of vital structures. E-G) Bone Scintigraphy in FD. Representative 99Tc-

MDP bone scans which show tracer uptake at affected skeletal sites, and the

associated skeletal disease burden score are shown. E) A 50-year-old woman with

monostotic FD confined to a single focus involving contiguous bones in the

craniofacial region. F) A 42-year-old man with polyostotic FD shows the tendency

for FD to be predominantly (but not exclusively) unilateral, and to involve the skull

base and proximal femur. G) A 16-year-old boy with McCune-Albright syndrome

and involvement of virtually all skeletal sites (panostotic) is shown.

Reproduced from: Dumitrescu, CE, Collins, MT. McCune-Albright syndrome. Orphanet J

Rare Dis 2008; 3:12. Copyright ©2008 BioMed Central Ltd.




100



Clinical characteristics of forms of early pubertal development

Nonprogressive

precocious puberty

Central precocious

puberty (CPP)Peripheral precocity

Physical examination:

Advancement through

pubertal stages (Tanner

stage)

No progression in Tanner

staging during 3 to 6 months of

observation

Progression to next pubertal

stage in 3 to 6 months

Progression

Growth velocity Normal for bone age Accelerated (>6 cm per year)* Accelerated*

Bone age Normal to mildly advanced Advanced for height age Advanced for height age

Serum estradiol

concentration (girls)

Prepubertal Prepubertal to pubertal Increased in ovarian causes of

peripheral precocity, or with

exogenous estrogen exposure

Serum testosterone

concentration (boys, or

girls with virilization)

Prepubertal Prepubertal to pubertal Pubertal and increasing

Basal (unstimulated) serum

LH concentration

Prepubertal Pubertal Suppressed or prepubertal

GnRH (or GnRHa)

stimulation test

LH peak in the prepubertal

range

Lower stimulated LH to FSH

ratio

LH peak elevated (in the

pubertal range)

Higher stimulated LH to FSH

ratio

No change from baseline, or LH

peak in the prepubertal range

CPP: central precocious puberty (also known as gonadotropin-dependent precocious puberty); LH: luteinizing hormone; GnRH: gonadotropin-

releasing hormone; GnRHa: gonadotropin-releasing hormone agonist; FSH: follicle-stimulating hormone.

* UNLESS the patient has concomitant growth hormone deficiency (as in the case of a neurogenic form of CPP), or has already passed his or

her peak height velocity at the time of evaluation, in which case growth velocity may be normal or decreased for chronological age.

¶ Using most commercially available immunoassays, serum concentrations of gonadal steroids have poor sensitivity to differentiate between

prepubertal and early pubertal concentrations.

Δ In most cases these levels will be prepubertal, however in children with intermittently progressive CPP, these levels may reach pubertal

concentrations during times of active development.

◊ Using ultrasensitive assays with detection limit of LH <0.1 mIU/L, prepubertal basal LH concentrations are <0.2 to 0.3 mIU/L.

§ In most laboratories, the upper limit of normal for LH after GnRH stimulation is 3.3 to 5.0 mIU/mL. Stimulated LH concentrations above this

normal range suggests CPP.

¥ A peak stimulated LH/FSH ratio <0.66 usually suggests non-progressive precocious puberty, whereas a ratio >0.66 is typically seen with

CPP.

Reference:

1. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol

Metab 1990; 71:1251.

Courtesy of Drs. Mark Palmert and Jennifer Harrington.


¶

Δ

¶

Δ

¶

Δ◊ ◊ ◊

¶ Δ§

¥

§

¥

[1]



101



Height velocity in American boys

Height velocity by age for American boys. The main set of curves (black lines) is

centered on the population w ith average timing of peak growth velocity (around 13.5

years for boys) and show an approximate trajectory for individual children with this

average pubertal timing. The two other curves outline a trajectory (50 percentile) for

a child w ith 'early' (solid blue) or 'late' (solid orange) timing of peak growth velocity.

Other height velocity curves (not shown here) have been developed that reflect

population averages; those curves are substantially flatter than the trajectory

followed by any individual patient . Those curves are based on data from a more

recent and ethnically diverse population of children, and are valuable for

understanding overall growth patterns in the population, but are less appropriate for

evalua tion of the growth of an individual patient.

SD: standard deviations.

Reference:

1. Kelly A, Winer KK, Kalkwarf H, et al. Age-based reference ranges for annual height velocity

in US children. J Clin Endocrinol Metab 2014; 99:2104.

Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for height

and height velocity for North American children. J Pediatr 1985; 107:317. Copyright © 1985

Elsevier.


th

[1]



102



Height velocity in American girls

Height velocity by age for American girls. The main set of curves (black lines) is

centered on the population w ith average timing of peak growth velocity (around 11.5

years for girls), and show an approximate trajectory for individual children with this

average pubertal timing. The two other curves outline a trajectory (50 percentile) for

a child w ith 'early' (solid blue) or 'late' (solid orange) timing of peak growth velocity.

Other height velocity curves (not shown here) have been developed that reflect

population averages; those curves are substantially flatter than the trajectory

followed by any individual patient . Those curves are based on data from a more

recent and ethnically diverse population of children, and are valuable for

understanding overall growth patterns in the population, but are less appropriate for

evalua tion of the growth of an individual patient.

SD: standard deviations.

Reference:

1. Kelly A, Winer KK, Kalkwarf H, et al. Age-based reference ranges for annual height velocity

in US children. J Clin Endocrinol Metab 2014; 99:2104.

Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for height

and height velocity for North American children. J Pediatr 1985; 107:317. Copyright © 1985

Elsevier.


th

[1]



103



Reference chart for testicular volume

Reference chart of testicular volume measured with an orchidometer, based upon data from

769 healthy Dutch boys aged 6 months to 19 years.

Reference:

1. Joustra S, van der Plas E, Goede J, et al. New reference charts for testicular volume in Dutch

children and adolescents allow calculation of standard deviation scores. Acta Paediatrica 2015;

104:e271.

Reproduced with permission. Copyright ©2015 TNO.


[1]



104



Contributor Disclosures

Jennifer Harrington, MBBS, PhD Nothing to disclose Mark R Palmert, MD, PhD Nothing to disclose Peter J Snyder,

MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism (Testosterone gel)]; Novo Nordisk [Growth hormone

(Somatropin)]; Novartis [Cushing's (LCI699)]; Cortendo [Cushing's]. Consultant/Advisory Boards: AbbVie [Hypogonadism

(Testosterone gel)]; Novartis [Cushing's (LCI699)]; Pfizer [Acromegaly (Pegvisomant)]; Watson [Testosterone (Testosterone

gel)]. William F Crowley, Jr, MD Consultant/Advisory Boards: Juniper Pharmaceuticals [Endocrinology (Vaginal progesterone)];

Quest Diagnostics [Reproductive endocrinology]. Other Financial Interest: Stock ownership: Juniper Pharmaceuticals [Endocrinology

(Transvaginal ring delivery systems)]. Mitchell E Geffner, MD Consultant/Advisory Boards: Daiichi-Sankyo [Type 2 diabetes

(Colesevelam)]; NovoNordisk [Growth (Somatropin)]; Nutritional Growth Solutions [Growth]; Pfizer [Growth (Somatropin)]. Spruce

Biosciences [congenital adrenal hyperplasia]. Other Financial Interest: McGraw-Hill [Pediatric endocrinology (Textbook

royalties)]. Alison G Hoppin, MD Nothing to disclose Kathryn A Martin, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting

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REVIEW

Abstract

J Clin Res Pediatr Endocrinol 2017;9(Suppl 2):33-48

Introduction

Gonadotropin-releasing hormone analogues (GnRHa) are the treatment of choice for nearly four decades in children with central precocious puberty (CPP) (1). Treatment effectively suppresses hypothalamo-pituitary-gonadal axis, which results in arresting early and accelerated activation of sex hormone synthesis, progression of secondary sexual characteristics and undue maturation of the skeletal development, thus meeting the aims of the treatment, which are 1) to prevent potential psycological problems related to early pubertal development, and 2) to restore genetic growth potential otherwise compromised by sex-hormone-driven premature closure of bone growth plates.

Although the majority of the studies in the field suggests beneficial effects of treatment, there have been ongoing uncertainties about the achievement of both aims of the treatment due to methodological limitations of the present studies. This review wil focus on the effect of GnRHa treatment on height outcome in girls with CPP.

Uncertainties about the benefits of GnRH analog treatment on growth of children with CPP comes from the fact that there is no randomised controlled study on this respect. Some of the studies in this field compare treatment group with a historical control groups which are reported decades ago, include limited number of subjects and heterogeneous with respect to nuances of pubertal development. Some studies have their own untreated control group (but not

Central precocious puberty (CPP) is a diagnosis that pediatric endocrinologists worldwide increasingly make in girls of age 6-8 years and

is mostly idiopathic. Part of the reason for increasing referral and diagnosis is the perception among the doctors as well as the patients

that treatment of CPP with long-acting gonadotropin-releasing hormon analogues (GnRHa) promote height of the child. Although, the

timing and the tempo of puberty does influence statural growth and achieved adult height, the extent of this effect is variable depending

on several factors and is modest in most cases. Studies investigating GnRHa treatment in girls with idiopathic CPP demonstrate that

treatment is able to restore adult height compromised by precocious puberty. However, reports on untreated girls with precocious

puberty demonstrate that some of these girls achieve their target height without treatment as well, thus, blurring the net effect of GnRHa

treatment on height in girls with CPP. Clinical studies on treatment of girls with idiopathic CPP on adult stature suffers from the solid

evidence-base due mainly to the lack of well-designed randomized controlled studies and our insufficiencies of predicting adult height

of a child with narrow precision. This is particularly true for girls in whom age of pubertal onset is close to physiological age of puberty,

which are the majority of cases treated with GnRHa nowadays. Heterogeneous nature of pubertal tempo (progressive vs. nonprogressive)

leading to different height outcomes also complicates the interpretation of the results in both treated and untreated cases. This review

will attemp to summarize and critically appraise available data in the field.

Keywords: Central precocious puberty, gonadotropin-releasing hormon analogues, treatment, final height, adult height, growth, triptoreli,

leuprolide

Conflict of interest: None declaredReceived: 20.12.2017Accepted: 22.12.2017

Address for Correspondence: Abdullah Bereket MD,Marmara University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, İstanbul, TurkeyPhone: +90 532 285 88 30 E-mail: [email protected] ORCID ID: orcid.org/0000-0002-6584-9043©Copyright 2017 by Turkish Pediatric Endocrinology and Diabetes SocietyThe Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.

Marmara University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, İstanbul, Turkey

Abdullah Bereket

A Critical Appraisal of the Effect of Gonadotropin-Releasing Hormon Analog Treatment on Adult Height of Girls with Central Precocious Puberty

DO I: 10.4274/jcrpe.2017.S004



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Bereket A. Gonadotropin-Releasing Hormon Analog Treatment of Girls with Central Precocious Puberty


randomised) which brings biases to the interpretation of the data. Finally, many studies are comparing the achieved adult height with predicted adult height (PAH) at initiation of treatment which suffers from the limitations of our ability to assess bone age (BA) and predict adult height precisely, and disregard the genetic height potential of the child.

The Relationship Between Height and Timing of Puberty

It has been known for a long time that physiological variations in the time of pubertal development has an effect on statural height. Shangold et al (2) evaluated the relationship between recalled menarcheal age and adult height, in 425 women. After exclusion of those in whom menarche occurred after age 16, the overall linear regression equation for the remaining 416 patients, height = 153.95 + 0 .7353 x (age of menarche), was significant. Average height in women who had menarche at age 9 was 159.5±6.5 whereas those with menarche at age 11-13 yrs was 163 cm. Overall the data suggested that menarcheal age significantly correlates with adult height as an independent variable (2).

A large longitudinal study on American girls also evaluated the effect of timing of spontaneous puberty on height was indicated a higher adult height in girls with late (>12.9 years) versus early (<11.7 years) age at menarche. The median difference was of 2.6 and 1.7 cm in white and black girls respectively (3). A recent Korean study of 4218 post-menarcheal girls between the ages of 16 and 18 years reported mean heights of early (9.9±0.2 years), average (12.5±0.9 years) and late (15.1±0.3 years) menarche groups as 160.4±5.2 cm, 161.8±4.9 cm, 162.3±4.7 cm respectively p=0.001) (4).

In contrast to above studies, a recent longitudinal study from Thailand followed 104 girls with breast development at 7.0-9.0 years. Despite the average age at menarche was early (10.2±0.9), their near final height obtained at 12.6±0.4 years was 154.0±4.9 cm, which was similar to their average target height (TH) of 153.1±4.8 cm (5).

It can be concluded from above mentioned studies that “early” puberty within the currently accepted physiological range has “if any” a very small (2-4 cm) effect on adult height reached, an observation consistent with none to very small height gain achieved in GnRH analog treatment of girls with “early” puberty (6,7,8). However, “truely” precocious puberty starting at a very young age is expected to result in more loss in height potential depending on the age at start and the tempo of puberty. Precise estimation of the height loss caused by precocious puberty is difficult to estimate because of the scarcity and imperfections of data in that respect.

Height Outcome in Girls with Precocious Puberty without Treatment

Historical series of untreated patients (Table 1) reported mean heights of 152 cm in girls and 156 cm in boys, a loss of ~10 cm in girls and 20 cm in boys (9,10,11,12,13,14). However, these data should be interpreted very cautiously. First of all, those data come from a limited number of patients from the 1950s and 1960s with cases that are very severe and early onset CPP, with cases due to organic reasons constituting the great part of it. Thus, more severe than the average patient treated today. In fact, in most of these historical series, there was a negative correlation between the age of onset of precocious puberty and adult height, confirming the poor height prognosis of the most severe and early cases. Furthermore, some of the untreated patients with organic CPP may have had growth limitation due to factors associated with their central nervous system disorder, such as growth hormone (GH) deficiency. Secondly, these were not large series, especially for the figure of boys which derived from total of 38 untreated boys in total of four studies (9,10,11,12). Lastly, these studies do not take into account the secular increase in height.

In one of the early studies, Paul et al (11) compared their treated patients with untreated subjects from the literature (9,10,13,14). The final height of treated females was 160.5±6.6 cm whereas matched untreated historical females had a height of 152.7±8.6 cm (difference of treated vs. untreated 7.8 cm). Although treated girls’ mean final height was still -1 standard deviation (SD) below mean midparental TH, this was better compared to untreated ones who had height -2.4 SD below TH. Further classification of

Table 1. Historical data of untreated children with precocious puberty

Reference No. of patients(female/male)

Mean final height ± SD (cm)

Females Males

Thamdrup (9) 26/18 151.3±8.8 155.4±8.3

Sigurjonsdottir and Hayles (10)

40/11 152.7±8.0 156.0±7.3

Paul et al (11) 8/4 153.8±6.8 159.6±8.7

Bovier-Lapierre et al (12)

4/5 150±6.2 156±6.3

Lee (14) 15/0 155.3±9.6 -

Werder et al (13) 4/0 150.9±5.0 -

Total: 107 F/38 M

SD: standard deviation



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the patients according to age revealed that untreated girls who were <5 years of age had a mean final/near final height of 150.2±7.6 cm whereas those treated reached 164.3±7.7 (difference of treated vs. untreated 14.1 cm). Untreated girls who were >5 years of age had a mean final height of 153.4±8.4 cm whereas those treated reached 157.6±6.6 (difference of treated vs. untreated 4.2 cm).

Kletter and Kelch (15) reviewed this matter in 1994. They found more modest height gains in treated girls compared to untreated girls (6.5 cm and 0.5 cm in <6 yrs and >6 yrs respectively). However, when they compared patients with their TH, the effect of GnRHa treatment on height was much less (only 2.7 cm in whom puberty started before 6 years of age and no height gain in those >6 yrs). The authors concluded that treatment with GnRH agonist analog does not significantly alter the final adult height of girls with idiopathic CPP whose age at diagnosis is greater than 6 years.

The obvious difference between the conclusion of these studies might arise from the heterogeneity of the subjects in regard to TH, and the tempo of puberty in the subjects (both treated and untreated). As most untreated patients in

these series were seen before the introduction of computed tomography it is quite possible that some who had a small intracranial lesion, for example a small hypothalamic hamartoma, were included in this untreated “seemingly” idiopathic CPP groups.

Nevertheless, those studies with untreated control groups (Table 2) (11,15), as well as later studies without control groups (Table 3) (16,17), confirmed that age is an important determinant of treatment outcome and that earlier the age of onset of CPP, the worst is the height outcome if left untreated. Thus, earlier the onset of treatment, height gain achieved by the GnRHa treatment is bigger.

However, unlike historical untreated cohorts mentioned above, some studies afterwards reported final height of untreated girls with CPP demonstrated less, or no decrease in height compared to their TH. Bar et al (18) reported final height data of 20 and near final of 7, girls with idipathic CPP. The appearance of breast tissue occurred at 5.6±1.6 years; the first evaluation was performed at 7.0±2.4 years. Six children were less than 6 years of age at the time of the initial evaluation. Although the mean BA was 8.4±3 years, one third of the girls had a BA at least 2 years (range, 2 to 3.7

Table 2. Adult heights (cm) of treated and untreated (historical) girls with central precocious puberty according to the age of onset

Paul et al (11)

Untreated <5 yr (n=41) Treated <5 yr (n=11) Untreated >5 yr

(n=75)Treated >5 yr (n=15)

Final height 150.2±7.6 164.3±7.7 153.4±8.4 157.6±6.6

Height difference: 14.1 cm Height difference: 4.2 cm

Kletter and Kelch (15)

Untreated <6 yr (n=10)

Treated <6 yr(n=17)

Untreated >6 yr(n=54)

Treated >6 yr(n=114)

FH 153.9±3.8 160.4±1.8 157.0±0.9 157.5±0.6

Height difference: 6.5 cm Height difference: 0.5 cm

TH 160.7±1.7 164.5±1.4 159.0±0.9 161.4±0.6

FH-TH -6.8 cm -4.1 cm -2 cm -3.9 cm

Net height gain from treatment: 2.7 cm Net height gain from treatment: -1.9 cm

FH: final height, TH: target height

Table 3. Effect of age of onset of treatment on height (studies with no control group)

CA at onset BA at onset <6 yr >6 yr

<6 yr >6 yr <6 yr >6 yr PAH TH FH PAH TH FH

Partsch et al (16)

5.0±0.4 7.8±0.2 8.4±0.5 10.4±0.3 152.1±2.2 162.4± 1.08 161.6±1.43 157.7±1.8 165.3±1.43 159.4±1.75

Lazar et al (17) 6.4±1.2 7.5±0.6 11.3±0.4 11.3±0.3 154.6±6.6 159.3±5.0 162.8±5.0 157.8±5.2 153.7±6.7 157.9±5.1

CA: chronological age, BA: bone age



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years) greater than their chronologic age. The mean age of menarche was 10.5 years which was 4.9±2.4 years (range, 3 to 13 years) after thelarche. Despite that, adult height was normal in 90% of girls (mean, 161.4±7.7 cm). Although parental heights were not available in this study, mean final height of the untreated girls with ICCP were only slightly less than healthy average American women 163.8 cm.

In another study, untreated control group consisted of 10 girls with idiopathic precocious puberty who, at their parents’ request, were not treated. Mean age at the onset of pubertal signs was 6.05±0.3 years. There was no significant difference between final height of treated (152.4±1.4 cm) and untreated (149.5±2.0 cm) girls. Final height was significantly lower than TH in both treated (with ciproteron) (155.1±0.9 cm; and untreated (156.4±1.3 patients, but the mean height of treated patients is nearer to TH than that of untreated ones (19).

In a similar study, Kauli et al (20) reported final height of 28 untreated girls with ICCP. Fourteen of them had a slow course of puberty and reached final height of 160.2±7.1 (their TH was 159.5±6.6 cm); the other half (14/28) had an accelerated course of puberty with a final height well below TH (final height 150.8±4.3, TH 159.2±5.9 cm) and in most cases (14/28) below the height SD score (SDS) of both parents.

Obvious differences in the height outcome of untreated patients in different studies (historical cohorts versus more recent cohorts) reflect the heterogeneity of the patients in regard to pubertal hormonal activation. As in Kauli et al’s (20) study, it has been shown in several series that in a subgoup of the girls presenting with what appears to be idiopathic CPP, will either have stabilization or very slow progression in their pubertal signs. Progression of hormonal activation is somewhat slower in these girls and the final heights are not compromised. The BA is typically not as advanced compared with children with true CPP, and serum lutenizing hormone (LH) concentrations are within the pre- or early-pubertal range, indicating that the hypothalamic-pituitary-gonadal axis is not fully activated. GnRH stimulation test in these children demonstrate a follicle-stimulating hormone (FSH) dominant response. These children are considered to have slowly progressive form of CPP.

Palmert et al (21) reported 12-yr follow-up of 20 patients who initially presented with unsustained or slowly progressive puberty by the presence of one or more of the following findings: menses, pubic hair, accelerated growth velocity, and/or BA greater than 2 SD above chronological age. None of the 20 patients had a pubertal response to exogenous GnRH; (by that time with an radioimmunoassay LH increase of less than 25 IU/L above baseline and a peak FSH greater than or equal to the peak LH in response to exogenous

GnRH). Thus, at that time, these girls were not considered candidates for long term pituitary-gonadal suppression with a GnRH agonist. Seventy percent of those patients experienced cessation of their early pubertal development, whereas the remainder reported a slowly progressive course. Those with a slowly progressive course were significantly older than those with an unsustained course [mean age of thelarche, 6.1 vs. 3.4 yr; age of pubarche, 6.0 vs. 4.0 yr. They also had more advanced skeletal maturation (BA, 10.2 vs. 7.3 yr; at the time of evaluation. Both groups, however, had similar outcomes with respect to linear growth and young adult reproductive function. On the average, the study patients reached their genetic targets for final height (mean final height, 165.5±2.2 cm; mean genetic TH, 164.0±1.1 cm; p 5 NS). The average age of menarche was 11.0±0.4 yr.

Léger et al (22) also followed 9 patients (mean age 6.5 years, range 4.8-7.7 years) with a slowly progressing variant of CPP without treatment; final height (161.8±4.6 cm) was similar to the pre-treatment predicted height (163.1±-6.2 cm) and was not significantly different from TH (161.0±5.9 cm).

Table 4 summarizes height outcome of girls with untreated CPP (slowly progressive, milder, or older onset) patients in different series. Final height-TH ranged between -6.8 cm to 1.6 cm. On average, final height was -4.4 cm shorter than TH in six studies (15,18,19,20,23,24) but similar to TH in the remaining seven studies (20,21,22,25,26,27,28). Thus, it can be concluded that the different height outcome of girls with untreated idiopathic CPP in various studies are due to the fact that natural course of precocious puberty differs from one subject to another, i.e. some are more progressive hence have unfavorable outcome whereas some are slowly progressive hence favorable outcome in regards to final height.

Identification of Girls with Progressive Central Precocious Puberty

There is not enough data about the ratio of progressive vs. nonprogressive precocious puberty among girls who develop breast development before 8 years of age. Kaplowitz (29) reported 9% of true precocious puberty in 104 children referred for any signs of early puberty, whereas this ratio was higher (47%) in another US study of 223 girls referred for precocious puberty between ages 7 and 8 (white girls) or 6 and 8 (black girls) (30). Mogensen et al (31) reported nearly 20% true precocious puberty, among 449 girls referred for early pubertal signs. All of these cohorts included all variants of early pubertal development including premature thelarche, premature adrenarche and early normal variants (those >age 8 yrs). However, we have recently reviewed 236 girls who presented with breast development between ages



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4-8 years (thus excluding premature adrenarche, thelarche variant etc.). 59% of these girls were eventually diagnosed with true precocious puberty and given GnRHa treatment (32). This was nearly 34% in Mogensen et al’s (31) series after exclusion of other variants.

Although the mechanism of why puberty is nonprogressive in certain girls is unknown, some clinical features have been proposed to help identifying those who will likely to progress rapidly, although specifity and sensitivity of these criteria varies greatly (33,34,35,36,37,38,39,40) (Table 5). Along with clinical and anthropometric criteria, GnRH-stimulated LH levels of 5 IU/L have been suggested to mark the beginning of puberty using one modern immunochemiluminometric assays (34,35). Stimulated LH limit of 5 IU/L to define CPP was found to have specificity of (77%), and sensitivity of (95%) (36). In one study, randomly measured LH values of 0.3 IU per liter and above were reported to be 100% specific for peak values above 5 IU per liter (37). However, in young children (2-4 years) gonadotropin levels are normally high and therefore LH (basal or peak) should be carefully interpreted in this age group (38). In the consensus report on the use of GnRHa treatment, mentioned values for uterine length range from 3.4 to 4.0 cm (1). The cutoffs for a pubertal ovarian volume range between 1 and 3 mL (volume: length x width x height x 0.5233) (39). A uterine volume greater than 2.0 mL has been reported to have 89% sensitivity and specificity for precocious puberty (40).

As distinguishing progressive form of CPP from nonprogressive forms is important for therapeutic decision-making, the Consensus Conference Group has recommended that progressive pubertal development be documented for 3-6 months before starting GnRHa treatment This observational period may not be necessary if the child is at or past Tanner stage 3 (breast), particularly with advanced skeletal maturation (1).

In addition to above mentioned anthropometric and clinical criteria, we should be aware of certain risk groups in whom precocious puberty is likely to be progressive. These are, family history for precocious puberty, being born small for gestational age (SGA), and adopted children. One has to carefully follow these children when they develop breast development early, as they likely to have progressive precocious puberty. Familial forms of precocious puberty tend to be more progressive than those of sporadic ones. Comparison of 43 familial cases among the total cohort of 156 (147 girls and 9 boys) cases of idiopathic CPP, it was found that the familial group had lower maternal age at menarche than the sporadic group (mean, 11.47 +/- 1.96 vs. 12.66 +/- 1.18 yr; p=0.0001) and more advanced puberty at admission (Tanner stage 2, 56.5% vs. 78.1%; p=0.006). Segregation analysis suggested autosomal dominant transmission with incomplete, sex-dependent penetrance (41). Similarly reviewing case histories of familial CPP due to MKRN mutations reveal early and progressive nature of puberty in these girls (42).

Table 4. Final height of girls with untreated central precocious puberty (slowly progressive, milder, or older onset) patients in different series

n CA BA Age of menarche

TH FH Difference (FH-TH) cm

Bar et al (18) 20 5.6 (7.0)# 8.4 10.5 163.8* 161.4 -2.4

Kauli et al (20) 14^

14- - - 159.5±6.6

159.2± 5.9160.2±7.1150.8±4.3

0.7-8.4

Antoniazzi et al (23) 10 7.2±0.9 9.6±2.2 - 156.4±1.3 149.6±6.3 -6.8

Cisternino et al (19) 10 6.1 - - 156.4 152.4 -4.0

Palmert et al (21)^ 16 5.5 7.9 11 164.0 165.5 1.5

Brauner et al (25)^ 15 7.9 9.4 10.4 161.0 162.0 1.0

Bertelloni et al (26)^ 9 6.5 161.0 161.8 0.8

Léger et al (22)^ 17 7.4 9.2 11.9 161.3 160.7 0.7

Allali et al (27) 52 8.0 9.1 - 161.4 163 1.6

Kletter and Kelch (15) 66 7.6±0.24 10.1±0.29 - 159.3±1.1 156.5±0.9 -2.8

Magiakou et al (28) 14 7.9 10.75 - 161.2 161.5 0.3

Balanli et al (24) 16 7.5±2.0(9.0±2.1)#

10.9±2.8 10.0 156.5±5.2 154.5±7.2 -2.0

#CA at the time of bone age determination is given in parenthesis

*Parental heights were not available. The height given is average healthy American women^Patients were slowly progressing variants and or who had height prognosis above 155 cm thus treatment was not given

FH: final height, TH: target height, CA: chronological age, BA: bone age



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SGA-born girls are another special group of children in regard to puberty. Although being born SGA and having catch-up growth is clearly associated with premature pubarche and exagerated premature adrenarche, these children also have accelerated skeletal maturation and tend to have early (not necessarily precocious) but fast puberty resulting in short stature (43).

Finally the risk of developing precocious puberty was significantly increased in adopted girls and in these girls pubertal process usually continue progressively resulting in early menarche, rapid progression of BA and compromised adult height (44,45,46).

Bone Age-Based Treatment Decision

Some authors suggested predicted height-based decisions regarding GnRHa treatment of girls with CPP. Adan et al (47) used the criteria for treatment as; a PAH <155 cm and/or a LH/FSH peaks ratio of >0.6. Treatment group had greater breast development and BA advances (2.0±0.2 years) and higher plasma estradiol concentrations than the group left untreated. Treated group achieved adult height of 159.5 cm, 3 cm taller than predicted height (156 cm), whereas untreated patients reached an adult height of 162,7 cm, 1.4 cm shorter than predicted height of 164.1 cm. Similarly, Léger et al (22) based treatment decision on BA and LH peak. They did not give treatment in those BA advancement is less than 2 years and peak LH <6 mIU/mL at the initial evaluation. However they decided to begin treatment in girls whose PAH declined during treatment, and were able to achieve a final height better than PAH and surpassing the TH (22).

Thus, BA advancement, and as closely related to it, PAH have major determinants in decision making in regard to GnRHa treatment.

Handicaps in Bone Age Assessment

BA assessment is one of the key parameters in the management of patient with CPP as it allows the

identification of rapidly progressing forms of CPP with compromised PAH, who are thought to benefit most from the treatment in respect to height. Periodical BA evaluation is also a part of monitoring treatment efficacy, as deceleration of BA maturation is expected as a result of treatment. However, BA assessment is affected by a great intra-observer variance, especially around BA of 8-10 years. Nowadays, the majority of girls who are being treated with GnRHa are those between the ages of 6 and 8 years with their BA in the range of 8-10 years.

Although there are several methods for evaluation of BA, the most commonly used method by pediatric endocrinologists is the Greulich-Pyle (GP) method. The GP method is an atlas method in which BA is evaluated by comparing the radiograph of the patient with the nearest standard radiograph in the atlas. Its simplicity, speed and precision made this method the most commonly used standard of reference for skeletal maturation worldwide. However, the GP method was developed using radiographs of upper-middle class Caucasian children in Cleveland, Ohio, United States, and the radiographs were obtained between 1931 and 1942 (48). One has to take the potential insufficiencies of this evaluation into account when evaluating children of today and children from various populations of different ethnic background. Furthermore, these BA methods are based on manual BA determination, the assessment is necessarily subjective and thus, have certain degree of inter-observer and intraobserver difference. In a study, three second year radiology registrars performed both Tanner-Whitehouse 2 (TW2) and GP assessments on each of the BA films. The average spread (the difference between the highest and the lowest of the three results) of BA readings was 0.74 years for TW2 method, and 0.96 years for the GP method (49). Bull et al (50) investigated 362 consecutive “BA” radiographs of the left hand and distal radius performed in a large provincial teaching hospital. Data were analysed using the “method comparison” statistical technique. Ten per cent of the radiographs were re-analysed to assess intra-observer variation. The 95% confidence interval for the difference between the two methods was 2.28 to -1.52 years. Intra-observer variation was greater for the GP method than for the TW2 method (95% confidence limit, -2.46 to 2.18 versus -1.41 to 1.43).

There is now, a recently developed an automated system of BA measurement using computerized image analysis based on both GP and TW2. The use of this automated system was validated in healthy children and in children with various endocrine disorders. It has been shown that automated systems have a better precision and accuracy compared to radiologists’ reading (51). However, still, there

Table 5. Criteria for identifying girls who are likely to have progressive precocious puberty

Progression of breast staging in less than 3-6 months

Growth velocity >6 cm/year

Bone age advancement of more than 1.5-2 years

PAH below target height and decline in PAH during follow-up

Uterine volume >2.0 mL, long diameter >35 mm, presence of endometrial echo

Ovarian volume >2-3 mL

Peak LH >5.0 mIU/L at GnRH test, peak LH/FSH ratio >0.66

Basal LH >0.3 mIU/L, detectable basal E2

PAH: predicted adult height, LH: lutenizing hormone, GnRH: gonadotropin-releasing hormon, FSH: follicle-stimulating hormone, E2: estradiol



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are differences in the interpretation of BA, which are big enough to influence clinical decision-making. In a recent study using an automated BA reading the BA difference between the most advanced and most retarded individual bones exceeded 2.0 years. The BA mean differences between the most advanced and most retarded individual bones were 2.58 and 2.25 years for the automated method and GP atlas methods, respectively (52).

Predicting Height in Girls with ICCP

Height prognosis of the child i.e. “PAH” is of major importance in clinical decision making in girls with CPP. Several alghoritms based on current height and BA to estimate adult height are available but none of them have been fully validated. Predicting adult height with accuracy is hampered by the problems in the accuracy of BA determination as well as problems of methodology in height prediction methods themselves. Bayley-Pinneau method is the most commonly used method for estimating adult height in children have been validated for height prediction in normal children (53). Bayley-Pinneau method estimates adult height as a percentage of current height, based on BA and its relationship to chronological age. It has a wide 95% confidence interval of about 6 cm below to 6 cm above the predicted value, a range which is large enough to mask or blunt small losses or gains in height that occurs due to precocious puberty or its treatment. The prediction equation differs for children whose BA is similar, retarded or advanced in comparison to chronological age (retarded, average and advanced columns in the Bayley-Pinneau height prediction table). Since children with precocious puberty has advanced BA, “advanced column” is used to predict height in girls with CPP. However, it has been shown in several studies that in untreated girls with precocious puberty, Bayley-Pinneau method tend to overrestimate final height by 3.7-5.9 cm in different studies (18,20,23).

To overcome this systematic error it has been proposed that “average column” should be used instead of advanced column (20). This approach might correct the systematic error but is unlikely to increase the precision. Studies reporting PAH in GnRHa treated girls by both advanced and average column demonstrates that final height is closer to PAH calculated with the advanced column than that of the average column (20,26,28,54,55,56). A recent study, when PAH was calculated using the average standards of GP, the median delta final height-PAH was 6.96 and 3.34 cm in GnRHa-treated and nontreated subjects, respectively, whereas when the accelerated standards were used, the differences were less (1.7 and 1.2 cm, p:NS). Final height-PAH-average and final height-PAH-accelerated were comparable among the nontreated subjects but among GnRHa-treated

subjects, final height-PAH-average was significantly higher than final height-PAH-accelerated (28). Thus it appears that using advanced column for height prediction gives a better estimation of final height to be reached.

Height Outcome in Studies with Gonadotropin-Releasing Hormone Analogues Treatment of Progressive Central Precocious Puberty (Table 6)

GnRHa treatment has been a standart of care in girls with progressive CPP for nearly four decades now. GnRHa treatment decreases gonadotrophins, estradiol and the growth velocity and decelerates the skeletal advancement. Linear growth gradually decrease to a rate which is normal for a prepubertal child (~5 cm/year) during the first or second year of treatment, sometimes further deceleration happens in the following years (57,58). Bone maturation also slows down beginning from the 6 months of treatment, averaging 0.5+0.2 BA year/year (59). Similar values have been recorded in other reports (60,61,62). This decrease in bone maturation is progressive and does not occur before six months of treatment (63). As a result of the progressive normalization of BA, and continued linear growth, treatment provides increase in PAH despite the decreased growth velocity, although it is difficult to predict precisely the effect of GnRHa treatment on height gain of these patients, due to handicaps discussed above. Reviewing the available 28 studies on GnRHa treatment of CPP (7,15,16,17,20,22,23, 28,47,54,55,56,59,60,61,62,63,64,65,66,67,68,69,70,71, 72,73,74) (Table 6) and our own experience (75) demonstrate that the mean age at onset of pubertal development ranged 3-8 years, usually younger and more severe cases in older studies, older and milder cases in recent studies. Nevertheless, in most series, the age of treatment initiation was around 7 years, (5.4-8.7 years) with again recent studies tend to be a year later around 7.5-8 years. Mean BA was around 10 years (8.9-12.5 years) at the beginning of treatment and most series report mean treatment durations around 3.0 years. Mean chronological age at the end of treatment was around 11.1 (9.4-12.7) years of age with a mean BA of 12.4 (11.9-13.6) years. At the achievement of final height all studies except two (69,73) reported final height better than PAH (ranging 2.0-10.5 cm). On average, final height was ~4.0 cm higher than height predicted at the time of initiation of GnRHa treatment.

Comparison of final height of treated patients with their TH eliminates the handicaps of predicting adult heigt thus allows perhaps a better estimation of the effect of GnRHa treatment on height. When compared to TH, in most studies (nineteen studies), final height was 0.4 to 5.2 cm shorter than TH (15,16,20,28,47,54,60,61,62,63,64,65,66,67, 68,69,70,71,74) but 0.4-4.2 cm taller in the remaining nine



112

40



studies (17,22,23,55,56,59,72,73,75). On average, final height was ~1 cm shorter than TH.

However, one should also be aware that, even with comparison with TH is not free of biases. Calculation of midparental TH assumes equal contribution of each parents heights to the offsprings height, thus neglects the effect of dominant genes from one parent. Although TH correlates well with the offsprings height on a population level, it may not correlate well with individual subject. This is especially true for children whose parents are discordant for height.

Finally, in a limited number of studies when adult height of treated patients were compared with untreated study subjects, mean difference ranged from -3.0 to +11 cm) (20,23,28,75). Again, height gain was highly variable among studies depending on sample characteristics including the progression of pubertal development. It should be bear in mind, that the treatment effect also might be overestimated since most of the studies describe observed cases and none of them comprise an intention-to-treat analysis. It is possible that the patients who interrupt the treatment early and are not followed to adult height might have a poorer height outcome than those who continued to the end. Finally, predicted height values obtained during treatment are often overestimated in comparison to the adult height eventually achieved by the patient (7,33).

Factors Influencing Height Outcome

As mentioned earlier, and seen in the Table 2 data of historical untreated girls with CPP demonstrated that earlier the age of onset of puberty, worse the height prognosis. In line with that, evaluation of treatment series also show that younger age of onset of CPP and hence, younger age of initiation of treatment (which also means longer duration of treatment) is associated with bigger height gain, although a few studies refute that showing no correlation between height gain and age at puberty onset or initiation of treatment (20,59). Greater effectivenesss of GnRHa treatment on younger girls who are destined to poorer height prognosis without treatment, proves further that GnRH treatment is an effective strategy to preserve diminished height potential in these children.

BA advance at start of treatment and at the end, is negatively associated with height outcome (7,47,54,65,73). BA/statural age ratio at the onset of treatment and adult height is negatively associated with outcome suggesting that treatment is not capable of restoring a full adult height potential if started after a certain critical advancement of BA. Kauli et al (20) demonstrated that therapy is more beneficial if started before BA exceeds 12 years.

Height SDS at the onset (7,17,33,54,56,62,67) and at termination of treatment (7,17,54,56,59,67,73), as well as higher TH (7,17,65,67,72) have also been positively associated with adult height, supporting that influence of genetic factors on height is dominant among other factors.

Naturally, BA at the end of treatment, is associated with final height, as it determines posttreatment residual growth potential (7,59,71). Although data are scarce in this respect, stopping treatment at a BA of 12-12.5 years (7) or even <11.5 years (26) seemed to be associated with best height outcome, while continuing treatment after a BA ≥13 years negatively impacted on statural growth (7). Three factors explained 66% of adult height variance: BA advance before treatment, height at the end of treatment and height gain after interruption of treatment (33).

In summary, among the factors associated with the height outcome, height SDS and TH reflecting genetic potential, are always associated with positive outcome, BA advance and delay in treatment are negative factors. This highlights the importance of rapid recognition, evaluation and treatment of patients with true precocious puberty. However, one has to balance this with careful follow-up in some girls to not treat those with slow progression unnecessarily.

In terms of effcicacy of treatment, various GnRHa appeared similar as regards to height outcome (26,62,71,74), except for a study (69) demonstrating slightly better adult height SDS in patients treated with leuprolide depot compared to triptorelin depot.

Optimal Age of Discontinuation of Gonadotropin-Releasing Hormone Agonist Treatment in Girls with Central Precocious Puberty

Data is also missing on this respect. In the literature, (Table 6) the mean age at interruption of treatment ranges 9.4 to 12.7 averaging around age 11 year and BA ranging from 11.9 to 13.6 averaging 12.5 years. BA at the end of treatment correlates negatively with height gain after treatment. Carel et al (33) using multivariate analysis estimated that an 11 year old girl, growing 4 cm and gaining 0.5 BA year per year, could loose 2.6 cm of adult height if treatment was discontinued 1 year later. Opposite results were found by Klein et al (62) who found a positive correlation between age at discontinuation of treatment and adult height (r=0.25, p=0.03), suggesting that prolonging the treatment could increase height. Obviously, this discrepancy only can be solved with a formal controlled trial (i.e. randomizing girls between “early” and “late” age at discontinuation of treatment). However, such a trial would be difficult to perform since patients and the parents prefer to stop



113

41



Tabl

e 6.

Hei

ght

outc

ome

in s

tudi

es w

ith

gon

adot

roph

in‐r

elea

sin

g h

orm

one

agon

ists

tre

atm

ent

of p

rogr

essi

ve i

diop

ath

ic c

entr

al p

reco

ciou

s pu

bert

y

Au

thor

(re

f n

o),

year

nC

A a

t on

set

BA a

t on

set

CA

at

ETBA

at

ETTH

PH

FHFH

-TH

FH-P

H

Kle

tter

and

K

eltc

h (1

5),

1994

131

7.6±

0.13

<6

year

s 4.

7±0.

3>

6 ye

ars

8.1±

0.1

10.9

±0.

1

9.4±

0.6

11.2

±0.

1

161.

8±0.

7

164.

5±1.

416

1.4±

0.6

155.

915

7.9±

0.6

160.

4±1.

815

7.5±

0.6

-3.9

-4.1

-3.9

2.0

Oos

tdijk

et

al

(60)

, 199

631

7.7

10.8

11.1

12.5

168.

7±6.

415

8.2±

7.4

161.

6±7.

0-7

.13.

4

Kau

li et

al (

20),

1997

(AD

-AV

)48 28

8.3±

1.5

Unt

7.8

±1.

0

12.5

±0.

7

Unt

10.

2±1.

3

11.5

±0.

512

.5±

0.7

157.

7±5.

7

Unt

159

.3±

6.1

AD

: 156

.6±

6.7

AV: 1

52.3

±6.

015

9.6±

6.3

Unt

155

.5±

7.5

1.9

-3.8

3.0

7.3

Ber

tello

ni e

t al

(2

6), 1

998

146.

2±1.

89.

6±1.

616

3.3±

6.2

153.

5±7.

215

8.1±

5.2

-5.2

4.6

Gal

luzz

i et

al

(61)

, 199

8 22

7.3±

1.1

10.3

±0.

911

.3±

0.7

12.6

±0.

815

5.2±

4.7

158.

5±5.

33.

2

Car

el e

t al

(59)

, 19

99

587.

5±1.

310

.1±

1.5

11.2

±1.

012

.2±

0.8

160.

1±4.

415

6.4±

6.3

161.

1±5.

91.

04.

7

Heg

er e

t al

(6

4), 1

999

506.

2±2.

09.

3±2.

511

.0±

1.1

163.

6±6.

215

4.9±

9.6

160.

6±8.

0-2

.05.

7

Arr

igo

et a

l (7)

, 19

9971

7.0±

1.3

9.8±

1.4

11.0

±1.

012

.4±

0.8

161.

5±6.

915

5.5±

7.0

158.

4±5.

8-2

.92.

9

Lége

r et

al

(22)

, 200

0 9

8.7±

0.4

11.1

±0.

410

.8±

0.6

11.8

±0.

515

9.8±

4.6

155.

3±5.

616

0.2±

6.7

0.4

4.9

Part

sch

et a

l (1

6), 2

000

526.

2±0.

3 <

6 ye

ars

5.0±

0.35

>

6 ye

ars

7.8+

0.18

9.3±

0.3

11.1

±1.

112

.6±

0.2

164

162.

4±1.

0816

5.3±

1.43

154.

9±9.

6

152.

1±2.

22

157.

7±1.

80

160.

6±8.

0

161.

6±1.

43

159.

4±1.

75

-3.4

-0.8

-5.9

5.7

9.6

1.7

Kle

in e

t al

(62)

, 20

01

80 <6

yr >6

yr

5.4±

1.9

10.0

±2.

711

.1±

1.0

12.8

±1.

116

3.7±

5.6

164.

5±5.

9N

A

149.

3±9.

6

NA

151.

1±8.

6

159.

8±7.

6

162.

1±7.

015

7.9±

7.6

-3.9

-2.4

NA

10.5

14.5

6.8

Baj

pai e

t al

(6

5), 2

002

(AV

)30

6.5±

1.8

10.1

±1.

610

.2±

2.5

12.0

±0.

515

4.7±

6.1

143.

4±8.

314

9.8±

6.9

-4.9

6.4



114

42



Tabl

e 6.

Con

tin

ue

Ant

onia

zzi e

t al

(23)

, 200

0 15 10

7.6±

0.5

Unt

7.2

±0.

99.

8±1.

0U

nt 9

.6±

2.2

11.0

±0.

9 12

.1±

0.8

157.

6±5.

9U

nt 1

56.4

±1.

3 16

0.6±

5.7

Unt

149

.6±

6.3

3.0

Adan

et

al (4

7),

2002

43

7.9±

1.3

10.3

±1.

310

.8±

0.7

12.2

±0.

716

1.2±

4.6

156.

0±7.

815

9.5±

5.3

-1.7

3.5

Tana

ka e

t al

(5

4), 2

005

(AD

-AV

)

637.

7±2.

210

.2±

1.5

11.6

±1.

412

.0±

0.8

154.

9±4.

6A

D: 1

54.5

±7.

1AV

: 151

.1±

7.3

154.

5±5.

7-0

.40 3.

4

Tung

et

al (6

6),

2007

118.

0±1.

511

.5±

1.3

12.7

±0.

913

.6±

0.6

157.

0±4.

514

6.7±

4.8

156.

3±4.

3-0

.79.

6

Laza

r et

al

(17)

, 200

760

<6

year

s 6.

4±1.

2

>6

year

s 7.

5±0.

6

8.9

10

11.3

±0.

4

11.3

±0.

3

12.1

±0.

5

12.4

±0.

5

159.

3±5.

0

157.

8±5.

2

154.

6±6.

6

153.

7±6.

7

162.

8±5.

0

157.

9±5.

1

3.1

4.2

8.2

0.1

Pasq

uino

et

al (5

5), 2

008

(AD

-AV

)

878.

4±1.

511

.1±

1.6

12.6

±1.

013

.1±

0.5

157.

6±4.

7A

D: 1

54.2

±5.

2

AV: 1

50.0

±5.

1

159.

8±5.

32.

25.

6

9.8

Bri

to e

t al

(67)

, 20

08 (A

D-A

V)

457.

3±2.

010

.6±

2.2

10.7

±0.

812

.4±

0.9

157.

5±4.

5A

D: 1

51.6

±9.

7AV

: 147

.3±

9.0

155.

3±6.

9-2

.23.

78.

0

Nab

han

et a

l (6

8), 2

009

(P)

267.

2±2.

010

.1±

2.2

10.9

±1.

212

.4±

0.9

164.

0±5.

715

8.5±

6.8

163.

0±7.

6-1

.04.

5

Mas

sart

et

al

(69)

, 200

9 47

L gr

oup:

7.6

±0.

7

T gr

oup:

7.4

±0.

8

L gr

oup:

10

.5±

1.3

T gr

oup:

10

.2±

1.3

Lgro

up:

10.6

±1.

1

T gr

oup:

9.

4±1.

2

L gr

oup:

12

.3±

0.9

T gr

oup:

12

.0±

0.7

Ht

SDS

L gr

oup:

-0.2

±0.

3

T gr

oup:

0.1

±0.

2

Ht

SDS

L gr

oup:

-1.0

±0.

6

T gr

oup:

-0.6

±0.

6

Ht

SDS

L gr

oup:

-1.5

±0.

7

T gr

oup:

-0.9

±0.

5

Mag

iako

u et

al

(28)

, 201

0 (A

D-A

V)

33

14

7.92

Unt

7.9

5

10.0

Unt

10.

75

158.

75

Unt

161

.2 c

m

AD

: 158

.16

AV:1

51.5

3

Unt

AD

: 160

.2AV

: 154

.3

158.

5

Unt

161

.5

-0.2

50.

4

7.0

Lee

et a

l (70

), 20

1129

7.3±

1.9

10.2

±2.

1316

3.8

157.

416

2.5

-1.3

5.1

Poom

thav

orn

et a

l (56

), 20

11

(AD

-AV

)

478.

5±1.

011

.1±

1.7

11.8

±1.

013

.3±

0.5

155.

8±4.

1A

D: 1

55.3

±6.

7

AV: 1

50.8

±5.

5

158.

6±5.

22.

83.

3

7.8



115

43



treatment when the girl has reached an age that peers of the patients have already started puberty which is usually around age 11 year.

Could the BA be a useful parameter to decide when to stop treatment? Although the optimal age for treatment interruption is not clearly defined by international guidelines, it has been proposed that the best heights are achieved when treatment is discontinued at around 12-12.5 years in girls (7,76) However, in girls around the age of 11 years with previous advance in BA and a long-standing treatment with GnRH agonists, BA often is approximately 12 years with little variation and is therefore of little help to orient decisions. Furthermore, reduction of growth velocity, commonly observed around this age, due to the increasing dependence of growth on sex steroids (77) with time, necessitates stopping treatment.

Treatment of Gonadotropin-Releasing Hormone Analogues Combined with Growth Hormone Treatment (Table 7)

The growth velocity in some CPP patients decreases below the normal for prepubertal children during GnRHa therapy. Subnormal growth velocity during GnRHa therapy may be associated with a decrease in GH and insulin-like growth factor 1 secretion due to suppression of gonadal steroids (77). Therefore, some studies investigated in girls with precocious puberty and poor predicted height, whether adding GH to GnRHa treatment is associated with a better height outcome (78,79,80,81,82,83,84). Data is even more limited and biased about this type of approach. In short, it can be stated that at present, studies are insufficient to make definite conclusions about the height outcomes of GnRHa plus GH treatment. Lanes and Gunczler (78) treated 15 short children (boys and girls) entering into normally timed puberty with both GnRHa and GH and compared them with an identical number of untreated children. In their study, no relevant height gain was observed after 2.5 years of treatment.

Pasquino et al (79) and Pucarelli et al (80) on the other hand, showed differences of about 6-8 cm of height gain on girls with CPP treated with GnRHa plus GH, compared to

Tabl

e 6.

Con

tin

ue

Gill

is e

t al

(71)

, 20

13 (A

V)

23 11

T gr

oup:

8.4

±0.

3

HIS

impt

gro

up:

8.7±

0.3

10.0

±0.

3

10.4

±0.

4

10.6

11.7

160.

8±0.

8

160.

1±1.

0

155.

2±1.

9

156.

8±2.

6

157.

9±1.

7

161±

2.0

-0.9

1.0

2.7

4.3

Jung

et

al (7

2),

2014

598.

7±0.

810

.2±

1.6

10.6

±0.

811

.9±

0.5

159.

9±3.

515

6.6±

4.0

160.

4±4.

20.

53.

8

Ata

y et

al (

75),

2014

48 52

7.76

±1.

2

Unt

: 8.0

8±0.

8

9.66

±1.

4

Unt

: 10

.0±

1.5

159.

0

Unt

: 160

.0

154.

616

0.6

Unt

: 158

.1

1.6

Unt

: -1.

9

6.0

Lian

g et

al

(73)

, 201

5 17

8.1±

0.2

9.2±

0.3

158.

3±0.

916

1.6±

0.9

159.

8±1.

21.

5-1

.8

Ber

tello

ni e

t al

(74)

, 201

5 (A

D-A

V)

13

12

Thre

e m

onth

ly:

7.9±

0.6

Mon

thly

: 8.0

±0.

6

10.6

±0.

9

10.4

±0.

9

159.

7±3.

8

158.

4±5.

0

AD

: 155

.0±

3.5

AV: 1

49.9

±3.

5

AD

: 155

.4±

5.9

AV: 1

50.2

±5.

3

157.

1±4.

9

158.

1±6.

6

-2.6

-0.3

2.1

7.2

2.7

7.9

n: n

umbe

r of

sub

ject

s, C

A: c

hron

olog

ical

age

, BA

: bon

e ag

e, E

T: e

nd o

f tr

eatm

ent,

TH

: mid

pare

ntal

targ

et h

eigh

t, P

H: p

redi

cted

hei

ght

at t

reat

men

t in

itiat

ion,

FH

: fina

l hei

ght,

T: t

ript

orel

in d

epot

, Unt

: un

trea

ted

cont

rol g

roup

, NA

: not

ava

ilabl

e, L

: leu

prol

ide,

HIS

impt

: his

trel

in im

plan

t, H

t SD

S: h

eigh

t st

anda

rd d

evia

tion

scor

e, A

V: P

H c

alcu

late

d ac

cord

ing

to a

vera

ge ta

bles

, AD

: PH

cal

cula

ted

acco

rdin

g to

tabl

es fo

r ad

vanc

ed b

one

age;

if n

ot s

peci

fied,

adv

ance

d ta

bles

wer

e us

ed, P

: PH

cal

cula

ted

acco

rdin

g to

the

mod

el p

ropo

sed

by “

Post

E, R

ichm

an R

. A c

onde

nsed

tabl

e fo

r pr

edic

ting

adul

t st

atur

e. J

Pedi

atr

1981

;98:

440-

442”

All

valu

es a

re p

rese

nted

as

mea

n ±

sta

ndar

d de

viat

ion

whe

n av

aila

ble.

Hei

ght

is e

xpre

ssed

in c

entim

eter

s, a

ge in

yea

rs, I

N: i

ntra

nasa

l



116

44



Tabl

e 7.

Stu

dies

in

vest

igat

ing

gon

adot

roph

in‐r

elea

sin

g h

orm

one

anal

og p

lus

grow

th h

orm

one

trea

tmen

t on

fin

al h

eigh

t of

gir

ls w

ith

cen

tral

pr

ecoc

iou

s pu

bert

y

Auth

or (r

ef),

year

C

ompa

riso

nTr

eatm

ent

Dur

atio

n

of t

hera

py

(yea

r)

Subj

ects

(n

) CA

at

onse

tBA

at

onse

tTH

PA

H

FHFH

-PA

HFH

-TH

Pasq

uino

et

al (7

9), 1

999

GnR

Ha

GnR

Ha

+ G

H

Trip

tore

lin, 1

00 m

g/kg

/q 2

1 da

ys Tr

ipto

relin

+ G

H

0.3

mg/

kg/w

eek

(afte

r 2-

3 ye

ars

of

GnR

H th

erap

y)

4.9

5.1

(tota

l)

10 10

7.6±

0.2

7.9±

0.6

10.0

±0.

5#

10.4

±0.

3

10.6

±0.

4&12

.0±

0.2#

155.

5±2.

1

155.

6±2.

0

155.

5±2.

0

152.

7±1.

7

157.

1±2.

5

160.

6±1.

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1.6±

1.2

7.9±

1.1

1.6

5.0

Puca

relli

et a

l (8

0), 2

003

GnR

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GnR

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+ G

H

Trip

100

mg/

kg/2

1 da

ys, i

.m.

Trip

tore

lin +

GH

0.

3 m

g/kg

/wee

k

2-4

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s18 17

7.9±

0.8

9.9±

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12.1

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8

157.

2 ±

6.0

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8

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AV

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5 AV

156.

6±5.

7 16

1.2±

4.8

2.3±

2.9

AD

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AV

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8.2±

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NA

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9

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Mul

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12 14

9.6±

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1

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8N

A

156.

0±5.

7 A

D14

9.8±

5.6

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151.

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0 A

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6.8±

4.8

AV

155.

0±5.

6

155.

0±5.

5

-1.0

±3.

6 5

.2±

3.7

3.3±

3.5

8.2±

3.4

Jung

et a

l (8

3), 2

014

GnR

H

GnR

Ha

+ G

H

GnR

Ha*

75-

150

µg/

kg q

28

days

GnR

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H 0

.25

mg/

kg p

er w

eek

2 ye

ars

59 23

8.7±

0.8

8.8±

0.59

10.2

±1.

6

10.5

±0.

86

159.

9±3.

5

158.

1±3.

31

156.

6±4.

0

154.

6±2.

55

160.

4±4.

2

159.

3±5.

33

3.8

4.7

0.5

1.2

*Gon

adot

roph

in‐r

elea

sing

hor

mon

e an

alog

not

spe

cifie

d, a

nd a

t th

e be

ginn

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of g

onad

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orm

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the

rapy

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the

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f gr

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: pre

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tre

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: int

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sal



117

45



GnRHa alone. In their first report, the gain in centimeters, (calculated between pretreatment PAH (152.7±1.7 cm) and final height (160.6±1.3 cm), was 7.9±1.1 in patients treated with GH plus GnRHa, whereas in patients treated with GnRHa alone, the gain between pretreatment PAH (155.5±1.7) and final height (157.1±2.5 cm) was just 1.6 cm ± 1.2. The difference between the gain obtained in the groups is significant, in favor of combination group (p<0.001) (79). However, the same group reported four years later a larger number of patients with a longer follow-up period that, adult height versus pre-treatment PAH was 6 cm greater in combination treatment than that of GnRHa alone but concluded that true efficacy of the addition of GH to GnRHa therapy is still questionable (80). They recommended caution regarding such an invasive and expensive treatment, outside a research setting.

It should also be taken into account that, in the above studies, the treatment period was not standardized, and the authors treated a selected group of patients, i.e. those whose height velocity decreased to value <p25 for chronological age under GnRHa treatment. Besides, the duration of treatment in these studies was remarkably longer than in other studies with combined treatment and GH dosage was higher.

A randomized controlled study, in short adopted girls with early puberty, Mul et al (81) treated girls with onset of puberty before 10 years of age for 3 years with either GnRHa alone (group A, n=12) or with GnRHa and GH (group B, n=14). Height gain defined as the difference between initial height prediction and attained final height, was significantly different between group A and B (5.2±3.7 cm and 8.2±3.4 cm, p<0.05) using average tables for height prediction. However, with advanced tables for height prediction, the numbers were much less (-1.0±3.6 and 3.3±3.5 cm, respectively).

A recent Korean study in 82 girls with idiopathic CPP showed a height gain of approximately 3.8 cm in the GnRHa alone group, while 4.7 cm in the combination group compared to PAH before treatment with no statistically significant difference between two groups. (83). Finally a recent meta-analyses, evaluating a total of six randomized controlled trials (RCTs) (162 patients) and six clinical controlled trials (CCTs) (247 patients) reported that compared to the GnRHa therapy group, the combination therapy group achieved taller final height (mean difference=2.81 cm, four CCTs and 4.30 cm, in one RCT); and 3.9 cm better final height compared with THs (84).

The results of these studies (comparing adult height vs. predicted height) should again be interpreted in the context

of the before mentioned methodological handicaps of accurately predicting adult height. Furthermore, the number of treated patients are much less, and most likely involves selection biase as those who have poor height potential or attenuated growth velocity might tend to choose or given the combined GnRHa GH treatment. Finally, since GH treatment requires the consideration of cost, economic status may be another affecting factor to select the patients treated with GnRHa plus GH. Cost-effectiveness of combined GH treatment in patients with CPP has also to be elucidated.

Ethics

Peer-review: Internally peer-reviewed.

Financial Disclosure: The author declared that this study received no financial support.

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76. Lazar L, Phillip M. Pubertal disorders and bone maturation. Endocrinol Metab Clin North Am 2012;41:805-825.

77. Mansfield MJ, Rudlin CR, Crigler JF Jr, Karol KA, Crawford JD, Boepple PA, Crowley WF Jr. Changes in growth and serum growth hormone and plasma somatomedin-C levels during suppression of gonadal sex steroid secretion in girls with central precocious puberty. J Clin Endocrinol Metab 1988;66:3-9.

78. Lanes R, Gunczler P. Final height after combined growth hormone and gonadotrophin-releasing hormone analogue therapy in short healthy children entering into normally timed puberty. Clin Endocrinol (Oxf) 1998;49:197-202.

79. Pasquino AM, Pucarelli I, Segni M, Matrunola M, Cerroni F. Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone analogues and growth hormone. J Clin Endocrinol Metab 1999;84:449-452.

80. Pucarelli I, Segni M, Ortore M, Arcadi E, Pasquino AM. Effects of combined gonadotropin-releasing hormone agonist and growth

hormone therapy on adult height in precocious puberty: a further

contribution. J Pediatr Endocrinol Metab 2003;16:1005-1010.

81. Mul D, Oostdijk W, Waelkens JJ, Drop SL. Final height after treatment

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Häger A, Ivarson S, Kriström B, Marcus C, Nilsson KO, Westgren U,

Westphal O, Aman J, Proos LA. Final height after combined growth

hormone and GnRH analogue treatment in adopted girls with early

puberty. Acta Paediatr 2004;93:1456-1462.

83. Jung MK, Song KC, Kwon AR, Chae HW, Kim DH, Kim HS. Adult height

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causas periféricasVâniA MARTinS

Bibliografia:

Harrington J., MBBS. Definition, etiology, and evaluation of precocious puberty. Post TW, ed. upToDate. Waltham, MA: upToDate inc. http://www.uptodate.com (Accessed on oct 26, 2018.)

Guillén LS y Argente J. Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos. An Pediatr (Barc). 2012;76(4):229.e1-229.e10

puberdade precoce


PuBerdAde PreCoCe | CAusAs PerifériCAs | VâniA MArTins

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Official reprint from UpToDate

www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Definition, etiology, and evaluation of precocious puberty

Authors: Jennifer Harrington, MBBS, PhD, Mark R Palmert, MD, PhD

Section Editors: Peter J Snyder, MD, William F Crowley, Jr, MD, Mitchell E Geffner, MD

Deputy Editors: Alison G Hoppin, MD, Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2018. | This topic last updated: Sep 04, 2018.

INTRODUCTION — Precocious puberty is the onset of pubertal development at an age that is 2 to 2.5 standard deviations (SD)

earlier than population norms. The cause of precocious puberty may range from a variant of normal development (eg, isolated

premature adrenarche or isolated premature thelarche) to pathologic conditions with significant risk of morbidity and even death (eg,

malignant germ-cell tumor and astrocytoma).

The clinician faced with a child who presents with early development of secondary sexual characteristics should consider the

following questions:

The definition of precocious puberty and its causes and evaluation will be reviewed here. The treatment of precocious puberty is

discussed separately. (See "Treatment of precocious puberty".)

DEFINITION — Precocious puberty is traditionally defined as the onset of secondary sexual characteristics before the age of eight

years in girls and nine years in boys [1]. These limits are chosen to be 2 to 2.5 standard deviations (SD) below the mean age of

onset of puberty. In most populations, attainment of pubertal milestones approximates a normal distribution, with a mean age of

onset of puberty of about 10.5 years in girls and 11.5 years in boys (figure 1A-B) and an SD of approximately one year [1-9].

NORMAL PUBERTAL DEVELOPMENT — The hypothalamic-pituitary-gonadal axis is biologically active in utero and briefly during

the first week of life. It then becomes more active again during infancy, with peak activity between one and three months of age [10].

This state yields sex steroid levels comparable with those seen in early-to-mid puberty, but without peripheral effects. In boys,

gonadotropin concentrations then decrease to prepubertal levels by six to nine months of age. In girls, luteinizing hormone (LH)

levels decrease at approximately the same time as in boys, but the follicle-stimulating hormone (FSH) concentrations can remain

elevated into the second year of life. This hypothalamic-pituitary-gonadal activity during infancy is known as the "mini puberty of

infancy"; its biological relevance is unknown.

The neonatal stage is followed by a long period of pre-puberty, which is a state of active suppression of the hypothalamic-pituitary-

gonadal axis. Puberty occurs when there is reactivation of the hypothalamic-pituitary-gonadal axis. The physiologic and genetic

mechanisms that affect timing of pubertal maturation are discussed separately. (See "Normal puberty", section on 'Sequence of

pubertal maturation'.)

In 1969 and 1970, Marshall and Tanner defined the standards of normal pubertal development in children and adolescents, known

as sexual maturity ratings or "Tanner stages" (picture 1A-C) [2,3]. These studies reported that the first sign of puberty in English girls

was breast development at an average age of 11 years (thelarche), followed by pubic hair growth (pubarche), and then menarche. In

English boys, the first sign was testicular enlargement at an average age of 11.5 years followed by penile growth and pubic hair

growth. (See "Normal puberty".)

Since these reports by Marshall and Tanner, several studies in the United States and other countries suggest that children,

especially overweight children, are entering puberty at a younger age than previously [4-9,11]. In addition, there are racial

differences, with puberty occurring earlier in African-American children compared with non-Hispanic Caucasian and Hispanic

children. These data and the proposed explanations for the trends are discussed separately. (See "Normal puberty", section on

'Trends in pubertal timing'.)

EPIDEMIOLOGY — Using the traditional definition of precocious puberty as the development of secondary sexual characteristics

before age eight in girls and nine in boys (2 to 2.5 standard deviations [SD] below the average age of pubertal onset in healthy

®

Is the child too young to have reached the pubertal milestone in question? – To answer this question, the clinician needs to

know the normal ages for pubertal milestones and how to separate normal from abnormal development.

●

What is causing the early development? – To answer this question, the physician ascertains whether the development of

secondary sexual characteristics is attributable to androgen and/or estrogen effects, and whether the source of sex hormone is

centrally mediated through the hypothalamic-pituitary-gonadal axis, from an autonomous peripheral origin, or has an exogenous

basis.

●

Is therapy indicated, and, if so, what therapy?●

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children), one would expect that the prevalence rate should be around 2 percent, or 2 in every 100 children. However, population

studies looking at the prevalence rates of precocious puberty yield markedly different rates depending on the population studied:

These observations suggest that the definition of precocious puberty is problematic, at least in girls, and that selection of children for

evaluation should not only depend on age but also clinical features, race/ethnicity, and presence/absence of obesity [13]. (See

'Definition' above and 'Threshold for evaluation' below.)

There is a strong female predominance of children with precocious puberty. In a retrospective review of 104 consecutive children

referred for evaluation of precocious puberty, 87 percent were female [14].

THRESHOLD FOR EVALUATION — We suggest careful evaluation of children presenting with signs of secondary sexual

development younger than the age of eight years in girls or nine years in boys. The level of concern and extent of evaluation should

increase with younger age at presentation. Given the trend towards earlier pubertal development, in girls who are between the ages

of seven and eight, a comprehensive history and physical examination and clinical follow-up may be sufficient if the clinical

evaluation does not raise any additional concerns [15]. (See 'Epidemiology' above and 'Evaluation' below.)

A more controversial approach was suggested in 1999 by the Lawson Wilkins Pediatric Endocrine Society (LWPES), which

recommended that evaluation for a pathologic cause of precocious puberty be reserved for Caucasian girls who have breast and/or

pubic hair development before seven years of age and for African-American girls who have these findings before six years of age

[16]. This recommendation was based on a study describing the first signs of pubertal development among approximately 18,000

girls in the United States and Puerto Rico, among whom development occurred at a younger age than had been previously reported

(figure 2) [11]. The study did not distinguish between girls with isolated thelarche or adrenarche from those with true precocious

puberty. This same study reported an average age at menarche of approximately 12.5 years, which was not substantially earlier than

had been reported in the 1940s [17].

This LWPES recommendation is controversial because of concerns that lowering the age threshold for evaluation of precocious

puberty will result in failure to identify some children with pathologic disease [18,19]. As an example, a retrospective review of 223

girls referred to a tertiary center for evaluation of pubertal development before eight years of age found that utilization of the LWPES

guidelines would have resulted in failure to identify a substantial number of patients with treatable disease [19]. Twelve percent of

these girls were ultimately diagnosed with an endocrinopathy that was amenable to early intervention, including congenital adrenal

hyperplasia, McCune-Albright syndrome, pituitary adenoma, and neurofibromatosis.

CLASSIFICATION — Precocious puberty can be classified based upon the underlying pathologic process (algorithm 1).

CAUSES OF CENTRAL PRECOCIOUS PUBERTY (CPP) — Central precocious puberty (CPP, also known as gonadotropin-

dependent precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. Although the onset is early,

the pattern and timing of pubertal events is usually normal. These children have accelerated linear growth for age, advanced bone

age, and pubertal levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

In a population-based United States study, breast and/or pubic hair development was present at age eight in 48 percent of

African-American girls and 15 percent of White girls [11]. At seven years of age, the proportions were 27 percent and 7 percent,

respectively.

●

In a population-based study of data from Danish national registries from 1993 to 2001, the incidence of precocious puberty was

20 per 10,000 girls and less than 5 per 10,000 boys [12]. The diagnostic age limit utilized in this study was eight years for girls

and nine for boys. About half the patients had central precocious puberty (CPP) and the remainder were isolated premature

thelarche or adrenarche, or early normal pubertal development. (See "Premature adrenarche".)

●

Central precocious puberty – Central precocious puberty (CPP, also known as gonadotropin-dependent precocious puberty or

true precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. CPP is characterized by

sequential maturation of breasts and pubic hair in girls, and of testicular and penile enlargement and pubic hair in boys. In these

patients, the sexual characteristics are appropriate for the child's gender (isosexual). CPP is pathologic in up to 40 to 75 percent

of cases in boys [20,21], compared with 10 to 20 percent in girls [22-24] (table 1) (See 'Causes of central precocious puberty

(CPP)' below.)

●

Peripheral precocity – Peripheral precocity (also known as peripheral precocious puberty, gonadotropin-independent

precocious puberty) is caused by excess secretion of sex hormones (estrogens or androgens) from the gonads or adrenal

glands, exogenous sources of sex steroids, or ectopic production of gonadotropin from a germ cell tumor (eg, human chorionic

gonadotropin, hCG) (table 2). The term precocity is used instead of puberty here because true puberty requires activation of the

hypothalamic-pituitary-gonadal (HPG) axis, as occurs in CPP. Peripheral precocity may be appropriate for the child's gender

(isosexual) or inappropriate, with virilization of girls and feminization of boys (contrasexual). (See 'Causes of peripheral

precocity' below.)

●

Benign or non-progressive pubertal variants – Benign pubertal variants include isolated breast development in girls

(premature thelarche), or isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and

apocrine odor) in boys or girls that result from early activation of the hypothalamic pituitary adrenal axis as confirmed by mildly

elevated levels of dehydroepiandrosterone sulfate (DHEAS) for age (premature adrenarche) (table 3). Both of these disorders

can be a variant of normal puberty. However, repeat evaluations are warranted in these children to be certain that the diagnosis

is correct. (See 'Types of benign or non-progressive pubertal variants' below.)

●





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CPP can be treated with a gonadotropin-releasing hormone (GnRH) agonist, which leads to downregulation of the pituitary response

to endogenous GnRH, produces a prepubertal hormonal state, and stops the progression of secondary sexual development,

accelerated growth, and undue bone age advancement. (See "Treatment of precocious puberty", section on 'Treatment for CPP'.)

Idiopathic — CPP is idiopathic in 80 to 90 percent of cases of girls, but in only 25 to 60 percent of boys [20-24].

CNS lesions — Although CPP is idiopathic in up to 90 percent of girls and 60 percent of boys, some cases are caused by lesions of

the central nervous system (CNS), a condition often referred to as neurogenic CPP (table 1). Contrast-enhanced magnetic

resonance imaging (MRI) is therefore recommended, even in the absence of clinically evident neurologic abnormalities [20,22,24].

The low prevalence of CNS lesions in girls with the onset of puberty that begins after age six years raises the question if all girls in

this age group need imaging [23].

Many different types of intracranial disturbances can cause precocious puberty, including the following:

Genetics — Specific genetic mutations have been associated with CPP, although each appears to be present in only a minority of

cases:

Previous excess sex steroid exposure — Children who have been exposed to high serum levels of sex steroid (eg, those with

McCune Albright Syndrome and poorly controlled congenital adrenal hyperplasia) may sometimes develop superimposed CPP,

either from the priming effect of the peripheral precocity-derived sex steroid on the hypothalamus, or in response to the sudden

lowering of the sex steroid levels following improved control of the sexual precocity [38-40]. (See "Treatment of classic congenital

adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Monitoring therapy' and 'McCune-Albright

syndrome' below.)

Pituitary gonadotropin-secreting tumors — These tumors are extremely rare in children and are associated with elevated levels

of LH and/or follicle-stimulating hormone (FSH) [41,42].

CAUSES OF PERIPHERAL PRECOCITY — Peripheral precocity (also known as peripheral precocious puberty or gonadotropin-

independent precocious puberty) is caused by excess secretion of sex hormones (estrogens and/or androgens) derived either from

the gonads or adrenal glands, or from exogenous sources (table 2). Further characterization is based upon whether the sexual

characteristics are appropriate for the child's gender (isosexual) or inappropriate, with virilization of girls and feminization of boys

(contrasexual). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are suppressed (in the prepubertal range)

and do not increase substantially with gonadotropin-releasing hormone (GnRH) stimulation.

Hamartomas – Hamartomas of the tuber cinereum are benign tumors that can be associated with gelastic (laughing or crying)

and other types of seizures [25]. They are the most frequent type of CNS tumor to cause precocious puberty in very young

children, although in most cases, the mechanism by which these tumors lead to CPP is unknown.

●

Other CNS tumors – Other CNS tumors associated with precocious puberty include astrocytomas [26], ependymomas,

pinealomas, and optic and hypothalamic gliomas [22]. Sexual precocity in patients with neurofibromatosis is usually, but not

always, associated with an optic glioma [27]. (See "Clinical manifestations and diagnosis of central nervous system tumors in

children".)

●

CNS irradiation – Precocious puberty caused by CNS irradiation is commonly associated with growth hormone (GH) deficiency

[28]. In this setting, regardless of height velocity, the GH axis should be evaluated. If testing shows GH deficiency, such patients

should be treated with GH combined with GnRH agonist therapy. (See "Endocrinopathies in cancer survivors and others

exposed to cytotoxic therapies during childhood", section on 'Growth hormone (GH) deficiency'.)

●

Other CNS lesions – Precocious puberty has been associated with hydrocephalus, cysts, trauma, CNS inflammatory disease,

and congenital midline defects, such as optic nerve hypoplasia. (See "Congenital anomalies and acquired abnormalities of the

optic nerve", section on 'Hypoplasia'.)

●

Gain-of-function mutations in the Kisspeptin 1 gene (KISS1) [29] and its G protein-coupled receptor KISS1R (formerly known as

GPR54) [30] have been implicated in the pathogenesis of some cases of CPP, while loss-of function mutations in KISS1R can

cause hypogonadotropic hypogonadism. These observations suggest that KISS1/KISS1R is essential for gonadotropin-

releasing hormone physiology and for initiation of puberty [31].

●

CPP also can be caused by loss-of-function mutations in MKRN3 (makorin ring finger protein 3), an imprinted gene in the

Prader-Willi syndrome critical region (15q11-q13). The decline of hypothalamic MKRN3 gene expression in mice [32] and serum

protein levels in girls prior to the onset of puberty [33] suggest that MKRN3 is one of the factors involved in repressing pubertal

initiation. Thus, loss of function mutations in this gene would lead to diminished inhibition and early onset of puberty. Paternally-

inherited loss of function mutations in MKRN3 have been demonstrated to be associated with up to 46 percent of familial cases

of CPP [32,34,35].

●

A loss-of-function mutation in another gene, DLK1 (Delta-like 1 homolog), leads to undetectable serum concentrations of the

DLK1 protein and has been associated with isolated CPP in five members of one family [36]. DLK1 is a paternally expressed

gene, mostly in adrenal, pituitary, and ovarian tissue. No definitive mechanistic link between DLK1 function and pubertal

development has been determined to date, but polymorphisms in this gene as well as in MKRN3 are associated with variation in

the age of menarche in large genome-wide association studies providing further evidence of a mechanistic link [37].

●





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The approach to treatment for peripheral precocity depends on the cause. GnRH agonist therapy is ineffective, in contrast to patients

with central precocious puberty (CPP). (See "Treatment of precocious puberty", section on 'Treatment for peripheral precocity'.)

In the following discussion, the causes of peripheral precocity are described based upon sex.

Girls

Ovarian cysts — A large functioning follicular cyst of the ovaries is the most common cause of peripheral precocity in girls [43].

Affected patients often present with breast development, followed by an episode of vaginal bleeding, which occurs due to estrogen

withdrawal once the cyst has regressed. These cysts may appear and regress spontaneously, so conservative management is

usually appropriate [44]. Large cysts may predispose to ovarian torsion.

Ovarian tumors — Ovarian tumors are a rare cause of peripheral precocity in girls. Granulosa cell tumors, the most common

type, typically present as isosexual precocity; Sertoli/Leydig cell tumors (arrhenoblastoma), pure Leydig cell tumors, and

gonadoblastoma may make androgens and cause contrasexual precocity [45-47]. (See "Sex cord-stromal tumors of the ovary:

Granulosa-stromal cell tumors", section on 'Granulosa cell tumor'.)

Boys

Leydig cell tumors — Leydig cell tumor should be considered in any boy with asymmetric testicular enlargement. Even if a

distinct mass cannot be palpated and none is evident on ultrasonography, the larger testis should be biopsied if it enlarges during

follow-up. These testosterone-secreting tumors are almost always benign and are readily cured by surgical removal [48]. Radical

orchiectomy is the most common procedure; however, successful treatment by direct enucleation of the tumor with sparing of the

remainder of the testis has been reported [49]. (See "Testicular sex cord stromal tumors", section on 'Leydig cell tumors'.)

Human chorionic gonadotropin (hCG)-secreting germ cell tumors — Germ-cell tumors secrete hCG, which in boys activates

LH receptors on the Leydig cells, resulting in increased testosterone production [50]. The increase in testicular size (usually only to

an early pubertal size) is less than expected for the serum testosterone concentration and degree of pubertal development. This is

because most of the testis is made up of tubular elements whose maturation depends upon FSH. In girls, hCG-secreting tumors do

not lead to precocious puberty because activation of both FSH and LH receptors is needed for estrogen biosynthesis.

These tumors occur in the gonads, brain (usually in the pineal region), liver, retroperitoneum, and anterior mediastinum, reflecting

sites of embryonic germ cells before their coalescence in the gonadal ridge [50]. The histology of hCG-secreting tumors ranges from

dysgerminoma, which respond readily to therapy, to the more malignant embryonal cell carcinoma and choriocarcinoma. All males

with anterior mediastinal germinomas should have a karyotype because these tumors may be associated with Klinefelter syndrome.

(See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Pathology of mediastinal tumors", section

on 'Germ cell tumors'.)

Familial male-limited precocious puberty — This rare disorder (also known as testotoxicosis) is caused by an activating

mutation in the LH receptor gene, which results in premature Leydig cell maturation and testosterone secretion [51]. Although

inherited as an autosomal dominant disorder, girls are not affected clinically because (similar to hCG-secreting germ tumors)

activation of both the LH and FSH receptors is required for estrogen biosynthesis [52]. Also similar to hCG-secreting tumors, the

increase in testicular size is usually only to an early pubertal size. Affected boys typically present between one to four years of age.

Treatment of this disorder is discussed separately. (See "Treatment of precocious puberty", section on 'Familial male-limited

precocious puberty'.)

Both girls and boys — The following causes of peripheral precocity can occur in either girls or boys. Physical changes either may

be isosexual or contrasexual depending on the sex of the child and the type of sex hormone produced. Excess estrogen will cause

feminization, while excess androgen will result in virilization.

Primary hypothyroidism — Children with severe, long-standing primary hypothyroidism occasionally present with precocious

puberty. In girls, findings include early breast development, galactorrhea, and recurrent vaginal bleeding, while affected boys present

with premature testicular enlargement [53-55]. Historically this has been referred to as the "overlap" or Van Wyk-Grumbach

syndrome [56]. The signs of pubertal development regress with thyroxine therapy. (See "Acquired hypothyroidism in childhood and

adolescence".)

A proposed mechanism is cross-reactivity and stimulation of the FSH receptor by high serum thyrotropin (TSH) concentrations, given

that both TSH and FSH share a common alpha subunit [57].

Exogenous sex steroids — Feminization, including gynecomastia in boys, has been attributed to excess estrogen exposure

from creams, ointments, and sprays. Caretakers using these topical estrogens to treat menopausal symptoms may inadvertently

expose children to the hormones [58,59]. Other possible sources of estrogen exposure include contamination of food with hormones,

phytoestrogens (eg, in soy), and folk remedies such as lavender oil and tea tree oil [60,61]. A food source was suspected for local

"epidemics" of early thelarche in Italy and Puerto Rico during the 1980s, but no single causative substance was found in food

samples [62-64]. Similarly, virilization of young children has been described following inadvertent exposure to androgen-containing

creams [65,66].

Adrenal pathology — Adrenal causes of excess androgen production include androgen-secreting tumors and enzymatic defects

in adrenal steroid biosynthesis (congenital adrenal hyperplasia). Boys who have an adrenal cause for their precocity will not have





126

testicular enlargement (testes will be <4 mL testicular volume or <2.5 cm in diameter). (See "Genetics and clinical presentation of

nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Premature pubarche may be the presenting feature of an inherited disorder of adrenal steroid metabolism, including 21-hydroxylase

deficiency, 11-beta hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase type 2 deficiency, hexose-6-phosphate

dehydrogenase deficiency, and PAPSS2 deficiency. (See "Uncommon congenital adrenal hyperplasias".)

Adrenal estrogen-secreting tumors can lead to feminization. Rarely, adrenal tumors may produce androgen and estrogen, the latter

because of intra-adrenal aromatization of androgen (or production of enough androgen that is peripherally aromatized to estrogen),

causing both male and female pubertal changes [67]. (See "Clinical presentation and evaluation of adrenocortical tumors".)

McCune-Albright syndrome — McCune-Albright Syndrome (MAS) is a rare disorder defined as the triad of peripheral

precocious puberty, irregular café-au-lait ("Coast of Maine") skin pigmentation (picture 2), and fibrous dysplasia of bone (image 1)

[68]. MAS should be considered in girls with recurrent formation of follicular cysts and cyclic menses [69]. The skin manifestations

and bone lesions may increase over time. In girls presenting with vaginal bleeding, the ovarian enlargement has often been mistaken

for an ovarian tumor, leading to unnecessary oophorectomy [70]. Girls presenting with premature vaginal bleeding should therefore

be evaluated for features of McCune-Albright syndrome to avoid this potential mistake.

The clinical phenotype varies markedly, depending on which tissues are affected by the mutation, but precocious puberty is the most

commonly reported manifestation [71]. As in other forms of peripheral precocity, the sequence of pubertal progression may be

abnormal, in that vaginal bleeding often precedes significant breast development [72]. Prolonged exposure to elevated levels of sex

steroids may cause accelerated growth, advanced skeletal maturation, and compromised adult height. Although the precocious

puberty is typically peripheral precocity, a secondary component of CPP may develop because of sex steroid withdrawal leading to

activation of the hypothalamic-pituitary-gonadal axis [73] (see 'Previous excess sex steroid exposure' above). In boys with MAS,

while sexual precocity is less common, there is a high prevalence of testicular pathology on ultrasound, including hyper-and

hypoechoic lesions (most likely representing areas of Leydig cell hyperplasia), microlithiasis, and focal calcifications [74].

Patients with MAS have a somatic (postzygotic) mutation of the alpha subunit of the Gs protein that activates adenylyl cyclase [75-

77]. This mutation leads to continued stimulation of endocrine function (eg, precocious puberty, thyrotoxicosis, gigantism or

acromegaly, Cushing syndrome, and hypophosphatemic rickets) in various combinations. Mutations can be found in other non-

endocrine organs (liver and heart) resulting in cholestasis and/or hepatitis, intestinal polyps, and cardiac arrhythmias, respectively. A

heightened risk of malignancy has also been reported [78]. Germline occurrences of this mutation would presumably be lethal

[75,77,79,80].

Treatment of MAS is described in a separate topic review. (See "Treatment of precocious puberty", section on 'McCune-Albright

syndrome'.)

TYPES OF BENIGN OR NON-PROGRESSIVE PUBERTAL VARIANTS — Early pubertal development fits into this category when

the early development of secondary sexual characteristics does not herald underlying pathology and is not followed by progressive

development (table 3). However, monitoring for evidence of pubertal progression is important, as some children presenting with an

apparent benign pubertal variant will instead turn out to have a different disorder. As examples, thelarche may be the initial

presenting feature of central precocious puberty (CPP), or progressive pubic hair development may herald a form of peripheral

precocity.

Premature thelarche — Most cases of premature thelarche are idiopathic and present under two years of age (and may even start

at birth). Many cases will remit spontaneously, and most others do not progress. However, follow-up is warranted because

premature thelarche can represent the initial presentation of true CPP in 10 to 20 percent of children referred to pediatric endocrine

units [81-83].

Key features of premature thelarche are:

Serum luteinizing hormone (LH) and estradiol concentrations are typically in the prepubertal range, but one should be cautious in

interpreting these levels in children under the age of two years because elevations can be seen as part of the normal transient "mini-

puberty of infancy," and CPP can be diagnosed inappropriately (See 'Normal pubertal development' above.)

Toddlers and children — Premature thelarche occurs in two peaks: one during the first two years of life and the other at six to

eight years of age [83], with potentially different underlying pathophysiology accountable for each of these peaks. Postulated

mechanisms include transient activation of the hypothalamic-pituitary-gonadal axis with excess follicle-stimulating hormone (FSH)

secretion [84]. In infants, soy-based formulas have been implicated, although the evidence is weak and may represent only a slower

waning of breast tissue during infancy [85-87]. Use of lavender oil, tea tree oil, or hair care products that contain placental extract

has also been implicated in some cases of premature thelarche [60]. In most instances, no cause can be found.

Isolated breast development, either unilateral or bilateral – Typically not developing beyond Tanner stage 3●

Absence of other secondary sexual characteristics●

Normal height velocity for age (not accelerated)●

Normal or near-normal bone age●





127

In most cases, premature thelarche requires only reassurance. However, the patient should be examined for other signs of pubertal

development, and growth data should be plotted; an accelerated height velocity may be indicative of progressive puberty and

requires further evaluation. To identify patients with progressive puberty, patients should be monitored for several months for

evidence of pubertal progression. (See 'Evaluation' below.)

Neonates — Breast hypertrophy can occur in neonates of both sexes, and is sometimes quite prominent. It is caused by

stimulation from maternal hormones and usually resolves spontaneously within a few weeks or months. The breast development

may also be associated with galactorrhea ("witch's milk"), which also resolves spontaneously [88]. While in most cases neonatal

thelarche disappears over the first months of life, failure to do so almost never has any pathologic significance. (See "Breast masses

in children and adolescents", section on 'Neonates and infants'.).

Premature adrenarche — Premature adrenarche is characterized by the appearance of pubic and/or axillary hair (pubarche) prior

to the age of eight years in girls and nine years in boys, in conjunction with a mild elevation in serum dehydroepiandrosterone sulfate

(DHEAS) for age. It is more common in girls, African-American and Hispanic females, and individuals with obesity and insulin

resistance [15]. Premature adrenarche is considered a variant of normal development, but may be a risk factor for later development

of polycystic ovary disease in girls. (See "Premature adrenarche" and "Definition, clinical features and differential diagnosis of

polycystic ovary syndrome in adolescents".)

In the child presenting with isolated adrenarche, monitoring for the development of other secondary sexual characteristics (breast or

testicular enlargement) is important to ensure that the child's presentation is not the first feature of CPP or a form of peripheral

precocity. Premature adrenarche can be associated with mild growth acceleration and advance in bone age. In children with

progressive virilization or with a more advanced bone age (>2 standard deviations [SD] beyond chronological age), further

investigation for other causes of early pubertal development should be considered. (See "Premature adrenarche", section on

'Evaluation of premature pubarche'.)

Pubic hair of infancy — Pubic hair of infancy is usually a benign condition where infants present with isolated genital hair, usually

finer in texture than typical pubic hair and located along the labia or over the scrotum (rather than on the pubic symphysis) [89-91].

The steroid profile of these infants demonstrates normal or mildly elevated DHEAS concentrations for age. Unlike premature

adrenarche, the condition is transient and the hair typically disappears within 6 to 24 months [92]. In the absence of progressive

development of further genital hair or other secondary sexual characteristics during follow-up, extensive evaluation is not needed.

Benign prepubertal vaginal bleeding — Benign prepubertal vaginal bleeding is characterized by the presence of isolated, self-

limited vaginal bleeding in the absence of other secondary sexual characteristics [93]. The underlying etiology is unknown but

potential mechanisms include increased endometrial sensitivity to circulating estrogens or transient stimulation of the HPG axis [94].

Pelvic ultrasonography is normal and gonadotropins are pre-pubertal. Genital or vaginal trauma, infection, and sexual abuse should

be excluded. In girls with recurrent episodes of vaginal bleeding, other diagnoses such as recurrent functional ovarian cysts or

McCune Albright Syndrome should be considered. (See 'McCune-Albright syndrome' above.)

Non-progressive or intermittently progressive precocious puberty — A subgroup of patients presenting with what clinically

appears to be CPP (often with evidence of both gonadarche and pubarche) will either have stabilization or very slow progression in

their pubertal signs [95]. The bone age is typically not as advanced compared with children with true CPP, and serum LH

concentrations are within the pre- or early-pubertal range, indicating that the hypothalamic-pituitary-gonadal axis is not fully activated

and a FSH-predominant response is typically seen if gonadotropin-releasing hormone agonist (GnRHa) stimulation testing is

performed. Monitoring for evidence of pubertal progression is important to distinguish these children from those with true CPP. In

children with non-progressive precocious puberty, treatment with a GnRHa is not needed because their adult height is not affected

(ie, their final height untreated is concordant with their midparental height) [95,96].

EVALUATION

Guiding principles — The evaluation for precocious puberty focuses on answering the following questions:

Who should be evaluated? – Evaluation is warranted in children presenting with signs of secondary sexual development

younger than the age of eight (girls) or nine (boys) years. The concern and extent of evaluation should increase with decreasing

age at presentation. In girls who are between the ages of seven and eight, a comprehensive history and physical examination

may be sufficient if this examination does not raise any additional concerns.

●

Is the cause of precocity central or peripheral? – The sequence of pubertal development in children with central precocious

puberty (CPP) recapitulates normal pubertal development but at an earlier age (figure 1A-B). By contrast, individuals with

peripheral precocity have a peripheral source of gonadal hormones and are more likely to display deviations from the normal

sequence and/or pace of puberty. As an example, a girl who progresses to menstrual bleeding within one year of the onset of

breast development is more likely to have ovarian pathology (a cause of peripheral precocity) rather than CPP [97,98].

●

How quickly is the puberty progressing? – The pace of pubertal development reflects the degree and duration of sex steroid

action.

●

A rapid rate of linear growth and skeletal maturation (measured as advanced bone age) suggests either CPP or peripheral

precocity with high concentrations of sex steroids (table 4). Pubertal progression would be considered slow if there is

minimal or no change in stage of breast, pubic hair, or genital development during six or more months of observation.

Height velocity is considered accelerated if it is more than the 95 percentile for age (figure 3A-B).

•

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128

Initial evaluation — The evaluation of a patient suspected to have precocious puberty begins with a history and physical

examination. In most cases, radiographic measurement of bone age is performed to determine whether there is a corresponding

increase in epiphysial maturation.

Initial laboratory evaluation — If there is evidence of progressive development of secondary sexual characteristics, further

evaluation is needed to determine its cause, whether therapy is needed, and, if so, which treatment is appropriate.

The first step is to measure basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and either estradiol and/or

testosterone concentrations. The results are used to differentiate between CPP and peripheral precocity, which then guides

additional testing (algorithm 1 and table 4).

Basal serum LH — A good initial screening test to identify activation of the hypothalamic-pituitary-gonadal axis is measurement

of basal LH concentration (ideally in the morning), using sensitive immunochemiluminescence assays with a lower limit of detection

of ≤0.1 mIU/mL (where mIU = milli-International Units) [104]. Results are interpreted as follows:

By contrast, a child with normal linear growth and skeletal maturation (bone age normal or minimally advanced) suggests a

benign pubertal variant with low concentrations of sex steroids, rather than true CPP or peripheral precocity.

•

Is the precocity because of excess androgen or estrogen? – Are the secondary sexual characteristics virilizing or

feminizing? Isolated contrasexual development (isolated virilization in girls or isolated feminization in boys) excludes central

etiologies. While in girls the most common cause of virilization is due to excess adrenal androgens, a rare ovarian cause of

virilization is ovarian arrhenoblastoma (Sertoli-Leydig cell tumor) [99]. Conversely, a rare testicular cause of feminization is a

feminizing Sertoli cell tumor, which may be associated with Peutz-Jeghers syndrome [100]. (See "Sex cord-stromal tumors of

the ovary: Sertoli-stromal cell tumors", section on 'Clinical features' and "Testicular sex cord stromal tumors", section on 'Sertoli

cell tumors'.)

●

Medical history – The history focuses on when the initial pubertal changes were first noted, as well as the timing of pubertal

onset in the parents and siblings. In addition, other questions are directed toward evidence of linear growth acceleration,

headaches, changes in behavior or vision, seizures, or abdominal pain (indicative of either a central nervous system [CNS] or

ovarian process) and previous history of CNS disease or trauma. The possibility of exposure to exogenous sex steroids

(medicinal or cosmetic sources) or compounds with sex-steroid-like properties should always be explored [58].

●

Physical examination – This includes height, weight, and height velocity (cm/year). Children with benign forms of precocious

puberty do not usually display the early growth acceleration pattern that is seen among those with progressive forms of

precocious puberty [101]. The physical examination should include assessment of visual fields (a defect suggests the possibility

of a CNS mass) and examination for café-au-lait spots (which would suggest neurofibromatosis or McCune-Albright syndrome)

(picture 2). (See 'McCune-Albright syndrome' above.)

●

Pubertal staging – Secondary sexual development should be assessed to determine the sexual maturity rating (Tanner stage)

of pubertal development. This means staging breast development in girls (picture 1A), genital development in boys, and pubic

hair development in both sexes (picture 1B-C). In girls, the diameter of glandular breast tissue (by direct palpation including

compression to differentiate from adipose tissue when warranted) and the nipple-areolar complex should be assessed. In boys,

measurements are made of the testicular volume (figure 4) [102]. Penile size (stretched length of the non-erect penis,

measuring from the pubic bone to tip of glans, excluding the foreskin) is rarely used for monitoring of pubertal progress because

penile growth is not an early event in puberty, accurate measurement is difficult and may be awkward for the adolescent boy,

and the "pubertal threshold" for penile-stretched length is not as clear as it is for testicular volume. Accurate measurements of

testicular volume are critical to determine whether further radiologic or laboratory testing is necessary. (See "Normal puberty",

section on 'Sexual maturity rating (Tanner stages)' and "Normal puberty", section on 'Sequence of pubertal maturation'.)

●

Bone age – In patients with early development of secondary sexual characteristics confirmed by physical examination,

evaluation of skeletal maturation by radiographic assessment of bone age can help with both the differential diagnosis and

assessment of whether there may be an impact on final height. However, in patients presenting with typical features indicative of

either isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for

pubertal progression is likely sufficient.

●

A significant advance in the bone age (greater than approximately 2 standard deviations [SD] beyond chronological age) is more

likely to be indicative of either CPP or peripheral precocity, rather than a benign pubertal variant. A significantly advanced bone

age does not, however, exclude a diagnosis of a benign pubertal variant. As an example, up to 30 percent of children with

benign premature adrenarche have bone ages more than two years in advance of their chronological age [103]. (See 'Types of

benign or non-progressive pubertal variants' above.)

LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal

variant such as premature thelarche.

●

LH concentrations greater than 0.2 to 0.3 mIU/mL (the threshold depends on the assay used) can identify children with

progressive CPP with high sensitivity and specificity [105,106].

●

LH concentrations are less informative in the evaluation of children with non-progressive or intermittently progressive precocious

puberty. While such children typically have basal LH concentrations <0.2 to 0.3 mIU/mL, levels can be in the early pubertal

●





129

Care should be used in the interpretation of LH levels in girls under the age of two years, as gonadotropin concentrations may be

elevated at this age in association with the "mini-puberty of infancy" and CPP can be misdiagnosed during this phase of

development [10,107].

An emerging approach is to identify cases of progressive CPP using first-morning urinary gonadotropin levels. These early results

need further validation, but this could be an important alternative diagnostic strategy in the future [108,109].

Basal serum FSH — Basal FSH concentrations have limited diagnostic utility in distinguishing children with CPP from those with

benign pubertal variants. FSH concentrations are often higher in children with CPP compared with benign pubertal variants, but

there is substantial overlap between these groups of children [104,105]. Like LH, FSH concentrations are typically suppressed in

children with peripheral precocity.

Serum estradiol — Very high concentrations of estradiol, with associated suppression of gonadotropins, are generally indicative

of peripheral precocity, such as from an ovarian tumor or cyst. Most estradiol immunoassays, however, have poor ability to

discriminate at the lower limits of the assay between prepubertal and early pubertal concentrations [110]. More sensitive methods of

estimating estradiol concentrations, such as tandem mass spectrometry, distinguish better between pre-pubertal and pubertal

estradiol concentrations [111], and should be ordered exclusively. However, further studies are still needed to clarify threshold

concentrations.

Serum testosterone — Elevated testosterone concentrations are indicative of testicular testosterone production in boys, or of

adrenal testosterone production or exogenous exposure in both sexes. Very high concentrations, with associated suppression of

gonadotropins, are generally indicative of peripheral precocity. Measurement of other adrenal steroids (eg, dehydroepiandrosterone

sulfate [DHEAS]) may be necessary to help discriminate between adrenal and testicular sources of the androgens. In children with

CPP, testosterone immunoassays cannot always distinguish between prepubertal and early pubertal testosterone concentrations,

but tandem mass spectroscopy methods are more discriminative [112] (similar to the estradiol assays discussed above), so these

should be ordered whenever available.

Subsequent laboratory testing — Subsequent laboratory testing depends on the results of the tests outlined above (basal LH,

FSH, and estrogen or testosterone), and on the patient's clinical characteristics:

Serum LH concentrations after GnRH agonist stimulation — In children in whom the clinical picture is discordant with the

initial baseline investigations (ie, ongoing pubertal progression with basal LH level <0.3 mIU/mL), a gonadotropin-releasing hormone

(GnRH) stimulation test may help differentiate those with CPP from those with a benign pubertal variant. This test consists of

measurement of serum LH concentrations before and after administration of GnRH. GnRH is not available in the United States; a

GnRH agonist may be used instead because of the initial stimulatory effect on the hypothalamic-pituitary-gonadal (HPG) axis

following a single dose of a GnRH agonist.

A common protocol is as follows:

The results are interpreted as follows:

As with basal LH levels, care must be taken in interpreting the results of GnRH stimulation test in girls under the age of two years, as

both basal and stimulated LH levels can be elevated as part of the normal hormonal changes associated with the mini-puberty of

infancy [107].

range in some children. Additional clinical characteristics such as lack of progression in secondary sexual characteristics or low

LH/FSH ratio post-gonadotropin stimulation test can help to differentiate these children from those with progressive CPP. (See

'Serum LH concentrations after GnRH agonist stimulation' below.)

Blood is sampled at baseline for LH, FSH, and either estradiol in girls or testosterone in boys. ●

The child is then given a single dose of GnRH at a dose of 100 mcg or the GnRH agonist leuprolide acetate at a dose of 20

mcg/kg.

●

LH is measured at 30 to 40 minutes post-GnRH or 60 minutes post-GnRH agonist [113-115]. Other protocols employ sampling

every 30 minutes for up to two hours [113,116] or testing of estradiol or testosterone 24 hours later [117,118].

●

Peak stimulated LH – The optimal cutoff value of peak stimulated LH for identifying children with CPP has not been established,

and varies somewhat among assays. For most LH assays, a value of 3.3 to 5 mIU/mL defines the upper limit of normal for

stimulated LH values in prepubertal children [113,119]. Stimulated LH concentrations above this normal range suggest CPP.

●

Peak stimulated LH/FSH ratio – Children with progressive CPP tend to have a more prominent LH increase post-stimulation,

and higher peak LH/FSH ratios, compared with those with non- or intermittently progressive precocious puberty [117,120]. While

a definite diagnostic threshold has not been well defined, a peak LH/FSH ratio >0.66 is typically seen with CPP, whereas a ratio

<0.66 suggests non-progressive precocious puberty [120].

●

Stimulated estradiol / testosterone – Children with progressive CPP tend to have higher stimulated serum estradiol and

testosterone concentrations when measured 24 hours after administration of GnRH or GnRH agonist [117,118]. However, the

disadvantage of requiring venipunctures on two consecutive days as well as the lack of consistent published diagnostic

thresholds limits the clinical utility of these measurements.

●





130

Serum adrenal steroids — In children with precocious pubarche, measurement of adrenal steroids may be necessary to help

distinguish between peripheral precocity and benign premature adrenarche. Children with premature adrenarche can have mild

elevation in adrenal hormones, with DHEAS concentrations of 40 to 135 mcg/dL (1.1 to 3.7 micromol/L), and testosterone levels ≤35

ng/dL (1.2 nmol/L) [121]. (See "Premature adrenarche", section on 'Hormonal measurements at baseline'.)

Concentrations above these thresholds warrant further investigation for causes of peripheral precocity, such as non-classical

congenital adrenal hyperplasia and virilizing adrenal tumors. In children with suspected non-classical congenital adrenal hyperplasia

(CAH) secondary to 21- hydroxylase deficiency who have an early morning 17-hydroxyprogesterone (17-OHP) concentration

between 82 ng/dL (2.5 nmol/L) and 200 ng/dL (6 nmol/L), follow-up adrenocorticotropic hormone (ACTH) stimulation testing should

be performed. A 17-OHP value >200 ng/dL has a high sensitivity and specificity for non-classical CAH [122,123], although an ACTH

stimulation test may still be needed to confirm the diagnosis. (See "Diagnosis and treatment of nonclassic (late-onset) congenital

adrenal hyperplasia due to 21-hydroxylase deficiency".)

Other biochemical tests — In boys, human chorionic gonadotropin (hCG) should be measured to evaluate for the possibility of

an hCG-secreting tumor. If a tumor is found in the anterior mediastinum, a karyotype should be performed to evaluate for Klinefelter

syndrome because of its association with mediastinal germinoma [50]. A thyroid-stimulating hormone (TSH) concentration should be

measured if chronic primary hypothyroidism is suspected as the underlying cause for the sexual precocity.

Imaging

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around

the world are provided separately. (See "Society guideline links: Puberty and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the

Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the

four or five key questions a patient might have about a given condition. These articles are best for patients who want a general

overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated,

and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth

information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your

patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of

interest.)

Central precocious puberty●

Brain magnetic resonance imaging (MRI) – We recommend performing a contrast-enhanced brain MRI for all boys with

CPP, and for girls with onset of secondary sexual characteristics before six years of age, because of higher rates of CNS

abnormalities in these groups of patients (see 'CNS lesions' above). In our practice, we usually do not perform MRI for girls

with CPP onset between seven and eight years of age if there is no clinical evidence of CNS pathology and if there is a

family history of earlier pubertal onset, or if the child has an increased body mass index (BMI).

•

In girls with CPP onset after their sixth birthday, there is ongoing debate about the utility of brain imaging in this age group

because of conflicting data about the risk for CNS pathology: In a meta-analysis, the prevalence of intracranial lesions was

3 percent among girls presenting with CPP after six years of age, compared with 25 percent among those presenting before

six years [124]. These findings are in contrast to a study of girls with precocious puberty that was not included in this part of

the meta-analysis, in which 13 of 208 girls (6.3 percent) had related MRI brain abnormalities, all of whom had onset of CPP

after the age of six years [22]. A younger age of onset of pubertal signs and higher basal LH and estradiol concentrations

have been proposed as predictive features for intracranial pathology [22,23,125]. Because these features and clinical

suspicion have been shown to have variable sensitivity to detect girls with abnormal brain MRIs, some have recommended

imaging for all girls with CPP [22,24].

Pelvic ultrasound – Pelvic ultrasonography may be a useful adjunct investigation to help differentiate between CPP and

benign pubertal variants, especially when the evaluation remains equivocal. Girls with CPP have greater uterine and

ovarian volumes compared with girls who are prepubertal or those with premature thelarche [126-129]. Diagnostic

thresholds for uterine and ovarian volumes have been proposed; however, these are variable and some studies have

suggested that there is considerable overlap between patients with and without CPP [126,127].

•

Peripheral precocity●

In girls with progressive peripheral precocity, a pelvic ultrasound can be performed to help identify the presence of an

ovarian cyst or tumor. For suspected adrenal pathology, for example when there is rapid virilization, an adrenal ultrasound

should be strongly considered.

•

Ultrasound examination of the testes can be performed in boys with peripheral precocity to evaluate for the possibility of a

Leydig-cell tumor.

•

In children where an adrenal tumor is suspected (due to evidence of progressive virilization and elevated serum adrenal

androgens, eg, DHEAS), an abdominal ultrasound and/or computerized tomography (CT) abdomen should be performed.

•

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SUMMARY

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Paul Saenger, MD, MACE, who contributed to

an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Boepple PA, Crowley WF Jr. Precocious puberty. In: Reproductive Endocrinology, Surgery, and Technology, Adashi EY, Rock

JA, Rosenwaks Z (Eds), Lippincott-Raven, Philadelphia 1996. Vol 1, p.989.

2. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969; 44:291.

Basics topic (see "Patient education: Early puberty (The Basics)")●

Precocious puberty is defined as the onset of pubertal development more than 2 to 2.5 standard deviations (SD) earlier than the

average age (figure 1A-B). (See 'Definition' above.)

●

Because of the trend of earlier pubertal development, there is controversy about the lower age limit for normal pubertal

development. Nonetheless, we recommend evaluation in children presenting with secondary sexual development younger than

eight years in girls or nine years in boys (figure 2). (See 'Definition' above and 'Evaluation' above.)

●

The etiology of precocious puberty is classified by the underlying pathogenesis into three categories (see 'Classification' above):●

Central precocious puberty (CPP) is caused by an early activation of the hypothalamic-pituitary-gonadal axis. CPP is

pathologic in up to 40 to 75 percent of boys and 10 to 20 percent of girls (table 1). (See 'Causes of central precocious

puberty (CPP)' above.)

•

Peripheral precocity is caused by secretion of sex hormones either from the gonads or adrenal glands, ectopic human

chorionic gonadotropin (hCG) production by a germ cell tumor, or by exogenous sources of sex steroids, and is

independent from the hypothalamic-pituitary-gonadal axis (table 2). (See 'Causes of peripheral precocity' above.)

•

Benign pubertal variants include isolated breast development (premature thelarche), isolated pubic hair development

(premature pubarche/adrenarche), benign pre-pubertal vaginal bleeding, and non-progressive precocious puberty (table 3).

These patterns are usually a variant of normal puberty and require no intervention. If the finding is isolated breast

development or isolated pubarche, and there is no evidence of pubertal progression or accelerated growth, laboratory

evaluation may not be necessary. However, close follow-up is recommended because some of these patients will turn out

to have progressive precocity. (See 'Types of benign or non-progressive pubertal variants' above.)

•

The first step in the laboratory evaluation of progressive development of precocious secondary sexual characteristics is to

measure basal luteinizing hormone (LH), follicle stimulating hormone (FSH), and either estradiol or testosterone concentrations.

The results are used to differentiate between CPP and peripheral precocity, which then guides additional testing (algorithm 1

and table 4). A good initial screening test to distinguish CPP from benign pubertal variants is measurement of a basal LH

concentration (see 'Basal serum LH' above):

●

In CPP, basal LH levels are often elevated into the pubertal range (greater than 0.2 to 0.3 mIU/mL, depending on the

assay).

•

LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign

pubertal variant such as premature thelarche.

•

If the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression with basal LH level

<0.3 mIU/mL), a gonadotropin-releasing hormone (GnRH) stimulation test can be performed to help distinguish CPP from a

benign pubertal variant. Children with CPP have a pubertal (heightened) LH response to GnRH stimulation (table 4). (See

'Serum LH concentrations after GnRH agonist stimulation' above.)

●

Recommendations for imaging depends on the type of precocious puberty (see 'Imaging' above):●

All boys with CPP should have brain imaging because of the high prevalence of central nervous system (CNS) lesions in

this group. While all girls with onset of CPP below the age of six years should also have a contrast-enhanced brain

magnetic resonance imaging (MRI), there is ongoing controversy about the need for more routine imaging of girls between

the ages of six and eight years.

•

Boys with peripheral precocity may warrant an ultrasound examination of the testes to evaluate for the possibility of a

Leydig-cell tumor. Girls with peripheral precocity may warrant a pelvic ultrasound performed to help identify the presence of

an ovarian cyst or tumor. In both sexes, ultrasound of the adrenal glands may be indicated if adrenal pathology is

suspected, and should be performed if there is suspicion for an adrenal tumor.

•

Other than a bone age, no further imaging is usually required for children with benign or non-progressive pubertal variants.•





132

Central (gonadotropin-dependent) precocious puberty

Etiology Clinical features Bone age Additional evaluation

Idiopathic

(80 to 90% of girls with CPP, and

25 to 60% of boys with CPP)

Early progressive pubertal development,

but proceeds in normal sequence.

↑↑ Increased ovarian and uterine volumes

on ultrasound may help differentiate girls

with CPP from those with premature

thelarche.

Contrast enhanced MRI to rule out CNS

abnormality.

Secondary to CNS lesions

(eg, hypothalamic hamartomas,

other CNS tumors and lesions,

cranial radiation)

Early progressive pubertal development,

but proceeds in normal sequence.

Central precocious puberty secondary to

a CNS lesion occurs more commonly in

boys and younger children.

↑↑

Post early exposure to sex

steroids

(after treatment for peripheral

precocity)

History of treatment of peripheral

precocity.

Progressive pubertal development with

breast development in girls and

testicular enlargement in boys.

↑↑ Basal and stimulated LH concentrations

are pubertal.

Central precocious puberty is characterized by basal LH concentrations >0.2 to 0.3 mIU/L, and/or stimulated LH concentration post GnRH

or GnRHa of >3.3 to 5.0 mIU/L.

↑↑: significantly advanced for chronological age (eg, ≥ 2 standard deviations); CPP: central precocious puberty; CNS: central nervous system; LH:

luteinizing hormone; MRI: magnetic resonance imaging; GnRH: gonadotropin-releasing hormone; GnRHa: gonadotropin-releasing hormone agonist.







133

Peripheral precocity (gonadotropin-independent precocious puberty)

Etiology Clinical featuresBone

ageAdditional evaluation

Girls only

Ovarian cysts Breast development and/or vaginal bleeding.

Occasionally presents with ovarian torsion and

abdominal pain.

↑ to ↑↑ Pelvic ultrasound may visualize the cyst,

although in some cases the cyst may have

involuted by the time of the study. Vaginal

bleeding is indicative of estrogen withdrawal.

Recurrent ovarian cysts suggest McCune

Albright Syndrome.

Ovarian tumor Development of either isosexual or contrasexual

sexual precocity, depending of tumor type.

↑↑ Pelvic ultrasound

Boys only

Leydig cell tumor Asymmetrical enlargement of the testes. ↑↑ Pubertal testosterone concentrations. Testicular

ultrasound aids in diagnosis.

hCG-secreting germ

cell tumors



expected for degree of pubertal development.


because hCG only activates LH receptors

(estrogen biosynthesis in the ovaries requires

both FSH and LH receptor activation).

↑↑ These tumors may occur in gonads, brain, liver,

retroperitoneum, or mediastinum.

When a tumor is identified in the anterior

mediastinum, a karyotype must be performed

because of an association of this finding with

Klinefelter syndrome.

Familial male-limited

precocious puberty



expected for degree of pubertal development;

spermatogenesis may occur.

Familial: Male-limited autosomal dominant trait.


because there is only activation of the LH

receptors (ovarian estrogen biosynthesis

requires both FSH and LH receptor activation).

↑↑ Genetic testing for mutations of the LH receptor

gene (LHCGR).

Girls and boys

Exogenous sex steroids

(estradiol and

testosterone creams)

Estrogen preparations cause feminization, while

topical androgens cause virilization in both

sexes.

↑ to ↑↑ Clinical history explores use of exogenous sex

steroids and folk remedies by caretakers.

McCune-Albright

syndrome

(girls>boys)

In girls, may present with recurrent episodes of

breast development, regression and vaginal

bleeding. In boys, sexual precocity less

common.

Skin: Multiple irregular-edged café-au-lait spots.

Bone: Polyostotic fibrous dysplasia.

↑ to ↑↑ Ultrasound: Ovaries enlarged, with follicular

cysts. In boys, testicular ultrasound can

demonstrate hyper-and hypoechoic lesions

(most likely representing areas of leydig cell

hyperplasia), microlithiasis and focal

calcifications.

May have other hyperactive endocrine

disorders: ie, thyrotoxicosis, glucocorticoid

excess and/or gigantism.

Primary hypothyroidism Girls: vaginal bleeding, breast development and

galactorrhea.

Boys: testicular enlargement.

Other clinical features of hypothyroidism such

as short stature.

↓ Elevated TSH

Congenital adrenal

hyperplasia

(untreated)

Boys have prepubertal testes with enlarged

phallus and pubic hair development. Girls with

"nonclassic" CAH may present with early pubic

and/or axillary hair, and other signs of androgen

excess.

↑↑ Sex hormone levels vary depending on the

adrenal enzyme block. An early morning 17-

OHP >200 ng/dL (6 nmol/L) has a high

sensitivity and specificity for congenital adrenal

hyperplasia secondary to 21 hydroxylase

deficiency. ACTH stimulation test is

recommended to confirm the diagnosis of CAH if

the 17-OHP level is intermediate (eg, between

200 and 1500 ng/dL). After therapy with

glucocorticoids, CPP may develop.

Virilizing adrenal tumor Boys: pubic and/or axillary hair and penile

growth with pre-pubertal testes.

Girls: pubic and/or axillary hair, other significant

signs of androgen excess (acne and

clitoromegaly).

May present with signs of glucocorticoid excess.

May be associated with hereditary cancer

syndromes.

↑↑ High DHEA or DHEAS, androstenedione and

testosterone.

CT and/or ultrasound of adrenal glands to locate

tumor.





134

Types of benign pubertal variants

Etiology Clinical Features Bone Age Additional Evaluation

Premature adrenarche

(boys or girls)

Isolated pubarche. Gonads are prepubertal in

size and there is no breast development in girls.

Typical age of onset four to eight years.

Seen more commonly in African-American and

Hispanic girls and in children with obesity and

insulin resistance.

↑ to ↑↑* Further investigations needed only if there is

significant progressive virilization, to help

exclude peripheral precocity.

Mild elevation in DHEAS for chronological age

(but appropriate for bone age).

Prepubertal concentrations of 17-

hydroxyprogesterone and testosterone.

Premature thelarche

(girls)

Isolated breast development with normal

growth velocity.

Most commonly seen in girls less than three

years of age.

Normal

(prepubertal)

No further evaluation needed in most cases,

unless evidence of pubertal progression.

Basal LH concentrations typically <0.2 to 0.3

mIU/L.

Non-progressive or

intermittently

progressive precocious

puberty

(boys or girls)

Development of gonadarche (breast or

testicular enlargement) with pubarche (pubic

and/or axillary hair), with either no progression

or intermittent slow progression in clinical

pubertal signs.

Normal to ↑ Basal LH concentrations typically <0.2 to 0.3

mIU/L, although can be in early pubertal range

in some children.

Lower stimulated LH/FSH ratio compared with

children with progressive central precocious

puberty.

Patients with non-progressive precocious

puberty do not need treatment with GnRH

agonist, because final height untreated is

concordant with mid-parental height.

If further evaluation is needed and performed, patients with benign pubertal variants typically have pre-pubertal basal LH concentrations

(<0.2 to 0.3 mIU/L) and/or stimulated LH concentration post GnRHa of <3.3 to 5.0 mIU/L.

↑: elevated for chronological age; DHEAS: dehydroepiandrosterone sulfate; LH: luteinizing hormone; FSH: follicle-stimulating hormone; GnRH:

gonadotropin-releasing hormone.

* Up to 30% of children with premature adrenarche can have a bone age more than two years advanced than their chronological age.

¶ Interpretation of basal LH and stimulated LH concentrations can be difficult in girls younger than two years of age because normal gonadotropin

concentrations can be elevated as part of the mini-puberty of infancy.[2]

Δ A peak LH/FSH ratio <0.66 suggests non-progressive precocious puberty, whereas a ratio >0.66 is typically seen with central precocious puberty.

1. DeSalvo, DJ, Mehra R, Vaidyanathan P, Kaplowitz PB. In children with premature adrenarche, bone age advancement by 2 or more years is

common and generally benign. J Pediatr Endocrinolo Metab 2013; 26: 215.

2. Bizzarri C, Spadoni G, Bottaro G et al. The response to gonadotropin releasing hormone (GnRH) stimulation test does not predict the

progression to true precocious puberty in girls with onset of premature thelarche in the first three years of life. JCEM 2014; 99:433.

3. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab

1990; 71:1251.


¶

Δ

[1]

[3]





135

Clinical characteristics of forms of early pubertal development

Nonprogressive

precocious puberty

Central precocious

puberty (CPP)Peripheral precocity

Physical examination:

Advancement through

pubertal stages (Tanner

stage)

No progression in Tanner staging

during 3 to 6 months of

observation

Progression to next pubertal

stage in 3 to 6 months

Progression

Growth velocity Normal for bone age Accelerated (>6 cm per year)* Accelerated*

Bone age Normal to mildly advanced Advanced for height age Advanced for height age

Serum estradiol concentration

(girls)

Prepubertal Prepubertal to pubertal Increased in ovarian causes of

peripheral precocity, or with

exogenous estrogen exposure

Serum testosterone

concentration (boys, or girls

with virilization)

Prepubertal Prepubertal to pubertal Pubertal and increasing

Basal (unstimulated) serum

LH concentration

Prepubertal Pubertal Suppressed or prepubertal

GnRH (or GnRHa) stimulation

test

LH peak in the prepubertal

range

Lower stimulated LH to FSH

ratio

LH peak elevated (in the pubertal

range)

Higher stimulated LH to FSH

ratio

No change from baseline, or LH

peak in the prepubertal range

CPP: central precocious puberty (also known as gonadotropin-dependent precocious puberty); LH: luteinizing hormone; GnRH: gonadotropin-

releasing hormone; GnRHa: gonadotropin-releasing hormone agonist; FSH: follicle-stimulating hormone.

* UNLESS the patient has concomitant growth hormone deficiency (as in the case of a neurogenic form of CPP), or has already passed his or her

peak height velocity at the time of evaluation, in which case growth velocity may be normal or decreased for chronological age.

¶ Using most commercially available immunoassays, serum concentrations of gonadal steroids have poor sensitivity to differentiate between

prepubertal and early pubertal concentrations.

Δ In most cases these levels will be prepubertal, however in children with intermittently progressive CPP, these levels may reach pubertal

concentrations during times of active development.

◊ Using ultrasensitive assays with detection limit of LH <0.1 mIU/L, prepubertal basal LH concentrations are <0.2 to 0.3 mIU/L.

§ In most laboratories, the upper limit of normal for LH after GnRH stimulation is 3.3 to 5.0 mIU/mL. Stimulated LH concentrations above this

normal range suggests CPP.

¥ A peak stimulated LH/FSH ratio <0.66 usually suggests non-progressive precocious puberty, whereas a ratio >0.66 is typically seen with CPP.

Reference:

1. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab

1990; 71:1251.

Courtesy of Drs. Mark Palmert and Jennifer Harrington.


¶

Δ

¶

Δ

¶

Δ◊ ◊ ◊

¶ Δ§

¥

§

¥

[1]





136

An Pediatr (Barc). 2012;76(4):229.e1---229.e10

www.elsevier.es/anpediatr

ARTÍCULO ESPECIAL

Pubertad precoz periférica: fundamentos clínicosy diagnóstico-terapéuticos

L. Soriano Guilléna y J. Argenteb,∗

a Unidad de Endocrinología Infantil, Servicio de Pediatría, Laboratorio de Endocrinología, Instituto de Investigación

Biomédica-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Espanab Servicios de Pediatría y Endocrinología, Hospital Infantil Universitario Nino Jesús, Departamento de Pediatría, Universidad

Autónoma de Madrid, CIBER Fisiopatología de la obesidad y nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Espana

Recibido el 12 de septiembre de 2011; aceptado el 14 de septiembre de 2011Disponible en Internet el 25 de noviembre de 2011

PALABRAS CLAVEPubertad precozperiférica;Síndrome deMcCune-Albright;Testotoxicosis

Resumen La pubertad precoz periférica (PPP) es el resultado de la aparición anormalmenteprecoz de la pubertad, debido al aumento de esteroides sexuales sin evidenciarse activacióndel eje hipotálamo-hipófiso-gonadal. Es una patología mucho más infrecuente que la pubertadprecoz central (PPC) y es secundaria a trastornos de origen genético o a patologías adquiridasmuy heterogéneas.

En los últimos anos, los avances moleculares han contribuido notablemente en el conoci-miento de la fisiopatología de algunos de estos trastornos, muy en particular, en el síndrome deMcCune-Albright y la testotoxicosis. Asimismo, las técnicas de imagen y de cuantificación hor-monal han permitido mejorar el diagnóstico precoz de trastornos adquiridos, especialmente,patología tumoral causante de PPP.

Desafortunadamente, los avances médicos objetivados en el diagnóstico no se han visto refle-jados en el tratamiento médico del síndrome de McCune-Albright y la testotoxicosis. A pesar dehaber probado diversas opciones terapéuticas en ambos trastornos, a día de hoy, los resultadosson muy desalentadores, especialmente en el síndrome de McCune-Albright. A nuestro enten-der, este fracaso se sustenta en la ausencia de ensayos clínicos bien disenados con la inclusiónde un número adecuado de pacientes seguidos hasta el final de su crecimiento.© 2011 Asociación Española de Pediatría. Publicado por Elsevier España, S.L. Todos los derechosreservados.

KEYWORDSMcCune-Albrightsyndrome;Peripheral precociouspuberty;Testotoxicosis

Peripheral precocious puberty: clinical, diagnostic and therapeutical principles

Abstract Peripheral precocious puberty (PPP) is the result of the presence of precociouspuberty due to the increase of sex steroids with no evidence of activation of the hypothalamic-pituitary-gonadal axis. It is much less common than central precocious puberty (CPP) and it issecondary to either genetic disorders or very heterogeneous acquired diseases.

∗ Autor para correspondencia.Correo electrónico: [email protected] (J. Argente).

1695-4033/$ – see front matter © 2011 Asociación Española de Pediatría. Publicado por Elsevier España, S.L. Todos los derechos reservados.doi:10.1016/j.anpedi.2011.09.014

Document downloaded from http://www.elsevier.es, day 30/10/2018. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.Document downloaded from http://www.elsevier.es, day 30/10/2018. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.



137

229.e2 L. Soriano Guillén, J. Argente

In recent years, molecular advances have made remarkable progress in understanding thepathophysiology of some of these disorders, most notably in McCune-Albright syndrome andtestotoxicosis. In addition, new imaging techniques and better hormone assays have improvedthe early diagnosis of acquired disorders, particularly tumour disease causing PPP.

Unfortunately, medical advances in the diagnosis of these disorders have not been reflectedin the medical treatment of McCune-Albright syndrome and testotoxicosis. Despite having triedvarious treatment options in both disorders, the results are very disappointing, especially inpatients with McCune-Albright syndrome. To our knowledge, this failure is based on the absenceof well-designed clinical trials that include an adequate number of patients followed up untilthe end of their growth.© 2011 Asociación Española de Pediatría. Published by Elsevier España, S.L. All rights reserved.

Introducción

El término pubertad precoz periférica (PPP) se utilizapara designar aquellos cuadros clínicos de pubertad pre-coz (aparición de caracteres sexuales junto a adelanto dela maduración ósea y aceleración del crecimiento antes delos 8 anos en ninas y 9 anos en ninos) que no son mediados porel eje hipotálamo-hipófiso-gonadal; es decir, aquellas situa-ciones en las que no hay elevación de gonadotropinas1---4.

A diferencia de lo que ocurre con la pubertad precoz cen-tral (PPC)5, no hay datos epidemiológicos generales sobrePPP. Tampoco existen datos de incidencia y prevalenciade algunos trastornos específicos como el síndrome deMcCune Albright (SMA) y la testotoxicosis.

Etiopatogenia

Mucho más infrecuente que la PPC, puede ser de origengenético o adquirido (véase tabla 1).

Tabla 1 Clasificación etiológica de la pubertad precozperiférica

NinoGenética

Variantes de LHR (testotoxicosis)Hiperplasia suprarrenal congénitaMutación gen DAX1

Adquirida

Tumor testicular/suprarrenalTumores productores de �-HCGEsteroides sexuales exógenos

NinaGenética

Síndrome de McCune-Albright (muy raro en ninos)Adquirida

Quiste ováricoTumor ovárico/suprarrenalEsteroides sexuales exógenos

Nino/ninaHipotiroidismo primario (excepcional)

Genética

La forma congénita más frecuente de PPP es la hiperplasiasuprarrenal congénita en el varón, ya que produce un excesode andrógenos y, secundariamente, aparición de caracteressexuales masculinos de manera precoz. En este trabajo, noscentraremos en otros trastornos genéticos causantes de PPP.

Síndrome de McCune-AlbrightDesde la descripción inicial de McCune y Albright en 19366,7

hasta el momento actual, el conocimiento de la fisiopa-tología y las bases moleculares de este síndrome se handesarrollado extraordinariamente. De manera que, aunquetradicionalmente se describía la tríada clásica de PPP, man-chas café con leche y displasia fibrosa ósea (figs. 1 y 2),en la actualidad, se considera un síndrome heterogéneocon un amplio espectro de manifestaciones endocrinas y noendocrinas8-10.

Este cuadro clínico se produce por una mutación somá-tica activante de la subunidad � de la proteína G (20q13.2),primordial en la senalización intracelular de células endo-crinas y de otros tejidos11. En la mayoría de las ocasiones, setrata de una mutación sin sentido ocasionada por una susti-tución de una arginina en posición 201 por una histidina. Conmenor frecuencia podemos encontrar una serina, leucina oglicina sustituida por una histidina. Por otra parte, es precisoresenar que aquellas mutaciones que aparecen en etapasprecoces de la embriogénesis presentan una distribuciónmuy amplia en distintos tejidos, constituyendo un fenotipomás severo, mientras que las mutaciones que ocurren mástardíamente en el desarrollo afectan a menor número detejidos y, por consiguiente, presentan un fenotipo más leveo incompleto12. Por tanto, la expresividad clínica es muyheterogénea y, en ocasiones, no es fácil encontrar la triadaclásica ni descubrir la mutación en sangre periférica, lo quepuede complicar el diagnóstico8-10.

La presencia de pubertad precoz es la anomalía endo-crina más frecuente asociada a este síndrome, apareciendoentre los 2 y 6 anos. Este cuadro se caracteriza por apariciónde telarquia fluctuante junto con episodios cíclicos de san-grado vaginal y aceleración de la velocidad de crecimiento.Es preciso resenar que en este síndrome no es habitualuna progresión puberal normal; es decir, pueden aparecerepisodios repetitivos de sangrado vaginal sin un desarrollomamario importante. Estos episodios cíclicos son fruto de laalteración de la subunidad � de la proteína G que resultaen una activación del ovario, formando quistes productores




138

Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos 229.e3

Figura 1 Manchas café con leche de gran tamano (cara interna de muslo izquierdo y dorso) de una nina de 7 anos y 6 meses deedad, afecta de síndrome de McCune-Albright.

de estrógenos. De esta forma, la resolución espontánea deestos quistes produce una caída de los estrógenos seguidade episodios de sangrado vaginal8.

La evolución natural de esta entidad es muy variable,alternando periodos asintomáticos con otros de frecuen-tes sangrados vaginales. Así, en los episodios de sangradovaginal abundante será necesario descartar la presencia dequistes ováricos de gran tamano que puedan producir tor-sión ovárica. Por otra parte, estas ninas presentan un malpronóstico de talla ya que desarrollan una aceleración pro-gresiva del crecimiento con una fusión precoz de las epífisis.De manera infrecuente pueden desarrollar otros trastor-nos endocrinos, como hipercortisolismo, hipertiroidismo,

acromegalia, hiperplasia adrenal autónoma y osteomalaciahipofosfatémica8-10.

La manifestación clínica no endocrina más frecuentedel SMA es la displasia ósea, que condiciona una morbi-mortalidad considerable por la presencia de dolores óseosimportantes y por el incremento notable del riesgo de frac-turas patológicas y de transformación sarcomatosa maligna.No obstante, en los últimos anos se está mejorando nota-blemente la calidad de vida de estos pacientes gracias alempleo de bifosfonatos8.

Los ninos afectos de SMA pueden presentar macroorqui-dismo sin otros signos clínicos ni biológicos de pubertadprecoz. Este hecho es debido a mutaciones de la subunidad

Figura 2 Radiografías antero-posteriores de fémur derecho (distintos ángulos) de nina de 7 anos afectada de síndrome de McCune-Albright. Se puede apreciar una fractura patológica subtrocantérea sobre lesión típica de displasia fibrosa ósea (de unos 4 × 2 cm).




139


� de la proteína G que se presentan únicamente en lascélulas de Sertoli, produciendo una hipertrofia de estas. Deforma infrecuente, menos del 15% de las ocasiones, los ninoscon SMA asocian PPP. Esta expresividad clínica tan diferenteobservada en ninos y ninas parece que pudiera estar rela-cionada con un fenómeno de imprinting, de tal forma quesi la mutación se expresa en células de Sertoli conduce amacroorquidismo, mientras que si lo hace en las células deLeydig se expresaría como PPP8,9.

Testotoxicosis o pubertad precoz familiar del varónEs una forma de PPP isosexual e independiente de la acti-vación de LHRH, que acontece únicamente en varones y esproducida por elevación de los niveles de testosterona deforma autónoma, condicionando la aparición de caracteressexuales secundarios en los varones afectos de forma muyprecoz (entre el primer y cuarto ano de vida), con incre-mento de la velocidad de crecimiento y aceleración de lamaduración ósea13.

Esta perturbación precoz de la síntesis de testosteronaes producida por una mutación activante del receptor de LHque se hereda de forma dominante, aunque pueden existirmutaciones de novo, afectando únicamente a varones14.

La testotoxicosis puede producir trastornos psicológicosen el nino afectado, derivados de la activación muy precozde la pubertad, así como virilización rápida, cierre pre-maturo epifisario y talla baja adulta. Por otro lado, estospacientes pertenecen al grupo de PPP, pero a diferencia delresto de entidades causantes de PPP en el varón, en estecaso existe aumento de tamano testicular bilateral, lo quepuede hacer sospechar una PPC. No obstante, la ausenciade elevación de LH tras test de estimulación junto a losantecedentes familiares, deben orientarnos a este cuadroclínico13,15.

Hipoplasia suprarrenal congénita por mutación del genDAX1 (dosage-sensitive sex reversal, adrenal congenital

hypoplasia, critical region on X chromosome)Los ninos con mutaciones en DAX1 presentan insuficienciasuprarrenal por hipoplasia de estas glándulas y, típicamente,en la etapa adulta desarrollan hipogonadismo hipogonado-tropo. Sin embargo, hay casos descritos de PPP en la primerainfancia. Este hecho parece estar relacionado con los nivelestan elevados de ACTH existentes que pudieran actuar sobrela célula de Leydig, estimulando la síntesis de testosterona.

Por tanto, las mutaciones del gen DAX1 tienen un efecto dualsobre el desarrollo puberal: PPP en la infancia e hipogona-dismo en la etapa adulta16, habiéndose descrito, finalmente,un efecto de mini-pubertad con aumento testicular17.

Adquirida

La PPP adquirida es secundaria al aumento de esteroidessexuales exógenos o endógenos. Aunque es infrecuente, sehan descrito sujetos que han presentado caracteres sexualessecundarios de forma precoz tras la ingesta de anticoncep-tivos orales o esteroides anabolizantes, así como tras elcontacto, a través de la piel, con preparados que contienenestrógenos o testosterona10.

De causa endógena, en los varones hay que descartartumores secretores de andrógenos originados en el testículo(tumores de células de Leydig) y en la glándula suprarrenal.Por otro lado, en las ninas con signos de PPP es menesterdescartar tumores secretores de estrógenos localizados enovario (fig. 3) o en glándula suprarrenal, sin olvidar la posi-ble presencia de quistes ováricos funcionales benignos comocausa de hiperestrogenismo10,18-20.

Los tumores germinales productores de gonadotropinacoriónica humana (HCG) son capaces de producir PPP en losvarones ya que la HCG tiene un efecto similar a la hormonaluteinizante sobre el testículo, estimulando la síntesis detestosterona. Estos tumores se localizan fundamentalmenteen hígado, cerebro, mediastino y gónadas. Por el contrario,en las ninas, estos tumores no son causantes de pubertadprecoz porque la presencia aislada de LH, sin un aumentoconcomitante de FSH, es insuficiente para desarrollar clínicade este tipo10,18-20.

Evaluación diagnóstica

Anamnesis

Debe interrogarse sobre la aparición cronológica de los dife-rentes caracteres sexuales.

Debe valorarse la existencia o no de aceleración de cre-cimiento en las gráficas de talla para edad y sexo.

Debe preguntarse sobre la existencia de síntomas dehipertensión intracraneal (cefalea, vómitos, disminución dela agudeza visual).

Figura 3 A) Lactante de 18 meses de edad que, en el momento del diagnóstico, presenta aceleración del crecimiento desdehace 5 meses (talla en +5 SDS), acompanada de telarquia bilateral y sangrado vaginal. Nótense la telarquia y el incremento depigmentación areolar bilaterales. B) Pieza de ovario izquierdo. El estudio anatomo-patológico reveló que existía un luteoma.




140


Debe conocerse la posibilidad de haber ingerido fármacosque contengan esteroides sexuales.

Debe demandarse información a los padres acerca desu talla (cálculo de talla diana) y de su desarrollo pube-ral, incluyendo también abuelos, tíos y hermanos del casoíndice3,4,18-20.

Examen físico

Ante cualquier paciente con sospecha de PPP será precisorecoger las siguientes variables 3,4,18-20.

--- Peso, talla, velocidad de crecimiento, índice de masa cor-poral.

--- Presión arterial, frecuencia cardiaca.--- Acné, vello corporal, estrías.--- Presencia de bocio.--- Palpación abdominal (tumor suprarrenal, hepático, ová-

rico) (fig. 3).--- Estadio puberal de Tanner.--- Palpación y medición de testículos para descartar asime-

tría testicular.--- Manchas café con leche (fig. 1).

Pruebas complementarias

La determinación de gonadotropinas basales y tras estímulocon LHRH (100 �g/m2 iv) es primordial para el diagnósticodiferencial entre PPC y PPP. Si bien no existe unanimidaden la comunidad científica internacional sobre el punto decorte de LH para definir PPC y PPP, la mayoría de autores lositúan entre 5 y 8 U/l3,4,21.

Además del estudio de gonadotropinas basales y trasestímulo, existen otras determinaciones sanguíneas que ser-virán de complemento en el diagnóstico diferencial dePPP3,4,18-20; son las que siguen:

--- Testosterona: sus niveles séricos son de utilidad para eldiagnóstico de pubertad precoz en el nino. Así, valorespor encima de 0,5 ng/ml se consideran en rango puberal.

--- 17-�-estradiol: escasa sensibilidad, ya que valores nor-males, no descartan pubertad precoz; sin embargo, seencuentra muy elevada en presencia de tumores ováricosy suprarrenales productores de estrógenos, así como antequistes ováricos aislados o asociados a SMA.

--- DHEA-S, androstendiona (�4) y 17-OH-progesterona: úti-les en el nino con sospecha de pubertad precoz. Siencontramos cifras de DHEA-S por encima de 700 �g/dl enun nino en edad prepuberal, es altamente sugerente detumor suprarrenal. Elevaciones moderadas, tras pruebade imagen normal, nos obligan a descartar una hiperplasiasuprarrenal de presentación tardía.

--- �-HCG (fracción � de gonadotropina coriónica humana):de utilidad como marcador tumoral en casos de pubertadprecoz periférica con tamano testicular menor de 4 ml enel que no se encuentra alteración testicular ni suprarrenal(cuando se trata de tumores germinales extragonadales:hígado, mediastino, cerebro). Los tumores germinalestesticulares productores de �-HCG producen asimetríatesticular (a veces tamano testicular > 4 ml).

--- T4 libre y TSH: para descartar hipotiroidismo primario,causa excepcional de pubertad precoz.

Por otra parte, disponemos de una serie de pruebas deimagen de enorme utilidad para el diagnóstico diferencialde las distintas formas de pubertad precoz3,4,18-21:

--- Cálculo de la edad ósea mediante radiografía de mano-muneca izquierda: en los casos de pubertad precoz hayparalelamente aceleración de la edad ósea, en compara-ción con las variantes de la normalidad. No obstante, encasos de reciente diagnóstico de PPP, la edad ósea puedeser similar a la edad cronológica.

--- Ecografía testicular: se realizará siempre que haya sos-pecha de pubertad precoz en el varón que presentaasimetría testicular. Asimismo en situaciones de sospe-cha de pubertad precoz con elevación de testosterona yvolumen testicular inferior a 4 ml.

--- Ecografía abdominal: de utilidad para valorar áreasuprarrenal, tanto en sospecha de tumores virilizantesen el varón, como en ninas con sospecha de pubertadprecoz periférica por un tumor productor de estróge-nos. Asimismo se realizará cuando haya indicios de tumorhepático productor de �-HCG.

--- Ecografía pélvica: se realizará en todos los casos depubertad precoz. Por un lado, permite descartar patolo-gía causante de PPP (tumores ováricos, quistes ováricos)y, por otro, valora la existencia de signos de impregnaciónestrogénica.

--- RM craneal: de obligada realización en todos los casos dePPC, tanto en ninos como ninas. También se efectuará encasos de PPP en el nino por sospecha de tumor productorde �-HCG extragonadal no hepático.

--- Serie ósea: para excluir la presencia de displasia fibrosaasociada a SMA.

Finalmente, ante una sospecha clínica elevada, procedere-mos al estudio genético:

--- Estudio del gen del receptor de LH (LHR) en la testotoxi-cosis.

--- Estudio del gen DAX1 ante la sospecha de una hipoplasiasuprarrenal congénita.

--- Estudio gen la subunidad � de la proteína G: la renta-bilidad en sangre periférica es modesta. Por lo que esde interés efectuar el estudio en tejidos afectos (ovario,hueso).

Diagnóstico diferencial

Telarquia prematura aislada

Desarrollo mamario uni o bilateral antes de los 8 anos deedad, sin evidencia de otros signos de pubertad precoz talescomo: aceleración del crecimiento, edad ósea incrementaday aparición de vello púbico y/o axilar. Es una entidad relati-vamente frecuente, con una incidencia de hasta 21,2 casospor 100.000/ano. En la mayoría de ocasiones (hasta un 60%)aparece antes de los 2 anos de edad y tiende a la regresiónespontánea (entre 6 meses a 6 anos). El otro pico de presen-tación es entre los 5 y 7 anos, y es en estas situaciones donde




141


se han descrito mayor porcentaje de telarquias exageradasy mayor prevalencia de pacientes (hasta un 14% según lasseries) que pueden progresar a un cuadro clínico de PPC.

A día de hoy, la etiología de este trastorno es desco-nocida, aunque se barajan varias hipótesis: a) activacióntransitoria parcial del eje hipotálamo-hipofisario-gonadal,con aumento de niveles séricos de FSH; b) fallo de lainvolución folicular con o sin formación ovárica quística;c) sensibilidad excesiva del tejido mamario a la mismacantidad de estrógenos; d) contaminantes ambientales oproductos alimentarios con actividad estrogénica; e) posi-bles formas incompletas de SMA (en particular, formas muyfloridas de telarquia prematura)22,23.

Menarquia prematura aislada

Proceso de sangrado vaginal periódico en ninas de edadescomprendidas entre 1 y 9 anos, sin acompanarse de otrossignos de desarrollo sexual secundario. De etiología desco-nocida, aunque se especula con las mismas teorías que en elcaso de la telarquia prematura. Se trata de un diagnósticode exclusión donde previamente deben descartarse otrasentidades que cursan con sangrado periódico: síndrome deMcCune-Albright, procesos tumorales vaginales o uterinos,enfermedad inflamatoria pélvica, cuerpo extrano en vaginao exposición a estrógenos exógenos22---24.

Tratamiento

Ante procesos adquiridos de PPP, se procederá, si es posible,a resolver la causa (quistes, tumores, esteroides exógenos).

Una atención especial merece el tratamiento del SMA yde la Testotoxicosis (tablas 2---4).

Síndrome de McCune-Albright

Los objetivos del tratamiento en este tipo de pacientesserán evitar trastornos psicológicos derivados de un ade-lanto puberal, frenar los sangrados cíclicos y conseguir unbuen pronóstico de talla final. A día de hoy, desafortunada-mente, no existe ningún tratamiento que haya demostradocumplir dichos objetivos en este tipo de pacientes, debido avarias razones: a) inexistencia de ensayos clínicos aleatori-zados; b) estudios piloto, sin grupo control, con un númeromuy reducido de pacientes; c) ausencia de datos de tallaadulta, y d) en muchas ocasiones, es necesario asociar aná-logos de GnRH al presentar secundariamente una activacióncentral de la pubertad (PP mixta)3,4,10,25.

Para el tratamiento de esta entidad, clásicamente, sehan utilizado dos grupos terapéuticos: inhibidores de la aro-matasa e inhibidores del receptor de estrógenos (véase latabla 2). Así, a mediados de los anos ochenta, aparecie-ron datos prometedores en 5 ninas tratadas con un inhibidor

Tabla 2 Fármacos utilizados en el tratamiento del síndrome de McCune-Albright

Fármaco Ano publicación(referenciabibliográfica)

Diseno/tamanomuestral

Duraciónestudio

Eficacia Efectossecundarios

Testolactona(40 mg/kg/día)

199327 Estudio piloto12 ninas

3 anos DudosaFrecuente activacióncentral de lapubertadIncumplimientoterapéutico frecuente

Dolor abdominalCefaleaDiarreaHipertransaminasemia

Fadrozol (240-480 �g/kg/día)


2-3 anos IneficazFrecuente activacióncentral de lapubertad

Dolor abdominalInhibición de lasíntesis de cortisoly aldosterona

Tamoxifeno(20 mg/día)


1 ano Disminuciónsignificativa desangrado vaginalDesaceleración de lavelocidad decrecimiento y de lamaduración ósea

Aumento detamano uterino yovárico durante eltratamiento

Letrozol (1,5-2 mg/m2/día)


1-3 anos Disminuciónsignificativa desangrado vaginalDesaceleración de lavelocidad decrecimiento y de lamaduración ósea

Aumento detamano ováricoIncremento dequistes ováricosUna nina presentórotura de quisteovárico tras 2 anosde tratamiento

Anastrozol(1 mg/día)


1 ano Ineficaz Bien tolerado




142

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143


de aromatasa de primera generación, la testolactona26; sinembargo, el seguimiento a largo plazo de este mismo grupode pacientes mostró que los sangrados vaginales no se dete-nían y persistía la recurrencia de quistes ováricos, con elriesgo de torsión que esto supone. Además, el cumplimientoterapéutico no era el adecuado debido a la ingente cantidadde pastillas diarias que debían tomar27. Con posterioridad,se disenó un nuevo estudio piloto en 16 pacientes con fadro-zol (inhibidor de segunda generación) obteniendo, de igualforma que con testolactona, unos resultados desalentado-res junto a un efecto inhibidor dependiente de la dosis dela síntesis de cortisol y aldosterona28.

Más recientemente, aparecieron los inhibidores de ter-cera generación: letrozol y anastrozol. En un estudio de9 pacientes con SMA tratadas con letrozol durante 12 a36 meses se mostró una desaceleración de la velocidad decrecimiento, una disminución de la edad ósea, así comouna reducción en el número de sangrados vaginales. Noobstante, durante el estudio se objetivó un aumento deltamano ovárico, así como un incremento de la formaciónde quistes ováricos, con un caso descrito de rotura de unquiste tras 2 anos de tratamiento29. Teniendo en cuentaestas últimas observaciones, habrá que esperar nuevos datosen mayor número de pacientes con un periodo de estu-dio más prolongado. Respecto al anastrozol, recientementese ha constatado su ineficacia en el tratamiento de laPPP30.

El otro fármaco utilizado en el tratamiento médico deestas pacientes ha sido el tamoxifeno, un inhibidor delreceptor de estrógenos. Los datos preliminares, tras unano de tratamiento, de un estudio piloto con tamoxifenopublicado en 200331 parecían alentadores, a pesar de haberobjetivado aumento de tamano uterino y ovárico duranteel período de estudio. Sin embargo, llama la atención quedesde el ano 2003 no se hayan comunicado nuevos datos.

Por otra parte, no existe un consenso firme en cuanto ala actitud terapéutica ante la presencia de quistes ováricos

en estas pacientes. En este sentido, parece que la tendenciaactual ante la presencia de un quiste en una nina o adoles-cente es considerar la realización de punción-aspiración delmismo, mediante laparoscopia, cuando supere un volumende 20 ml (3,2 cm de diámetro) y, muy especialmente, cuandosupere 75 ml (5,2 cm de diámetro) dado el enorme riesgo detorsión ovárica existente32. Estas consideraciones podríanser perfectamente aplicables a ninas afectas de SMA, dondeel riesgo de torsión es todavía mayor.

Testotoxicosis

Los objetivos del tratamiento son similares a los del grupoanterior y, al igual que en el SMA, carecemos de ensayosclínicos aleatorizados que hayan evaluado la eficacia realde las distintas opciones terapéuticas utilizadas. Además,disponemos de pocos datos a talla adulta y, en muchas oca-siones, ha sido necesaria la asociación de análogos de GnRH(véase la tabla 3).

En esta situación, debemos actuar sobre el exceso deandrógenos existente, inhibiendo su síntesis o bloqueandosu acción. De esta forma, tradicionalmente se han planteadodos formas de tratamiento9,10: a) inhibir la síntesis de testos-terona mediante la utilización de ketoconazol, y b) bloquearel receptor de andrógenos e inhibir la síntesis de estrógenos,que son los esteroides sexuales que actúan directamentesobre las epífisis y producen un cierre prematuro de estas.

Actualmente, disponemos de datos de talla adulta en5 pacientes tratados con ketoconazol. En este grupo deninos afectados de testotoxicosis, la talla final media fuede 173 cm (talla diana: 175 cm), el tratamiento fue bientolerado y ninguno de los ninos incluidos presentó una acti-vación central precoz de la pubertad15. Por el contrario, nodisponemos de datos de talla adulta del tratamiento quecombina testolactona y espironolactona. Únicamente apa-recieron datos preliminares a los 6 anos de seguimiento,

Tabla 4 Dosis y coste de distintos fármacos utilizados en el tratamiento de la pubertad precoz periférica

Mecanismo de acción Dosis habituales Intervalo de dosis(h)/presentación (mg)

Coste mensualaproximado (euros)a

Ketoconazol Inhibidor enzima p450 15-20 mg/kg/día 8/200 84Espironolactona Antiandrógeno débil 2-5 mg/kg/día 12/100 51Ciproterona Progestágeno con acción

antiandrogénica70 mg/m2/día 24/50 41

Bicalutamida Potente antiandrógenono esteroideo

2 mg/kg/día 24/50 96

Testolactona Inhibidor de aromatasade primera generación

20-40 mg/kg/día 6/50 1528

Anastrozol Inhibidor de aromatasade tercera generación

1 mg/día 24/1 282

Letrozol Inhibidor de aromatasade tercera generación

2,5 mg/día 24/2,5 293

Tamoxifeno Bloqueante del receptorde estrógenos

20 mg/día 24/20 8

Triptorelina Análogo de GnRH 80-120 (g/kg/mes) Mensual/presentación:3,75 mg/1 ml

162

a Cálculo basado en una dosis para 30 kg, 130 cm y superficie corporal de 1 m2 (peso y talla media de un nino de 9 anos). Adaptadode Lenz et al37.




144


objetivando desaceleración de la velocidad de crecimientoy del adelanto puberal; sin embargo, todos los pacientesdesarrollaron PPC y precisaron la asociación de análogos deGnRH33. Por otra parte, este régimen de tratamiento pre-senta el inconveniente de que su monitorización se realizamediante parámetros clínicos (velocidad de crecimiento,maduración ósea y estadio puberal), ya que no hay cambiosen los niveles de testosterona.

También se ha utilizado un progestágeno bloqueador delreceptor de andrógenos (ciproterona) como única terapia detestotoxicosis, siendo bien tolerado, aunque con modestosresultados en cuanto a talla final y con activación centralde la pubertad de forma precoz en un 40% de los pacientes.En este mismo trabajo, aparecen datos de talla adulta enninos tratados con ketoconazol siendo la eficacia similar ala ciproterona y con el mismo porcentaje de casos de PPCsecundaria34. Esta modesta eficacia de testolactona puedeser debida a que la dosis utilizada ha sido notablementeinferior a la empleada en estudios previos15.

Con posterioridad, han ido surgiendo distintas modalida-des terapéuticas que han asociado un inhibidor de aromatasade tercera generación con bloqueadores del receptor deandrógenos35-37. Estos trabajos tienen en común el escasonúmero de pacientes y la ausencia de datos a talla adulta.En la misma línea, el estudio piloto en fase II BATT38 incluyea 14 pacientes a los que se les pauta tratamiento con un anti-andrógeno no esteroideo muy potente (bicalutamida) a dosisprogresivas, junto con un inhibidor de aromatasa de tercerageneración (anastrozol). Los resultados preliminares de esteestudio, tras un ano de tratamiento, son muy modestos y noexentos de efectos secundarios (véase la tabla 3).

Finalmente, es preciso resenar que tanto en el SMA comoen la testotoxicosis deberemos tener en cuenta no sólo laeficacia y los posibles efectos secundarios de la terapia ainstaurar, sino también la manera de dosificar los fármacos(los comprimidos son difíciles de ingerir, más aún, si es cada6 horas) y el coste de los mismos (tabla 4). Así, por ejemplo,un paciente afecto de testotoxicosis, de unos 30 kg de peso,que reciba terapia con bicalutamida y anastrozol y que, a suvez, necesite terapia con análogos de GnRH (fenómeno deescape frecuente con esta terapia), estará gastando aproxi-madamente 540 euros mensuales.

Áreas de controversia y perspectivas futuras

Diagnóstico del síndrome de McCune-Albright

Será preciso continuar investigando aquellos pacientes confenotipo no clásico (falta de todos los criterios), en especial,aquellos sujetos con telarquia prematura exagerada y testde LHRH prepuberal. Para ello, será primordial el avance enlos conocimientos moleculares asociados a este trastorno y,muy en particular, en la búsqueda de métodos diagnósticosque puedan evitar la necesidad de estudios en tejidos comohueso y/o ovario.

Tratamiento del síndrome McCune-Albright

No hay evidencia científica suficiente para recomendar nin-guna terapia en este síndrome (grado de recomendación ynivel de evidencia científica AI). Es preciso continuar con los

estudios iniciados y conocer datos a talla adulta, evaluandolos posibles efectos secundarios del tratamiento instauradoa más largo plazo. A la espera de conocer los resultadosde estas investigaciones, será preciso individualizar cadapaciente y pautar el tratamiento del que se disponga de másexperiencia, teniendo en cuenta su tolerancia, así como sucoste (grado de recomendación y nivel de evidencia cientí-fica CIII).

Tratamiento de testotoxicosis

No hay evidencia científica suficiente para recomendarterapia con ketoconazol en este síndrome (grado de reco-mendación y nivel de evidencia científica AI). No obstante,a nuestro entender, presenta una serie de ventajas sobreel resto de fármacos utilizados hasta el momento: a) datosa talla adulta; b) bien tolerado, ocasionalmente producehipertransaminasemia transitoria a las dosis utilizadas; c) esmuy infrecuente la aparición de PPC durante esta terapia;d) control de la eficacia del tratamiento no sólo mediante elseguimiento de la velocidad de crecimiento y la regresión decaracteres sexuales, sino también con los niveles circulantesde testosterona, y e) bajo coste (grado de recomendación ynivel de evidencia científica CIII).

Conflicto de intereses

Los autores declaran no tener ningún conflicto de intereses.

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25. Shulman DI, Francis GL, Palmert MR, Eugster EA. Use ofaromatase inhibitors in children and adolescents with disor-ders of growth and adolescent development. Pediatrics.2008;121:975---83.

26. Feuillan PP, Foster CM, Pescovitz OH, Hench KD, Shawker T,Dwyer A, et al. Treatment of precocious puberty in the McCune-Albright syndrome with the aromatase inhibitor testolactone.N Engl J Med. 1986;315:1115---9.

27. Feuillan PP, Jones J, Cutler Jr GB. Long-term testolactone the-rapy for precocious puberty in girls with the McCune-Albrightsyndrome. J Clin Endocrinol Metab. 1993;77:647---51.

28. Nunez SB, Calis K, Cutler Jr GB, Jones J, Feuillan PP. Lackof efficacy of fadrozole in treating precocious puberty in girlswith the McCune-Albright syndrome. J Clin Endocrinol Metab.2003;88:5730---3.

29. Feuillan P, Calis K, Hill S, Shawker T, Robey PG, Collins MT.Letrozole treatment of precocious puberty in girls with theMcCune-Albright syndrome: a pilot study. J Clin EndocrinolMetab. 2007;92:2100---6.

30. Mieszczak J, Lowe ES, Plourde P, Eugster EA. The aromataseinhibitor anastrozole is ineffective in the treatment of preco-cious puberty in girls with McCune-Albright syndrome. J ClinEndocrinol Metab. 2008;93:2751---4.

31. Eugster EA, Rubin SD, Reiter EO, Plourde P, Jou HC,Pescovitz OH. Tamoxifen treatment for precocious pubertyin McCune-Albright syndrome: a multicenter trial. J Pediatr.2003;143:60---6.

32. Linam LE, Darolia R, Naffaa LN, Breech LL, O’hara SM,Hillard PJ, et al. US findings of anexal torsion in children andadolescents: size really does matter. Pediatr Radiol. 2007;37:1013---9.

33. Leschek EW, Jones J, Barnes KM, Hill SC, Cutler Jr GB. Six-year results of spironolactone and testolactone treatment offamilial male-limited precocious puberty with addition of des-lorelin after central puberty onset. J Clin Endocrinol Metab.1999;84:175---8.

34. Almeida MQ, Brito VN, Lins TS, Guerra-Junior G, de Castro M,Antonini SR, et al. Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproteroneacetate or ketoconazole. Clin Endocrinol (Oxf). 2008;69:93---8.

35. Kreher NC, Pescovitz OH, Delameter P, Tiulpakov A,Hochberg Z. Treatment of familial male-limited precociouspuberty with bicalutamide and anastrozole. J Pediatr.2006;149:416---20.

36. Eyssette-Guerreau S, Pinto G, Sultan A, Le Merrer M, Sultan C,Polak M. Effectiveness of anastrozole and cyproterone acetatein two brothers with familial male precocious puberty. J PediatrEndocrinol Metab. 2008;2:995---1002.

37. Lenz AM, Shulman D, Eugster EA, Rahhal S, Fuqua JS,Pescovitz OH, et al. Bicalutamide and third-generation aroma-tase inhibitors in testotoxicosis. Pediatrics. 2010;126:728---33.

38. Reiter EO, Mauras N, McCormick K, Kulshresrhtha B, Amrhein J,De Luca F, et al. Bicalutamide plus anastrozole for the treat-ment of gonadotropin-independent precocious puberty in boyswith testotoxicosis: a phase II, open-label pilot study (BATT).J Pediatr Endocrinol Metab. 2010;23:999---1009.



causas centraisRAqueL ALMeiDA

Bibliografia:

Delayed Puberty, Mark R. Palmert, M.D., Ph.D., and Leo Dunkel, M.D., Ph.D., n engl J Med 366;5, february 2, 2012

Approach to the patient with delayed puberty, William F Crowley Jr, nelly Pitteloud, in www.uptodate.com, topic last updated: Jul 23, 2018 link: Approach to the patient with delayed puberty

isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism), nelly Pitteloud, William F Crowley Jr, Ravikumar Balasubramanian MBBS, in www.uptodate.com, last updated: nov 21, 2017. link: Causes of delayed puberty

atraso pubertÁrio

https://www.uptodate.com/contents/approach-to-the-patient-with-delayed-puberty%3Fcsi%3D2638d85a-947e-41c8-8066-2566984819c6%26source%3DcontentShare

https://www.uptodate.com/contents/image%3Fcsi%3Df1f3effd-0e27-4a47-9f31-3482f12c72be%26source%3DcontentShare%26imageKey%3DENDO%252F62372


ATrAso PuBerTário | CAusAs CenTrAis | rAquel AlmeidA

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clinical practice

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 366;5 nejm.org february 2, 2012 443

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines,

when they exist. The article ends with the authors’ clinical recommendations.

An audio version of this article is available at NEJM.org

Delayed PubertyMark R. Palmert, M.D., Ph.D., and Leo Dunkel, M.D., Ph.D.

From the Division of Endocrinology, the Hospital for Sick Children, and the De-partments of Pediatrics and Physiology, University of Toronto — both in Toronto (M.R.P.); and the Centre for Endocrinolo-gy, William Harvey Research Institute, Barts and the London School of Medi-cine and Dentistry, Queen Mary Univer-sity of London, London (L.D.). Address reprint requests to Dr. Palmert at the Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada, or at [email protected]; or to Dr. Dunkel at the Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of Lon-don, Charterhouse Sq., London EC1M 6BQ, United Kingdom, or at [email protected].

N Engl J Med 2012;366:443-53.Copyright © 2012 Massachusetts Medical Society.

A 14-year-old boy with an unremarkable medical history presents because of lack of pubertal development. He has always been relatively short, but his growth velocity is slowing as compared with that of his peers. His height is 146 cm (57.5 in., <3rd percentile for age), and his weight is 37 kg (82 lb, 3rd percentile). His father, who is 168 cm (66.1 in.) tall, continued to grow until his second year in college; his mother is 153 cm (60.2 in.) tall and began menstruating at the age of 14.0 years. The patient’s target height on the basis of the parental heights is 167 cm (65.8 in.). The physical examination reveals Tanner stage 1 pubic hair and prepubertal-sized testes. How should the boy be evaluated and treated?

The Clinic a l Problem

Puberty leads to sexual maturation and reproductive capability. It requires an intact hypothalamic–pituitary–gonadal (HPG) axis and is heralded by the reemergence of gonadotropin-releasing hormone (GnRH) secretion from its relative quiescence during childhood. GnRH stimulates the secretion of luteinizing hormone and fol-licle-stimulating hormone (FSH), which then stimulate gonadal maturation and sex-steroid production. Much is known about components of the HPG axis, but the factors that trigger pubertal onset remain elusive. It is not understood why one boy begins puberty at the age of 10 years and another at the age of 14 years.

Delayed puberty is defined as the absence of testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SD later than the population mean (traditionally, the age of 14 years in boys and 13 years in girls). However, because of a downward trend in pubertal timing in the United States1-3 and other countries4,5 and differences in pubertal timing among racial and ethnic groups, some observers have advocated for updated definitions with younger age cutoffs for the general population or perhaps for particular countries or racial or ethnic groups. Development of pubic hair is usually not considered in the definition be-cause pubarche may result from maturation of the adrenal glands (adrenarche), and the onset of pubic hair can be independent of HPG-axis activation.

Late puberty can affect psychosocial well-being, and patients, families, and practitioners are often concerned that it may affect adult stature. Adult height can be affected but on average is only slightly below the genetic target.6 Many adoles-cents present with delayed puberty combined with relative familial short stature, compounding these concerns and leading to more subspecialty referrals than ei-ther condition alone.

Delayed puberty in boys usually represents an extreme of the normal spectrum of pubertal timing, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP). In one large series, approximately 65% of boys and 30% of girls with delayed puberty had CDGP.7 However, because the data were



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obtained from a tertiary referral center, these percentages may underestimate the frequency of CDGP encountered by primary care providers. The evaluation and treatment of boys with CDGP is the main focus of this review, but consider-ation is given to other causes of delayed puberty and issues specific to girls.

Although CDGP represents the single most common cause of delayed puberty in both sexes, it can be diagnosed only after underlying condi-tions have been ruled out. The differential diag-nosis of CDGP can be divided into three main categories7: hypergonadotropic hypogonadism (characterized by elevated levels of luteinizing hormone and FSH owing to the lack of negative feedback from the gonads), permanent hypogo-nadotropic hypogonadism (characterized by low levels of luteinizing hormone and FSH owing to hypothalamic or pituitary disorders), and transient hypogonadotropic hypogonadism (functional hy-pogonadotropic hypogonadism), in which puber-tal delay is caused by delayed maturation of the HPG axis secondary to an underlying condition (Table 1, and Table 1 in the Supplementary Ap-pendix, available with the full text of this article at NEJM.org).

The cause of CDGP is unknown, but it has a strong genetic basis. It has been estimated that 50 to 80% of variation in the timing of puberty in humans is due to genetic factors,8 and 50 to 75% of patients with CDGP have a family his-tory of delayed puberty.9,10 The inheritance of CDGP is variable but most often is consistent with an autosomal dominant pattern, with or without complete penetrance. CDGP is not sex-specific and is characterized by either relatively

delayed development among family members (e.g., the average age at menarche among moth-ers is 14.3 years, as compared with a mean of 12.7 years among controls9) or evidence of true CDGP. The investigation of patients with the Kallmann syndrome and isolated hypogonado-tropic hypogonadism has led to the identifica-tion of genes that play critical roles in the de-velopment and regulation of the HPG axis, but mutations that have been identified in such genes do not cause CDGP, except in rare in-stances.11,12 However, the genes causing 60 to 70% of cases of the Kallmann syndrome and isolated hypogonadotropic hypogonadism re-main unknown.13 Loci have also been identi-fied that are associated with the age of men-arche in the general population,14-18 but these particular loci have likewise not been associ-ated with CDGP.19

S tr ategies a nd E v idence

First-Line EvaluationRuling Out Underlying DisordersThe aim of initial evaluation is to rule out underlying disorders causing delayed puberty (Table 2, and Table 2 in the Supplementary Ap-pendix).20-28 Pubertal development is assessed clinically and biochemically, providing infor-mation that is important for counseling and predicting further pubertal development. Even-tual normal progression of puberty verifies the diagnosis of CDGP, whereas absent or slow development or cessation of development after onset is consistent with permanent hypogo-nadism.

key clinical points

delayed puberty

• Delayed puberty is diagnosed when there is no testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SD later than the mean age at which these events occur in the population (traditionally, 14 years in boys and 13 years in girls).

• Constitutional delay of growth and puberty (CDGP) is the single most common cause of delayed puberty in both sexes, but it can be diagnosed only after underlying conditions have been ruled out.

• The cause of CDGP is unknown, but most patients with CDGP have a family history of delayed puberty.

• Management of CDGP may involve expectant observation or therapy with low-dose sex steroids.

• When treatment is given, the goals are to induce the appearance of secondary sexual characteristics or the acceleration of growth and to mitigate psychosocial difficulties associated with pubertal delay and short stature.

• The routine use of growth hormone, anabolic steroids, or aromatase inhibitors is not currently recommended.



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Family HistoryA family history, including childhood growth patterns and age at pubertal onset of the parents, should be obtained. Delayed puberty in a parent or sibling followed by spontaneous onset of pu-berty suggests CDGP. However, if pubertal devel-opment was induced by sex steroids in family members, isolated hypogonadotropic hypogonad-ism is also possible, since reversal of hypogonad-ism is noted after the discontinuation of sex ste-roids in about 10% of patients with isolated hypogonadotropic hypogonadism.29,30

Patients and their parents should be ques-tioned about a history or symptoms of chronic disease, with emphasis on specific disorders (e.g., celiac disease, thyroid disease, and anorexia) that may cause temporary delay of puberty (functional hypogonadotropic hypogonadism), as well as medication use, nutritional status, and psycho-social functioning. Delayed cognitive develop-ment associated with obesity or dysmorphic features may suggest an underlying genetic syn-drome. Bilateral cryptorchidism or a small penis at birth and hyposmia or anosmia may suggest hypogonadotropic hypogonadism. A history of chemotherapy or radiotherapy may indicate pri-mary gonadal failure (Fig. 1).

Physical ExaminationPrevious height and weight measurements should be obtained and plotted so that longitudinal growth can be carefully assessed (Fig. 2). Delayed puberty is often associated with short stature and slow growth for age although the height and growth rate are within the prepubertal normal range. Children who are underweight for height

have an increased likelihood of having an under-lying condition delaying HPG-axis activation. Conversely, in boys, unlike girls, being overweight can be associated with later pubertal develop-ment.20,21 The most widely used pubertal rating system is Tanner staging31,32 (Fig. 3). In boys, the presence of Tanner stage 2 genitalia marks the onset of pubertal development and is character-ized by enlargement of the scrotum and testes and by a change in the texture and color of the scrotal skin. Testicular volume should be mea-sured, with a volume of more than 3 ml indicating the initiation of central puberty. In patients with CDGP, both adrenarche and hormonal activation of the gonads often occur later than average, but in isolated hypogonadotropic hypogonadism, adrenarche usually occurs at a normal age.7,33

Bone-Age RadiographyThe bone age should be reviewed by a practitio-ner who is experienced in interpreting such ra-diographs. A delay in bone age is characteristic but not diagnostic of CDGP and also may occur in patients with chronic illness, hypogonado-tropic hypogonadism, or gonadal failure. Adult height prediction is an important part of coun-seling if short stature is a component of the pre-sentation, and practitioners should be aware that the Bayley–Pinneau tables overestimate adult height in patients with CDGP if bone age is de-layed by more than 2 years (Table 2, and Table 2 in the Supplementary Appendix).

Hormone Measurements and Brain ImagingPubertal onset is characterized by the accentua-tion of diurnal secretion of gonadotropin and

Table 1. Frequency and Common Causes of Delayed Puberty Other Than Constitutional Delay of Growth and Puberty.*

Delayed PubertyHypergonadotropic

HypogonadismPermanent Hypogonadotropic

HypogonadismFunctional Hypogonadotropic

Hypogonadism

Frequency (%)

Boys 5–10 10 20

Girls 25 20 20

Common causes Turner’s syndrome, gonadal dysgen-esis, chemotherapy or radiation therapy

Tumors or infiltrative diseases of the central nervous system, GnRH deficiency (isolated hypogonado-tropic hypogonadism, Kallmann’s syndrome), combined pituitary-hormone deficiency, chemothera-py or radiation therapy

Systemic illness (inflammatory bowel disease, celiac disease, anorexia nervosa or bulimia), hypothyroid-ism, excessive exercise

* For a more comprehensive listing of causes of delayed puberty, see Table 1 in the Supplementary Appendix. GnRH denotes gonadotropin-releasing hormone.



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testosterone (in boys) and estrogen (in girls) be-fore apparent phenotypic changes. Basal levels of luteinizing hormone and FSH are low in patients with CDGP or hypogonadotropic hypogonadism, whereas such levels are usually elevated in those with gonadal failure. Serum levels of insulin-like growth factor 1 (IGF-1) can be helpful in the evaluation of growth hormone deficiency but must be interpreted carefully because levels are often low for chronologic age but within the nor-mal range for bone age. Thyroid-function tests are routinely obtained. Brain magnetic resonance imaging (MRI) is indicated when there are signs or symptoms to suggest a lesion in the central nervous system. Otherwise, although some clini-

cians routinely perform brain imaging, a reason-able strategy is to defer such evaluation until the age of 15 years, at which point many patients with CDGP will have spontaneously begun puberty and will require no further evaluation. Full neuro-endocrine testing is warranted in patients with hypothalamic–pituitary tumors causing hypogo-nadotropic hypogonadism, since they may have additional pituitary-hormone deficiencies.

Second-Line Evaluation

Most patients will not have an apparent alterna-tive cause for delayed puberty on initial evalua-tion, suggesting CDGP as the likely diagnosis. However, no test can reliably distinguish CDGP

Table 2. Investigations for Delayed Puberty.*

Variable Interpretation

First-line

Growth rate In early adolescence in both sexes, an annual growth rate of less than 3 cm is suggestive of a dis-ease specifically inhibiting growth (e.g., growth hormone deficiency, hypercortisolism, and hy-pothyroidism), but such rates can also be seen in CDGP. Boys with delayed puberty who are overweight tend to have height and predicted adult height consistent with their genetic height potential.20,21

Tanner stages In girls, Tanner stage 2 breast development is usually the first physical marker of puberty. In boys, a testicular volume of >3 ml is a more reliable indicator of the onset of puberty than Tanner stage 2 genital development.

Testis volume in boys A testicular volume of >3 ml (≥2.5 cm in length) indicates central puberty. Most healthy boys with a testicular volume of ³3 ml will have a further increase in testicular volume or pubic-hair stage, or both, at repeated examination 6 mo later.22

Bone age A bone-age delay of >2 yr has arbitrarily been used as a criterion for CDGP but is nonspecific. A bone-age delay of 4 years has been associated with a mean overprediction of adult height of 8 cm. In children with short stature who have no bone-age delay, adult height is usually under-estimated by the Bayley–Pinneau tables.23

Biochemical analyses To rule out chronic disorders, common tests include complete blood count, erythrocyte sedimenta-tion rate, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, and free thyroxine. Additional testing may be necessary on the basis of family history and symptoms and signs, including screening for celiac disease and inflammatory bowel disease.

Serum luteinizing hormone At low levels, values obtained on immunochemiluminometric (ICMA) assays are at least 50% lower than those obtained on immunofluorometric (IFMA) assays.24 Values of <0.1 IU per liter are not specific for hypogonadotropic hypogonadism. Values of >0.2 IU per liter on ICMA or >0.6 IU per liter on IFMA are specific but not sensitive for the initiation of central puberty; some adoles-cents in early puberty have lower values.24 In delayed puberty, elevated values suggest primary hypogonadism. In general, luteinizing hormone is a better marker of pubertal initiation than follicle-stimulating hormone.

Serum follicle-stimulating hormone At low levels, values obtained on ICMA are approximately 50% lower than those obtained on IFMA. Values of <0.2 IU per liter on ICMA or <1.0 IU per liter on IFMA suggest hypogonadotropic hy-pogonadism but are not diagnostic.24,25 In delayed puberty, a value above the upper limit of the normal range for the assay is a sensitive and specific marker of primary gonadal failure.

Serum insulin-like growth factor 1 Measurement is used to screen for growth hormone deficiency. An increase in the level during follow-up or during or after treatment with sex steroids makes the diagnosis of growth hormone defi-ciency less likely. Growth hormone provocation tests are needed to diagnose growth hormone deficiency.

Serum testosterone in boys A morning value of 20 ng per deciliter (0.7 nmol per liter) often predicts the appearance of pubertal signs within 12 to 15 mo.26



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from isolated hypogonadotropic hypogonadism, so the diagnosis of CDGP cannot be made with certitude. Observation usually resolves this conun-drum; isolated hypogonadotropic hypogonadism is diagnosed if endogenous puberty has not be-gun by the age of 18 years. Several tests have been proposed to distinguish CDGP from isolated hypogonadotropic hypogonadism (Table 2, and Table 2 in the Supplementary Appendix). If basal gonadotropin levels are inconclusive, stimulation by GnRH or a GnRH agonist may be helpful.24,25 Stimulated levels of luteinizing hormone in the pubertal range indicate that the HPG axis has been reactivated and that secondary sexual devel-opment is likely to occur within 1 year. However, the GnRH test alone often cannot differentiate CDGP from isolated hypogonadotropic hypogo-nadism because prepubertal values may be ob-served in isolated hypogonadotropic hypogonad-ism or in patients with CDGP in whom the HPG axis has not yet been activated. Recent data sug-gest that baseline levels of inhibin B may facili-tate discrimination between these conditions,28 but replication is needed before this or other tests can be routinely adopted.

Growth hormone secretion in the basal state, as well as after provocative testing, may be de-creased in patients with CDGP. If concern about growth is sufficient to warrant stimulation test-ing of growth hormone, sex-steroid priming with estrogen or testosterone is necessary for reliable results in patients with delayed puberty; estro-gen stimulates endogenous growth-hormone se-cretion, and sex-steroid priming facilitates sepa-ration of true growth hormone deficiency from the physiologic low growth hormone secretion that stems from low estrogen levels. If a patient has a normal growth rate, growth hormone provocation testing is not necessary, whereas low IGF-1 levels together with reduced growth veloc-ity warrant testing.

TreatmentPatients with CDGPThe options for management of CDGP include expectant observation or therapy with low-dose testosterone (in boys) or estrogen (in girls) (Table 3, and Table 3 in the Supplementary Appendix). If puberty has started, clinically or biochemical-ly, and stature is not a major concern, reassur-

Table 2. (Continued.)

Variable Interpretation

Second-line

Gonadotropin-releasing hormone test† A predominant response of luteinizing hormone over follicle-stimulating hormone after stimulation or peak luteinizing hormone levels of 5 to 8 IU per liter (depending on the assay) suggests the onset of central puberty. However, patients with CDGP or hypogonadotropic hypogonadism may have a prepubertal response.

Human chorionic gonadotropin test† Peak testosterone levels are lower in patients with hypogonadotropic hypogonadism than in those with CDGP.27

Serum inhibin B† Prepubertal boys with a baseline inhibin B level of >35 pg per milliliter have a higher likelihood of CDGP.28 In boys, unmeasurable inhibin B indicates primary germinal failure.

Serum prolactin Elevated levels may indicate hypothalamic–pituitary tumors causing hypogonadotropic hypogonad-ism. In such cases, additional pituitary-hormone deficiencies may be present. Measurement of macroprolactin (a physiologically inactive form of prolactin) is recommended in patients with unexplained hyperprolactinemia.

Brain magnetic resonance imaging Imaging is performed to rule out underlying disorders of the central nervous system. Imaging in patients with the Kallmann syndrome commonly shows olfactory-bulb and sulcus aplasia or hypoplasia and thus may help differentiate the Kallmann syndrome from hypogonadotropic hypogonadism in patients with an apparently normal or difficult-to-evaluate sense of smell.

Genetic testing Genotyping for known monogenic causes is currently a research procedure and not warranted in routine clinical practice.

* For a more comprehensive listing of investigations, see Table 2 in the Supplementary Appendix. CDGP denotes constitutional delay of growth and puberty.

† These tests are used to try to differentiate CDGP from isolated hypogonadotropic hypogonadism. However, validation in larger, independent studies is needed before the use of such tests can be fully endorsed. Often, clinical follow-up is needed to confirm the diagnosis; no endog-enous puberty by the age of 18 years is diagnostic of isolated hypogonadotropic hypogonadism.



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Family history of delayed pubertyHistory of chronic disease, cryptorchidism, anosmia,

anorexia, radiotherapy, or chemotherapy

First-line investigations: growth rate, Tanner stage,testis volume

Tests: biochemical analyses, bone-age radiography, basal serum LH, FSH, IGF-1, thyrotropin, freethyroxine, and testosterone (in boys)

Low or normal serum LH andFSH for early Tanner stages

Elevated FSH

Delayed Puberty

Growth rate in prepubertalrange

Growth rate below prepubertalrange

Hypergonadotropic hypogonadism(5–10% of boys, 25% of girls)

GnRH deficiency or CDGP(65% of boys, 30% of girls)

Functional hypogonadotropichypogonadism (secondaryto a chronic disease, anorexia)(20% of boys, 20% of girls)

Permanent hypogonadotropichypogonadism or hypopitui-tarism (10% of boys, 20%of girls)

Examine further for underlying cause:karyotype, serum inhibin B (in boys)

Treat with sex steroids

GnRH testhCG stimulation testSerum inhibin BOlfactory-function testGenetic testingMRI

Examine further for chronicdisease: MRI, prolactin

Normal BMI High BMILow BMI

Follow upEvaluate the need for the

induction of secondary sex characteristics

HypothyreosisHyperprolactinemiaGH deficiencyMultiple pituitary hor-

mone deficiency

Glucocorticoid excess(iatrogenic,Cushing’s disease)

Hypothyroidism

GI disorderUnderfeedingAnorexia

Treat underlying cause

First-LineEvaluation

WorkingDiagnosis

Intervention

Second-LineEvaluation(if CDGP isnot evident)

Second-LineDiagnosis



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ance with realistic adult height prediction is fre-quently sufficient. If therapy is initiated, it is usually to assuage psychosocial difficulties that may derive from negative interactions with peers, decreased self-esteem, and anxiety about growth rate or body habitus.

Numerous studies of treatment of CDGP in boys have been reported. Although some random-ized, controlled trials have been performed with small numbers of subjects, studies have been largely observational and have involved treat-ment with short courses of low-dose andro-gens.34-36 The data suggest that treatment leads to increased growth velocity and sexual matura-tion and positively affects psychosocial well-being, without significant side effects, rapid advance-ment of bone age, or reduced adult height. Similar data are not available for girls, but simi-lar outcomes are likely as long as therapy is initi-ated with appropriately low doses of estrogen.

For a subset of patients with CDGP, short stature can be more worrisome than delayed puberty, and indeed CDGP is considered by some observers to be a subgroup of idiopathic short stature. Although the Food and Drug Adminis-tration has approved the use of growth hormone for the treatment of idiopathic short stature and height that is 2.25 SD below average for age, this therapy has at best a modest effect on adult height in adolescents with CDGP, and its use in CDGP is not recommended.

In boys with CDGP and short stature, another potential therapeutic approach is aromatase inhi-bition, but this treatment requires further study before it should be incorporated into routine practice.37,38 Aromatase inhibitors block the con-version of androgens to estrogens; because es-trogen is the predominant hormone needed for epiphyseal closure, the use of aromatase inhibi-

tors could prolong linear growth and potentially increase adult height. In controlled trials in boys with short stature or delayed puberty, aromatase inhibitors delayed bone maturation and appeared to increase adult height.37,38 However, the amount of height gained as well as the optimal timing, dose, and duration of therapy with aromatase inhibitors remain uncertain.39 Moreover, poten-tially adverse effects, especially impaired devel-opment of trabecular bone and vertebral-body deformities, which were observed in boys with idiopathic short stature who were treated with letrozole,40 must be considered.

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Figure 2. Linear Growth in Delayed Puberty.

In children with delayed puberty (data points), linear growth progresses with a normal preadolescent height velocity (>3 cm per year). Height rela-tive to that of peers (height percentile) may decrease slightly before the usual adolescent age range, but this effect is accentuated when the child with delayed puberty does not undergo a growth spurt in concert with his or her peers. Consequently, the height percentile decreases in the early teen-age years. In children with constitutional delay of growth and puberty, a late growth spurt will facilitate subsequent catch-up growth, but adult heights are often slightly shorter than expected on the basis of parental heights.

Figure 1 (facing page). Algorithm for the Evaluation of a Patient with Delayed Puberty.

Percentages of patients with delayed puberty with vari-ous conditions are from Sedlmeyer and Palmert.7 Percent-ages do not add up to 100% because of rounding and because a small percentage of patients have disorders that cannot be classified with the use of this algorithm. BMI denotes body-mass index, CDGP constitutional delay of growth and puberty, FSH follicle-stimulating hormone, GH growth hormone, GI gastrointestinal, GnRH gonado-tropin-releasing hormone, hCG human chorionic gonado-tropin, IGF-1 insulin-like growth factor 1, LH luteinizing hormone, and MRI magnetic resonance imaging.



154



Permanent HypogonadismIn boys and girls with hypogonadotropic hypo-gonadism, initial sex-steroid therapy is the same as that for CDGP, but doses are gradually increased to full adult replacement levels during a period of approximately 3 years (Table 3). In hypogonadotropic hypogonadism, exogenous testosterone does not induce testicular growth or spermatogenesis and exogenous estrogen does not induce ovulation, and the induction of fertility in both sexes requires treatment with pulsatile GnRH42-45 or exogenous gonadotro-pins.44 In girls with hypogonadotropic hypo-gonadism, treatment with estrogen needs to be combined with progestin for endometrial cy-cling.

A r e a s of Uncerta in t y

Further research is needed to establish appro-priate age cutoffs for delayed puberty in differ-ent racial and ethnic groups and to better un-derstand the physiological basis of CDGP. Suggested causes of CDGP include increased to-tal energy expenditure46 and increased insulin sensitivity,47 but no definitive cause has been identified. Studies should carefully assess the psychosocial distress among children with de-layed puberty, whether this distress has long-term sequelae, and what effect sex-steroid sup-plementation has on these outcomes. It remains unclear whether adult bone mass is adversely affected by pubertal delay48 and whether this represents a medical reason to initiate sex-steroid replacement. Distinguishing between CDGP and isolated hypogonadotropic hypogonadism re-mains difficult in many cases, and further as-sessment of the role of inhibin B or other mark-ers for this purpose is needed. Randomized trials are needed to compare different estrogen for-mulations, routes of administration (oral vs. transdermal), and drug regimens to determine optimal therapy for girls with delayed puberty. Studies are needed to identify genes that cause CDGP, which would also elucidate factors that regulate the timing of puberty.

Guidelines

To our knowledge, there are no recent guidelines regarding the evaluation and treatment of CDGP.

Genital Development and Pubic Hair

Breast Development and Pubic Hair

Stage 2Stage 1

A

B

Stage 1 Stage 2

Stage 1 Stage 2

Figure 3. Tanner Stages in the Assessment of Delayed Puberty.

Delayed puberty is often associated with short stature and slow growth for age although the growth rate is within the prepubertal normal range. Physical markers of puberty can also be delayed. In girls (Panel A), breast development from Tanner stage 1 (preadolescent) to stage 2 (appearance of the breast bud) should tradi-tionally take place between 8 and 13 years of age, and in boys the development of genital Tanner stage 1 (pre-adolescent) to stage 2 (enlargement of the testes and scrotum and change in the texture and reddening of the scrotal skin) should take place between 9 and 14 years. Recent data regarding earlier timing of puberty suggest that these traditional age cutoffs should be adjusted downward, but new age ranges have not yet been defined.



155

clinical pr actice


Tabl

e 3.

Med

icat

ions

for

the

Trea

tmen

t of C

onst

itutio

nal D

elay

of G

row

th a

nd P

uber

ty (C

DG

P).*

Dru

g an

d Fo

rmul

atio

nIn

Chi

ldre

n w

ith C

DG

PSi

de E

ffec

ts a

nd C

autio

ns

Boy

s

Test

oste

rone

Eryt

hroc

ytos

is, w

eigh

t gai

n, p

rost

ate

hype

rpla

sia;

hig

h do

ses

can

caus

e pr

emat

ure

epip

hyse

al c

losu

re; n

ot fo

r us

e in

boy

s w

ith

a bo

ne a

ge o

f <10

yr

Enan

that

e, c

ypio

nate

, and

pro

pion

ate

Not

rec

omm

ende

d be

fore

14

yr o

f age

; ini

tial d

ose,

50–

100

mg

ever

y 4

wk

for

3 to

6 m

o; r

epea

ted

trea

tmen

t with

25-

to-5

0-m

g in

cre-

men

t in

dose

(no

t exc

eedi

ng 1

00 m

g)

All

adm

inis

tere

d by

intr

amus

cula

r in

ject

ion;

loca

l sid

e ef

fect

s: p

ain,

er

ythe

ma,

infla

mm

ator

y re

actio

n, a

nd s

teri

le a

bsce

ss; p

riap

ism

ca

n oc

cur

in p

atie

nts

with

sic

kle

cell

dise

ase;

long

er d

urat

ion

of

effe

ct fo

r te

stos

tero

ne e

nant

hate

than

pro

pion

ate

Und

ecan

oate

†N

o da

ta a

vaila

ble

on in

tram

uscu

lar

inje

ctio

n

Tran

sder

mal

pre

para

tions

No

data

ava

ilabl

eLo

cal i

rrita

tion;

app

lied

topi

cally

at b

edtim

e; a

fter

app

licat

ion,

mus

t av

oid

clos

e sk

in c

onta

ct w

ith o

ther

s

Aro

mat

ase

inhi

bito

rsN

ot y

et a

ppro

ved

for t

his

indi

catio

n; a

fter

ons

et o

f pub

erty

, may

in-

crea

se g

onad

otro

pin

secr

etio

n an

d ci

rcul

atin

g te

stos

tero

ne le

vels

41

Ora

l let

rozo

le2.

5 m

g da

ilyD

ecre

ased

leve

l of h

igh-

dens

ity li

popr

otei

n ch

oles

tero

l, er

ythr

ocyt

osis

, ve

rteb

ral d

efor

miti

es40

Ora

l ana

stoz

ole

1.0

mg

daily

Less

pot

ent t

han

letr

ozol

e

Gir

ls

Estr

ogen

Ethi

nyl e

stra

diol

(co

mpo

nent

of

con

trac

eptiv

e pi

lls)

Initi

al d

ose,

2 μ

g da

ily; i

ncre

ase

to 5

μg

daily

aft

er 6

–12

mo;

low

er-

dose

pill

s av

aila

ble

in E

urop

eLi

ver t

oxic

ity, i

ncre

ased

leve

ls o

f som

e pl

asm

a-bi

ndin

g pr

otei

ns, p

oten

-tia

lly g

reat

er r

isk

of th

rom

boem

bolis

m a

nd a

rter

ial h

yper

tens

ion

than

with

nat

ural

est

roge

ns

17β

-Est

radi

ol

Ora

lIn

itial

dos

e, 5

μg

per

kilo

gram

of b

ody

wei

ght d

aily

; inc

reas

e to

10

μg

per

kilo

gram

dai

ly a

fter

6–1

2 m

oN

atur

al e

stro

gen,

may

be

pref

erab

le to

syn

thet

ic e

stro

gens

; tra

nsde

r-m

al r

oute

may

hav

e ad

vant

ages

ove

r or

al a

dmin

istr

atio

n

Tran

sder

mal

pat

chO

vern

ight

pat

ch: i

nitia

l dos

e, 3

.1–6

.2 μ

g pe

r 24

hr

(one

-eig

hth

to o

ne-

four

th o

f 25-

μg 2

4-hr

pat

ch);

incr

ease

by

3.1–

6.2

μg p

er 2

4 hr

eve

ry

6 m

o

No

data

on

dose

equ

ival

ent b

etw

een

estr

adio

l pat

ches

and

gel

av

aila

ble

in y

oung

er p

atie

nts

Con

juga

ted

equi

ne e

stro

gens

Initi

al d

ose,

0.1

625

mg

daily

for

6–12

mo

with

sub

sequ

ent a

djus

tmen

t to

0.3

25 m

g da

ily; d

ose

depe

nds

on fo

rmul

atio

nN

ot e

stra

diol

pre

curs

ors;

use

is q

uest

ione

d as

not

bei

ng p

hysi

olog

ical

an

d be

caus

e of

rep

orts

of i

ncre

ased

car

diov

ascu

lar

risk

s in

pos

t-m

enop

ausa

l wom

en

Prog

estin

Var

ious

opt

ions

(us

ually

ora

l)U

sual

ly n

eces

sary

onl

y if

estr

ogen

trea

tmen

t con

tinue

s lo

nger

than

12

mo

Add

ed to

indu

ce e

ndom

etri

al c

yclin

g af

ter

12–1

8 m

o of

est

roge

n th

er-

apy

(lat

er if

est

roge

n do

se is

incr

ease

d sl

owly

, soo

ner

if br

eak-

thro

ugh

blee

ding

occ

urs)

* Fo

r fu

rthe

r di

scus

sion

of t

hese

age

nts

and

of t

reat

men

t of

per

man

ent

hypo

gona

dism

, see

Tab

le 3

in t

he S

uppl

emen

tary

App

endi

x.†

Tes

tost

eron

e un

deca

noat

e ta

blet

s or

ana

bolic

ste

roid

s ar

e no

t re

com

men

ded

for

the

indu

ctio

n of

sec

onda

ry s

exua

l cha

ract

eris

tics.



156



Conclusions a nd R ecommendations

The patient in the vignette has delayed puberty. Given that he is male and has a family history of late pubertal development, CDGP is the most like-ly diagnosis. Before making this diagnosis, a care-ful evaluation is required to rule out other causes; this is especially true among young women, in whom underlying disorders are more common.

In CDGP, in which pubertal delay is transient, the decision regarding whether to treat should be made by the patient; the goal of therapy, when used, is to induce the acceleration of sec-ondary sexual characteristics or growth and to mitigate psychosocial difficulties. For boys who elect to be treated, we initiate monthly intramus-cular injections of 50 mg of testosterone ester for 3 to 6 months; this regimen can be repeated for another 3 to 6 months with dose escalation (Table 3). If spontaneous puberty has not occurred after 1 year, other diagnoses, such as permanent

hypogonadotropic hypogonadism, should be re-considered, and MRI of the brain is indicated. We believe that when CDGP is treated, therapy should be with testosterone alone, even if stature is a prominent concern. We do not use growth hormone or anabolic steroids for delayed pu-berty, nor do we recommend aromatase inhibi-tors for this indication, pending more data from randomized trials.

Dr. Palmert reports receiving funding as a member of the Hvidøre Study of Childhood Diabetes, which is supported by Novo Nordisk; payment for lectures at the 2011 Japanese Endo-crine Society Meeting and the 2011 Asahikawa Winter Confer-ence on Molecular Medicine with support from Japan Chemical Research Pharmaceuticals; and payment for participating in a symposium sponsored by Sandoz at the 2011 Annual Meeting of the European Society of Pediatric Endocrinology, as well as for a Grand Rounds lecture at McGill University sponsored by Eli Lilly. Dr. Dunkel reports receiving lecture fees from Pfizer and pay-ment for participating in a symposium sponsored by Sandoz at the 2011 Annual Meeting of the European Society of Pediatric Endocrinology. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

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Bibliografia:

Howard SR, Dunkel L. Management of hypogonadism from birth to adolescence. Best Pract Res Clin endocrinol Metab. 2018 Aug;32(4):355-372.

Dye AM, nelson GB, Diaz-Thomas A. Delayed Puberty. Pediatr Ann. 2018 Jan 1;47(1):e16-e22

atraso pubertÁrio


ATrAso PuBerTário | CAusAs PerifériCAs | MAriAnA MArTinho

159

2

Management of hypogonadism from birth toadolescence

Sasha R. Howard, MBBS, PhD, Dr *, 1,Leo Dunkel, MD, PhD, Professor 1

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine andDentistry, Queen Mary, University of London, UK

a r t i c l e i n f o

Article history:Available online 6 June 2018

Keywords:pubertyhypogonadismgonadotropin therapyrFSHtestosteroneestradiol

Management of patients with hypogonadism is dependent on theunderlying cause. Whilst functional hypogonadism presenting asdelayed puberty in adolescence is relatively common, permanenthypogonadism presenting in infancy or adolescence is unusual.The main differential diagnoses of delayed puberty include self-limited delayed puberty (DP), idiopathic hypogonadotropic hypo-gonadism (IHH) and hypergonadotropic hypogonadism. Treatmentof self-limited DP involves expectant observation or short coursesof low dose sex steroid supplementation. More complex andinvolved management is required in permanent hypogonadism toachieve both development of secondary sexual characteristics andto maximize the potential for fertility. This review will cover theoptions for management involving sex steroid or gonadotropintherapy, with discussion of benefits, limitations and specific con-siderations of the different treatment options.

© 2018 Elsevier Ltd. All rights reserved.

Introduction

The hypothalamic-pituitary-gonadal (HPG) axis is measurably active in fetal life, and then un-dergoes a process of reactivation twice between birth and adulthood. The first is in early infant life,

* Corresponding author.E-mail addresses: [email protected] (S.R. Howard), [email protected] (L. Dunkel).

1 Full Address: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine andDentistry, Queen Mary, University of London, 1st Floor North, John Vane Science Centre, Charterhouse Square, London, EC1M6BQ. Fax: þ2078826197.

Contents lists available at ScienceDirect

Best Practice & Research ClinicalEndocrinology & Metabolism

journal homepage: www.elsevier .com/locate/beem

https://doi.org/10.1016/j.beem.2018.05.0111521-690X/© 2018 Elsevier Ltd. All rights reserved.

Best Practice & Research Clinical Endocrinology & Metabolism 32 (2018) 355e372



160

during the so-called ‘mini-puberty’, and the second after a period of dormancy between the age of oneand eight-to-nine years, during the onset of puberty [1]. While puberty is recognised as the matura-tional process of the reproductive endocrine system that results in achievement of adult height andbody proportion, in addition to development of the genital organs and the capacity to reproduce, mini-puberty has also been increasingly recognised as vital for normal fertility development [2].

Development of the clinical features of puberty is initiated by the reactivation of the HPG axis afterthis relative quiescence, but the nature of the puberty ‘brake’ that acts on the axis after the mini-puberty, and how and when this brake is released, is not well understood. Whilst the timing of pu-bertal onset varies within and between different populations, it is a highly heritable trait with esti-mates of up to 80% of individual variation being under genetic regulation [3]. However despite strongheritability, the key genetic factors that determine human pubertal timing in the normal populationand in cases of disturbed pubertal timing remain mostly unknown.

In healthy boys the normal age limits for Tanner genital stage 2 (G2) development are between 9and 14 years [4]. Similarly, the great majority of Caucasian girls have at least early signs of breastdevelopment (Tanner breast stage 2, B2) by 13 years of age (Fig. 1). Whilst a large variability in thetiming of pubertal onset exists in both genders, clear age cut-offs for normal pubertal developmenthave been drawn. However, for both genders the age limits for identifying children who need evalu-ation for delayed puberty (DP) may vary in different ethnic groups.

Diagnosis of hypogonadism, infants

Mini-puberty provides a window of opportunity for evaluation of the functionality of the HPG axisbefore puberty. However, even at birth a suspicion of hypogonadismmay be raised by the assessment ofgenital appearance. In conditionsof congenital gonadotropin-releasinghormone (GnRH)deficiency, suchas in idiopathic hypogonadotropic hypogonadism (IHH), both fetal and postnatal pituitary gonadotropinsecretion is low. Inmales during fetal life, placental human chorionic gonadotropin (hCG) stimulates thetestis, resulting in masculinization of the external genitalia. However, later in fetal life, when hCG con-centration in fetal circulation falls, luteinizing hormone (LH) stimulates further penile growth andtesticular descent. Consequently, boys with IHH often have micropenis and cryptorchidism at birth. It isimportant to consider the diagnosis of IHH in isolated congenital undescended testes [2]. Primaryhypogonadismmayalsopresent at birthwithunder-developedgenitalia inmale infants if the condition isgonadotropin dependent, or alternatively as ambiguous or female genitalia if the defect is of early-fetalonset due a disorder of sex development (DSD) [5]. A full review of the diagnosis and management ofDSD is beyond the scope of this review, and has been comprehensively addressed elsewhere [6].

If a suspicion of hypogonadism arises in the first 3e4months of life it can be investigated on the basisof sex steroid and gonadotropin levels without the need for stimulation tests. Gonadotropin levels inhealthy infants start to increase during the 1st week of life and then decrease towards the age of 6months, except for FSH levels in girls that remain elevated until 3e4 years of age [7] (Fig. 2). Testosteronelevels in boys increase in response to LH levels and peak at 1e3 months of age, but in girls estradiollevels fluctuate, probably reflecting ovarian follicular growth and atrophy. Estradiol levels in girls declinein the 2 nd year of life. Postnatal HPG axis activation during themini-puberty has important roles in bothsexes: in males, for penile and testicular growth [8] and in girls, for maturation of ovarian follicles anddevelopment of estrogen-sensitive target tissues (mammary gland and uterus) [9].

However, most studies on hormone levels during mini-puberty have had cross-sectional design,and hence the inter-individual differences in timing, duration, andmagnitude of themini-puberty haveremained largely unexplored. Serial blood sampling from healthy infants is problematic because of itsinvasiveness and non-invasive urine or salivary sampling are a way around this problem; however,urine and saliva assays are not widely used in clinical routine.

Recently, longitudinal data has provided new information about the hormonal patterns includingthe timing of the peak hormone levels and the decrease in hormonal activity according to develop-mental age [8e11]. Because of the large variability in reported estradiol levels during infancy, profilingof longitudinal hormone levels is particularly important to gain a better understanding of the nature ofovarian activity in infant girls. Consequently, these data may aid in defining aberrant HPG axis activityin infancy and facilitate early diagnosis of HPG axis disorders.

S.R. Howard, L. Dunkel / Best Practice & Research Clinical Endocrinology & Metabolism 32 (2018) 355e372356



161

Newermarkers of gonadal function are useful, particularly in males, for diagnosis of hypogonadism,both soon after birth and after the mini-puberty is completed. In healthy newborn boys, inhibin Alevels are undetectable [12], but rise from day 2 onwards to robust levels by the end of the first month[13], reflecting Sertoli cell activity. Inhibin B levels peak in boys at three months of age to levels higherthan in adult men, but then decrease by 15months of age [14], although remain detectable at the lowerlimit of the adult range through into mid-childhood [12]. In girls, inhibin B levels are low at birth butincrease during the first months of life and then decrease again towards one year of age [14]. Thus,

Fig. 1. The distribution of pubertal timing in healthy boys and girls. These data have been incorporated into UK growth charts andare available at www.growthcharts.rcpch.ac.uk. Original data from [107].

S.R. Howard, L. Dunkel / Best Practice & Research Clinical Endocrinology & Metabolism 32 (2018) 355e372 357



162

inhibin B is a useful marker of Sertoli cell function from the neonatal period into early childhood andcan be used to assess males infants with micropenis and/or cryptorchism, both due to central andprimary hypogonadism [5]. Its use in female infants is less clear.

Anti-mullerian hormone (AMH) is strongly expressed by Sertoli cells from the time of testiculardifferentiation to puberty and at much lower levels in females by the granulosa cells from birth untilmenopause. In boys, AMH levels increase after birth to peak levels around twomonths of age and thendecrease by the age of one year [15]. Undetectable AMH and inhibin B are diagnostic of anorchia. Ininfant girls, a similar pattern in AMH levels during the first months of life has also been reported, butthe levels in girls are significantly lower [16].

In primary hypogonadism with gonadal dysgenesis, anorchia or testicular regression, gonadotropinlevels in the mini-puberty are generally raised, but may fall to normal levels in later childhood (Table 1).However, in Turner syndrome, infant girls with the 45, X0 karyotype have higher FSH levels than healthygirls, and the levels remain elevated for several years. In contrast, Turner girls with other karyotypesthan 45, X0 often have close to normal FSH levels, suggesting some ovarian feedback effects on pituitaryFSH secretion in these patients [17]. Often, infant boys with Klinefelter's syndrome (47, XXY karyotype)have normal levels of inhibin B, AMH, and INSL3, suggesting normal Sertoli and Leydig cell function ininfancy, although they have elevated LH [18] and FSH levels [18,19]. Testosterone levels in these boys areeither normal (or slightly elevated).

Thus, low sex steroid and gonadotropin levels in an infant less than 3months of age indicate centralhypogonadism with an absence of the normal ‘mini-puberty’. In contrast, high gonadotropins asso-ciated with low/undetectable basal testosterone and INSL3 (in boys) are diagnostic of primary

Fig. 2. Patterns of postnatal gonadotropin and sex steroid secretion in boys (a) and girls (b). Gonadotropin levels start to increaseduring the 1st week of life, peak at 1e3 months, and then decline towards the age of 6 months. In boys, LH levels are higher than ingirls, and in girls, FSH levels predominate and remain elevated until 3e4 years of age. Testosterone levels in boys increase followingthe LH levels and show a clear peak at 1e3 months of age, but in girls, estradiol levels fluctuate, probably reflecting ovarian folliculargrowth and atrophy. Estradiol levels in girls decline in the 2 nd year of life. From [7]; reproduced with author permission.




163

hypogonadism. Outside of the mini-puberty period, useful tests for the investigation of hypogonadisminclude Inhibin B and AMH [5].

Diagnosis of hypogonadism, adolescence

Etiology

The pathogenesis of delayed puberty (DP) encompasses several conditions, but is most commonlydue to self-limited DP. There are threemain groups of differential diagnoses of self-limited DP (Table 2):functional hypogonadism, disorders causing primary hypogonadism and GnRH deficiency leading tohypogonadotropic hypogonadism (HH) [4,20], although up to 30 different aetiologies underlying DPhave been identified [21].

Self-limited DP, also known as constitutional delay of growth and puberty (CDGP), represents thecommonest cause of DP in both sexes. Up to 83% of boys, and 30e55% of girls, with pubertal delay haveself-limited DP [20e23]. Individuals with self-limited DP lie at the extreme end of normal pubertaltiming, with the absence of testicular enlargement in boys or breast development in girls at an age thatis 2e2.5 standard deviations (SD) later than the population mean [4]. In addition, self-limited DP mayalso encompass older childrenwith delayed pubertal progression, a diagnosis that is aided by the use ofpuberty normograms (Fig.1) [23]. Self-limited DP is associatedwith adverse health outcomes includingshort stature, reduced bone mineral density and compromised psychosocial health [24].

Self-limited DP segregates within families with complex patterns of inheritance including auto-somal dominant, autosomal recessive, bilineal and X-linked [25], although sporadic cases are alsoobserved. The majority of families display an autosomal dominant pattern of inheritance (with orwithout complete penetrance) [25,26]. 50e75% of subjects with self-limited DP have a family history ofdelayed pubertal onset [25].

Table 1Upper limits for creatinine-corrected urinary gonadotropin levels before term, at term, and at 2e6 months of corrected age.Values above the limits suggest primary gonadal failure.

Before term At term At 2e6 months corrected age

GirlsFSH (IU/mmol Cr) 250 13 5LH (IU/mmol Cr) 500 10 0.5

BoysFSH (IU/mmol Cr) 10 3 1.5LH (IU/mmol Cr) 20 5 0.5

Values are based on original data published in Kuiri-H€anninen, T., Kallio, S., Seuri, R. et al., 2011a. Postnatal developmentalchanges in the pituitaryeovarian axis in preterm and term infant girls. J. Clin. Endocrinol. Metab. 96, 3432; Kuiri-H€anninen, T.,Haanp€a€a, M., Turpeinen, U. et al., 2013b. Postnatal ovarian activation has effects in estrogen target tissues in infant girls. J. Clin.Endocrinol. Metab. 98, 4709.

Table 2Differential diagnoses of self-limited delayed puberty.

HypergonadotropicHypogonadism

HypogonadotropicHypogonadism

FunctionalHypogonadotropicHypogonadism

Common Causes: Male: Klinefelter's SyndromeCongenital anorchia/testicularregressionFemale: TurnerSyndrome Premature ovarianinsufficiencyBoth: Gonadaldysgenesis Chemotherapy/Radiation Therapy

Isolated HypogonadotropicHypogonadism Kallmannsyndrome Combined PituitaryHormone Deficiency CNSTumours/InfiltrativeDiseases Chemotherapy/Radiation Therapy

Inflammatory BowelDisease Coeliac DiseaseAnorexia NervosaHypothyroidism ExcessiveExercise

Table modified and reprinted with permission from Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med 2012;366:443e53 [4].




164

The absence of pathological medical history, signs and symptoms, and a positive family history ofpubertal delay in one or both of the parents suggests a diagnosis of self-limited DP; however, beforemaking the diagnosis, significant pathological conditions must be excluded. These include the afore-mentioned differential diagnoses of DP (Table 2) [4,20]: functional hypogonadotropic hypogonadism,where late pubertal development is due to maturational delay in the HPG axis secondary to chronicdisease (found in approximately 20%), malnourishment, excessive exercise, psychological or emotionalstress; hypergonadotropic hypogonadism, with primary gonadal failure leading to elevated gonado-tropin levels due to lack of negative feedback (found in approximately 7% of male patients and 25% offemale patients with DP); and permanent hypogonadotropic hypogonadism, characterized by low LHand FSH levels (9% of boys and up to 20% of girls).

A thorough history should note evidence of chronic disease, anorexia, the intensity of athletictraining, and the timing of puberty of both parents (Fig. 3). A history of chronic illnesses, such as coeliacdisease and inflammatory bowel disease, will suggest a temporary or secondary delay of puberty.

Permanent GnRH deficiency is due to congenital hypothalamic or pituitary disorders, or an acquiredcentral dysfunction secondary to irradiation, tumour or vascular lesion. A picture of IHH with noassociated anatomical or functional defect in the HPG axis occurs in 1e10 cases per 100,000 births.Because of different causes and incomplete penetrance, there is awide spectrum of phenotypes, rangingfrom complete HH with lack of pubertal development to a partial hypogonadism with an arrest ofpubertal development, and even reversible HH in some patients post treatment [27]. Despite recentadvances, with over thirty genes linked to this disorder identified, the pathophysiological basis of HH inapproximately 50% of individuals remains unclear. The condition may be due to failure of developmentof GnRH neurons, lack of activation of GnRH secretion or disrupted GnRH signaling. Kallmann Syndrome(KS, HH associated with anosmia) is the most common form of isolated HH, accounting for 60% of cases.

Assessment

It may be very difficult to distinguish clinically between the diagnosis of DP and congenital IHH inthe teenage years. In the majority of subjects with constitutional delay there is delayed maturationduring early childhood, and consequently they are shorter than their peers. It has been shown thatthose DP subjects who also have poor growth in childhood may not fully exploit their genetic heightpotential, resulting in an adult height below their mid-parental target height [28e31], with an averageloss of 4.2 cm if untreated [31]. However, other studies showed only a negligible difference in finalheight, even in DP subjects who have received no intervention [32e38]. This may imply a patho-physiological mechanism additional to lack of sex steroids contributing to the growth phenotype insome patients with DP, but not in others [38].

By contrast, patients with congenital IHH usually have steady linear growth during childhood andonly become short for their age with absence of the pubertal growth spurt. However, hypogonado-tropic states cannot be ruled out by short stature and slow growth rate. In DP adrenarche may alsooccur later than usual, in contrast to the normal age of adrenarche in patients with isolated HH [4].Bone age in DP (X-ray film of left hand and wrist) is behind chronological age, but the developmentalmilestones are achieved at a normal bone age; that is, onset of signs of pubertal development by thebone age of 13 years in girls and 13.5 years in boys. However, whilst bone age delay provides usefulinformation in the growth analysis, it contributes little to the differential diagnosis. Gonadotropin andtestosterone concentrations increase in concert with the development of the bone age. Thus, all stagesof pubertal development occur at an age later than usual.

In congenital IHH the diagnosis is typically made during the second or third decade of life. Commonpresenting signs are delayed onset of puberty, poorly developed secondary sexual characteristics,eunuchoid body proportions, or infertility. In some cases the diagnosis can be suspected before the ageof pubertal onset, as discussed above, during the mini-puberty. The presence or absence of “red flag”features remains the strongest discriminator between isolated DP and IHH. These red flags includemicroorchidism, cryptorchidism or micropenis, indicating a lack of prior ‘mini-puberty’, or the pres-ence of other features of GnRH deficiency which include anosmia or hyposmia due to hypoplasia of theolfactory bulbs (in Kallmann Syndrome) and occasionally cleft lip and palate, unilateral renal agenesis,short metacarpals, sensorineural hearing loss, synkinesia and color-blindness [39]. Evidence of other




165

syndromic diagnoses linked to central hypogonadism may also be present, particularly with neuro-logical phenotypes such as in the 4H syndrome (Hypomyelination, Hypodontia and HypogonadotropicHypogonadism) [40] or ataxia, as seen in GordoneHolmes syndrome [41,42].

Gonadotropin levels assessed by basal LH and FSH determination are often increased in adolescentswith primary hypogonadism due to e.g. Klinefelter syndrome, but the basal gonadotropin values arenot useful in the differential diagnosis of self-limited delay and HH [43]. Investigation of the differentialdiagnosis of these latter two conditions may involve a number of physiological and stimulation tests,including assessment of LH pulsatility by frequent sampling [44], prolactin response to provocation[45], gonadotropin response to GnRH [46,47], testosterone response to hCG [48e50] and first morning-voided urine FSH and LH [51]. Most recently, a single measurement of inhibin B < 35 pg/mL in pre-pubertal boys has been shown to discriminate IHH from self-limited DP with high sensitivity [52], butthis has not been demonstrated in girls. The trio of testicular volume (cut-off 1.1 ml), GnRH-inducedmaximal LH (cut-off 4.3 IU/L) and basal inhibin B level have been proposed as the most effectivediscriminators of IHH from DP in a new study [21]. However, follow-up is often warranted before adefinitive diagnosis can be made. An MRI pituitary with olfactory bulb views is warranted in cases ofsuspected hypogonadotropic hypogonadism.

With the major advances in the discovery of genes causing IHH that have taken place in the last twodecades, increasing genetic diagnosis is likely to inform future management [53]. However, variablepenetrance and evidence for geneegene interactions in the inheritance of IHH can make prediction ofphenotype from genetic testing difficult. Family history and certain clinical features, such as cleft palatein FGFR1/FGF8, obesity or sleep disorder in PROK2 or PROKR2, and anosmia in KAL1 can be used toguide genetic testing.

Fig. 3. Differential diagnosis of delayed puberty. Algorithm for the evaluation of a patient with delayed puberty. CDGP - constitu-tional delay of growth and puberty, GI - gastrointestinal, GH - growth hormone, GHD - GH deficiency, PRL - prolactin, IGF-1 - insulin-like growth factor 1. Reprinted with permission from Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med 2012;366:443e53 [4].




166

In cases of primary hypogonadism a karyotype is important to confirm or exclude a diagnosis ofTurner or Klinefelter's syndrome. Assessment of uterine development by ultrasound may aid diagnosisand response to treatment. Autoantibody screening may be informative in cases of female hyper-gonadotropic hypogonadism with premature ovarian insufficiency (POI). Measurement of AMH isvaluable in POI to assess ovarian reserve.

Treatment of hypogonadism e males

Infancy

Postnatal HPG axis activation in boys, which results in testicular activation and proliferation ofSertoli cells during this period, has a role in the development of reproductive capacity. The associationof testosterone levels at three months of age and early penile growth [54], and involution of the penisand scrotum in boys with IHH in infancy [55] suggests a role for postnatal testosterone in “stabilizing”male genitalia. Analogous to true puberty, androgens secreted early in life may also have effects onlinear growth, skeletal development, body composition, and psychosexual development [56].

Hormone therapy has thus been advocated for penile growth and testiculardescent in infant boyswithIHH or Kallmann syndrome [57]. In boys with primary hypogonadism, slightly higher FSH and LH levelsand lower inhibin B as well as INSL-3 levels are seen at threemonths of age compared to healthy controls[58]. Reported testosterone levels in cryptorchid boys are normal [59,60] or subnormal [61]. Decreasedserumandrogenbioactivityhas alsobeen reported in infant boyswithat least oneundescended testis [62].

Neonatal treatment with testosterone can be used to correct micropenis in both central and primaryhypogonadism. Standard therapy is with either IM testosterone enanthate 25mg every 3e4 weeks for 3months, or topical therapy with either 5% testosterone cream or DHT [63]. Management of cryptor-chidism is with surgical correction, with the use of hCG or GnRH therapy adjuncts only likely to providea small additional benefit [64]. However, these therapies will not address the microorchidism seen in amale infant with IHH. A small number of studies of infants with IHH have used recombinant LH and FSHtreatment to increase both penile length and testicular volume [65,66]. Outcomes included improvedtesticular size and function (measured with inhibin B and AMH), but it is not known if such therapy willimprove the response to pubertal treatments or fertility outcomes in men with IHH. Concerns remainabout the possible deleterious effects of hCG on germ cells in cryptorchid testes in infants, as its use hasbeen associated with smaller testis volumes and higher FSH levels in adulthood [67,68].

Adolescence

Induction or progression of puberty is commonly considered for adolescents who either havesignificantly delayed or arrested puberty, or have been diagnosed with hypogonadism. Appropriatetreatment modalities are directed according to the underlying diagnosis.

A management strategy of ‘watchful waiting’ may be appropriate in isolated DP, where pubertalonset is late but expected to occur spontaneously. However, this decision should be taken inconjunction with the patient, taking into consideration their concerns and expectations. One majorconcern often raised by patients and their families is the effect of pubertal delay on both current andadult height. Patients with DP are often short compared with their peers, and this is often compoundedby the fact that many have pubertal delay combined with familial short stature. However, reassurancecan be given to such patients as usually in DP an adult height only slightly below the genetic heightpotential (target height) is reached; although there may be large individual variation [30,69].

DP in adolescents can be associated with significant anxiety about body image in terms of physicalsize and pubertal immaturity, decreased self-esteem with social isolation, withdrawal from sportingactivities and psychosocial and peer relationship difficulties. In these circumstances, there is evidencethat hormonal therapy can be beneficial [70,71]. The link between DP and reduced academic perfor-mance, substance misuse and behavioral difficulties is less well established.

In contrast, if “red flag” markers of hypogonadism are present or if endogenous gonadotropin-dependent puberty has not started after one year of treatment, then permanent HH and other di-agnoses should be reconsidered. In such instances treatment should be initiated promptly in order to




167

optimise skeletal growth and to induce secondary sexual characteristics and, therefore, minimise thepsychosocial difficulties faced by adolescents with hypogonadism.

Self-limited DP managementThe options for management of male patients with DP include monitoring with reassurance or

therapy with low dose testosterone to augment growth rate and to induce secondary sexual charac-teristics (Table 3). There are a great number of published studies of treatment of DP in boys; these aremainly observational, with some small, randomized controlled trials [71e73]. Most report treatmentwith short courses of low dose androgens with outcomes of increased height velocity withoutadvanced bone age, advanced sexual maturation and often improvement in psychosocial parameters.

The most commonly used treatment regime with low dose testosterone for boys with DP issupplementation with intramuscular depot preparations of a testosterone ester [74], at a startingdose of 50 mg each month for 3e6 months; a further 3e6 months of treatment may be given, withdose escalation as required (Table 3). Monitoring via serum testosterone increase (to mid-referencerange one-week post injection), height velocity and virilisation is appropriate. The length of thepolymorphism Cytosine-Adenine-Guanine (CAG) trinucleotide repeats present in the androgen re-ceptor (AR) gene is associated with androgen receptor activity, which may in part modulateresponse to testosterone therapy [75]. A diagnosis of GH deficiency must be ruled out if heightvelocity does not increase on testosterone therapy. Testosterone esters are to be avoided in hepaticimpairment and hypercalcaemia and used with caution in renal impairment. Preparations aregenerally well tolerated but side effects may include headaches, depression and androgenic effectssuch as acne. Oral testosterone undecanoate can be prone to wide variations in serum testosteronebecause of its short half-life and thus requires careful monitoring, although has been successfullyused for pubertal induction at a dose of 40e160 mg daily [23]. Although anabolic steroids such asoxandralone have been used historically for short-term improvement in height velocity, they are lesseffective in stimulating pubertal virilisation and therefore they are not recommended for themanagement of DP.

As discussed, DP is commonly seen in combination with idiopathic short stature (ISS) and suchpatients may present with concerns about short stature far out-weighing those about DP. Afterexclusion of those patients with GH deficiency, for example by the use of a primed GH-provocation test,the treatment of GH-replete DP patients with growth hormone remains controversial: it has beenapproved by the US FDA for the treatment of ISS and height SDS �2.25 for age, but leads to only amodest increase in adult height and its use is not recommended [76,77].

A further potential pharmacological target in short boyswithDP is inhibition of estrogen biosynthesisfrom androgens with aromatase inhibitors [78,79]. Epiphyseal closure is dependent on estrogens andthus aromatase inhibitors (AIs) can potentially act to extend the time period of long bone growth. Somepublisheddata supports this possible effectofAIs todelaybonematurationand to increase adultheight inboys with short stature and/or DP [78,79]. However, despite recent data suggesting a good safety profile,there remains uncertainty about the efficacy and appropriateness of AI therapy in DP [80,81].

Permanent hypogonadismAlthough sex steroid replacement is used in nearly all conditions of hypogonadism for initiation of

male puberty, more complex and involved management including gonadotropin treatment may berequired in males with hypogonadism to achieve both the development of secondary sexual character-istics and to maximize the potential for fertility. Management of specific indications is discussed below.

Hypogonadotropic hypogonadismIn young men with a diagnosis of IHH, induction of puberty with sex steroid therapy is similar to

that in self-limited DP; however, treatment can be initiated at a younger age (12yrs) if the condition isconfirmed. In some patients, it may not be initially possible to distinguish between a diagnosis of IHHand DP and, therefore, commencement of testosterone therapymay be delayed until 14yrs. The startingdose of testosterone ester for IHH patients is also commonly 50 mg, but doses are gradually increasedto full adult replacement levels over approximately three years (Table 3). Monitoring of response totreatment and for possible side effects is required, and therapy is likely to be required life-long.




168

Table

3Med

icationsusedforthetrea

tmen

tof

self-lim

ited

delay

ofpube

rtyan

dperman

enthy

pog

onad

ism

emales.

Drugan

dFo

rmulation

Inductionof

Pube

rtyin

Boy

sSideEffectsan

dCau

tion

s

Isolated

DP

Hyp

ogon

adism

Testosterone

(T)a

Erythrocy

tosis,weigh

tga

in,p

rostatic

hyp

erplasia.

Highdoses

cancause

premature

epiphysea

lclosure.N

otforuse

inbo

yswithbo

neag

e<10

yrs.

Ten

anthate,

cypionate,

andpropionate.

Ten

anthatehas

longe

rduration

ofeffect

than

Tpropionate.

IMinjection.

Not

reco

mmen

ded

before

13.5

yrsof

age.

Initialdose50

e10

0mgev

ery4wee

ksfor

3e6mon

ths.

After

review

ofresp

onse:repea

ted

trea

tmen

twith25

e50

mgincrem

entin

dose(not

exceed

ing10

0mg)

Can

initiate

afterag

e12

yrsat

50mg/

mon

th.Increa

sewith50

mgincrem

ents

every6e

12mon

ths.After

reaching

100e

150mgmon

thly,d

ecreaseinterval

toev

ery2wee

ks.A

dultdose20

0mgev

ery

2wee

ks.

AllIM

preparations:

locals

ideeffects

(pain,e

rythem

a,inflam

matoryreaction

andsterile

abscess).P

riap

ism

canoc

curin

patients

withsick

lecelldisea

se.

Tundecan

oate

IMinjection

Nodataav

ailable.

Adultdoseis

1000

mgev

ery10

e14

wee

ks.

Veryrarely,p

arox

ysmsof

cough

ingan

ddyspnoe

apost-injection,a

scribe

dto

lipid

embo

lism

from

theve

hicle;hen

cenot

licen

sedin

USA

.Tge

l.Tran

sdermal

preparations,ap

plie

dtopically

atbe

dtime.

Nodataav

ailable.

Can

bestartedwhen

approximately50

%ad

ultdosewithIM

Thas

been

achieve

d.

Adultdose50

e80

mgdaily.

Localirritation

.After

applying,

avoidclose

skin

contact

withothers,especially

females

Trea

tmen

tofFe

rtilityin

Boys

andMen

b

Isolated

DP

Hyp

ogon

adism

Pulsatile

GnR

Hs.c.pump

Not

reco

mmen

ded

routinely

Initial:5e

25ng/kg

/pulseev

ery90

e12

0min;increa

seto

25e60

0ng/kg

/pulse

Req

uires

extensive

experience.M

ost

physiologicalform

ofreplacemen

t.hC

G(SCor

IM)plus

recombina

ntFSH

(SC).

Not

reco

mmen

ded

routinely

hCG:Dose50

0e30

00IU

twicewee

kly,

increa

sedto

every2day

s.Dosead

justed

basedon

serum

Tleve

ls.

rhFS

H:Dose75

e22

5IU

2e3times

wee

klyc.

hCG:Inflam

mationlocally

inthetestis,

may

induce

apop

tosisof

germ

cells

.In

hyp

ogon

adotropic

hyp

ogon

adism

with

prepube

rtal

onsetitis

necessary

toad

dFS

Hto

induce

testiculargrow

than

dsp

ermatog

enesis.N

odataon

effectson

future

fertility.

Tablemod

ified

andreprintedwithpermission

from

Palm

ertMR,D

unke

lL.C

linical

practice.

Delay

edpube

rty.

NEn

glJMed

2012

;36

6:44

3e53

(4).

aTe

stosteroneundecan

oate

POtabletsor

anab

olic

steroidsarenot

reco

mmen

ded

fortheinductionof

seco

ndarysexu

alch

aracteristics.

bInductionof

fertility

may

beless

successfulin

men

whohav

elower

baselin

etesticularvo

lumes,h

avereceived

previou

slytestosteronetrea

tmen

t,an

dhav

enot

previou

slyreceived

trea

tmen

twithGnRH

[82e

85]or

gonad

otropins.

cFS

Hpre-treatmen

tfor4mon

thsmay

bebe

nefi

cial

inmen

withprepube

rtal

testes

[91].




169

Maintenance therapy can be with IM testosterone, often as the longer acting testosterone undecanoate(Nebido), topical or oral therapy.

Importantly, testosterone therapy does not induce testicular growth or spermatogenesis in menwith HH, as this is dependent on high intra-testicular concentrations of testosterone produced by LH-stimulated Leydig cells, in conjunction with FSH acting on Sertoli cells. Therefore, induction of fertilityrequires treatment with either pulsatile GnRH [82e84] or exogenous gonadotropins [84]. Data fromthe last 5e10 years on a variety of regimens has been published, with treatments varying by indication,underlying diagnosis and severity of hypogonadism. Fertility outcomes also vary, with poorer re-sponses in patients with signs of absent mini-puberty (prepubertal testes, cryptorchidism, and/or lowinhibin B) [83,85]. Genetic diagnoses may also guide therapy: treatment of patients with KAL-1 mu-tations can bemore difficult as theymay have defects at several levels of the HPG axis [86], and patientswith IHH due to GnRHR mutations may be better treated with hCG and FSH than pulsatile GnRH [87].

A sub-set of adolescent patients with IHH will have had a spontaneous onset of pubertal develop-ment that has then arrested. In suchpatients,monotherapywith hCG canbe trialled for both completionof pubertal development and induction of fertility [88]. FSH can then be added if there is persistentazoospermia after 6e12months of treatment. In apubertal adolescent males, induction of puberty witheither hCGmonotherapy or with combinational therapy of hCGþ rFSH leads to better testicular growthand fertility outcomes than treatment with testosterone therapy [89]. Furthermore, a combined regimeof hCGþ FSH has greater potential efficacy in the induction of spermatogenesis thanmonotherapywithhCG [89,90]. Additionally, timing of treatment is important, as FSH pre-treatment may theoreticallyoptimise the Sertoli cell population prior to exposure to hCG or GnRH, and thus has the potential toimprove fertility outcomes [91,92]. Although the optimal regimen in severe cases, i.e. those withtesticular volume <4 mL, is unknown, FSH pre-treatment followed by GnRH or combination hCG andFSH treatment may maximize the potential for fertility [93]. Earlier age of treatment to induce sper-matogenesis may also be beneficial in increasing the capacity for and speed of sperm production oncefertility is desired; however, assisted reproductive technologies may still be required [94].

At the other end of the spectrum, patients can exhibit reversal of their phenotype during treatment.This phenomenon is being increasingly recognized in up to 20% of IHH cases [27]. Awareness of this isimportant as a ‘trial off treatment’ can be utilized intermittently to assess requirements for mainte-nance therapy. However, these casesmay also relapse off treatment and thus need ongoingmonitoring.Patients with acquired HH, usually secondary to tumours or other structural lesions of thehypothalamicepituitary axis or haemochromatosis, require treatment of their underlying conditionwith sex steroid or gonadotropin therapy depending on their specific requirements [92,95].

Hypergonadotropic hypogonadismThe commonest condition underlying hypergonadotropic hypogonadism in males is Klinefelter's

syndrome (47, XXY), with a prevalence of 1 in 667 live births. The majority of those affected will enterpuberty spontaneously at a normal age [96], although DP may be seen in those with a more complexkaryotype (48, XXYY, 48, XXXY, 49, XXXXY). Sex steroid replacement is therefore not normally requiredfor these patients at the start of puberty, but testosterone levels become increasingly deficient byTanner stages 4e5, possibly as a result of secondary regression. However, only 10% of boys aged10e14yrs with Klinefelter's syndrome have been diagnosed and many patients only come to theattention of an Endocrinologist in later adulthood [97]. These patients present potentially difficultmanagement decisions in terms of optimizing fertility outcomes, mainly relating to timing of in-terventions [98,99]. For patients with Klinefelter's syndrome requiring treatment due to fallingtestosterone levels, haematocrit, bone density, patient well-being or sexual function, low dose sexsteroid replacement is the most commonly used therapy (Table 3). However, testicular spermextraction and cryopreservation can be considered, even in adolescence prior to testosterone treat-ment, before the progressive seminiferous tubule degeneration that occurs in Klinefelter's syndromehas had an irreversible impact on sperm production [47]. Unfortunately, the most invasive (& suc-cessful) sperm retrieval techniques have the potential to cause the most testicular damage, and sowould ideally be reserved for thosemen actively desiring fertility. Balancing these opposing factors andgiving clear information to young men who may not yet be concerned about their future fertilityoptions, in order that they might make informed choices, is highly challenging.




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The treatment of anorchic young men, secondary to congenital absence, vanishing testis syndromeor failed orchidopexy, for induction and maintenance of puberty is similar to that in boys with IHH.Androgen replacement should be commenced at a low dose with incremental dose increases. IMtestosterone esters administered monthly is the treatment of choice for pubertal induction, withtestosterone gel via calibrated dispenser or 4-monthly intramuscular depot injections of Testosteroneundecanoate 1 g used for long-term maintenance therapy (Table 3).

Management of hypogonadism - females

Infancy

There is currently no evidence for therapy in hypogonadic female infants. These girls are lesscommonly diagnosed at birth or in infancy due to the lack of physical abnormalities (as compared tomales with cryptorchidism or micropenis). However, in future pre- or postnatal genetic diagnosis mayled to increased awareness and research in this area.

Adolescence

Self-limited delayed pubertySimilarly to male patients with self-limited DP, the options for management of female patients with

DP include monitoring with reassurance or therapy using low dose sex steroids to initiate pubertaldevelopment. Initial short-term therapy should be regularly reassessed and discontinued once pubertyis progressing (Table 4).

Permanent hypogonadismAs in boys, in cases of permanent hypogonadism more intensive and long-lasting therapy is

required. Goals of treatment are induction of secondary sexual characteristics, development ofreproductive capacity and increasing adult height. Once puberty is complete, ovulation and pregnancycan be achieved by pulsatile GnRH administration or combination gonadotropin therapy.

When estrogen therapy is required to induce pubertal development, the dosing and timing shouldbe aimed at simulating the normal growth and development of secondary sex characteristics as closelyas possible, taking account of the individual's desire to begin puberty and also of the family history ofage at onset of puberty. Doses should be adjusted according to the needs and priorities of the indi-vidual. Response to therapy should be monitored in terms of the development of secondary sexcharacteristics, bone maturation, height velocity and uterine volume, with additional monitoring ofblood pressure and bone density [100].

Both in young women with Turner syndrome and combined pituitary hormone deficiency, es-trogen therapy should be coordinated with the use of GH. Previous practice in Turner syndrometended towards delaying estrogen therapy until the mid-teens in order to optimize growth pro-motion with GH. However, more recent studies point to potential benefits from treatment withcombined very low-dose estrogen and GH from an early age, in terms of final height and potentiallyother areas including cognitive development and uterine maturation [101,102]. Whilst it remainsunclear as to the best timing to initiate estrogen therapy in young women with Turner syndrome,the current consensus is that induction of puberty should not be delayed in order to promote lineargrowth [103].

Additionally, whilst ethinylestradiol has traditionally been the estrogen of choice for pediatricpatients, 17b-estradiol in transdermal, gel or oral form displays a better risk profile in terms ofgrowth restriction, liver toxicity and vascular side-effects. Data from women with combined pitui-tary hormone deficiencies receiving combined estrogen and GH treatment indicate a markedlygreater impairment of GH-mediated IGF1 synthesis with ethinylestradiol than with 17b-estradiol.Uterine development may also be impaired with the use of ethinylestradiol as compared to 17b-estradiol ([104,105]). Conjugated equine estrogens have been used, but formulations vary in bio-logical potency and in view of reports of increased cardiovascular risks in postmenopausal womenare best avoided.




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Estrogen therapy should be initiated at a low dose (one-eighth to one-quarter of the adult dose) andincreased gradually (at intervals of 6e12 months) [100]. Doses can then be adjusted to the response(Tanner stage, bone age, and uterine growth), or if available, by ultrasensitive estradiol assay [106],with the aim of completing feminization gradually over a period of 2e3 years (Table 4).

Aprogestin suchasoralmedroxyprogesteroneacetate should beaddedeither ifmore thanoneepisodeof significant breakthrough bleeding occurs or after 24e36 months of estrogen therapy to establishmenstrual cycles, with a frequency of at least every 2e3 months to prevent endometrial hypertrophy.

Individuals with Turner syndromewho have functioning ovaries andwho progress through pubertyspontaneously should receive contraceptive and genetic counseling. However, ovulatory functionshould be documented (FSH and LHmeasurements) because a peri-menopausal pattern of anovulationcan lead to endometrial hyperplasia.

Table 4Medications used for the treatment of self-limited delay of puberty and permanent hypogonadism e females.

Drug and Formulation Induction of Puberty in Girls Side Effects and Cautions

Isolated DP Hypogonadism

Estrogens Not recommended before13 yrs of age.

Transdermal17b-estradiole.g Evorel 25

Overnight patch: initialdose, 3.1e6.2 mg per 24 h(1/8-1/4 of 25-mg 24-hr patch);increase by 3.1e6.2 mg per24 h after 6 monthsa

Starting dose as for DP,increase by 3.1e6.2 mg per24 h until 1 full Evorel 25patch continuouslyb

Then maintenance with adultCOCP or HRT

Patches may be difficult to useand fall off, especially if cuttingwhole patches into smallerfractions Reactions to adhesiveInter-individual variationin dose response

Oral 17b-estradiol(estradiol valerate)

0.5 mg (1/2 tablet) alternatedays or 5 mg/kg of bodyweight daily; increase to 0.5 mg(1/2 tablet) or 10 mg/kg dailyafter 6e12 months

Starting dose as for DP,increase by 5 mg/kg of bodyweight every 6e12 monthsuntil dose of 1 mg (1 tablet)daily Then maintenancewith adult COCP or HRT

Inter-individual variation indose response

Oral Ethinylestradiol(2 mg tablets)

2 mg daily, increase to 4 mgafter 6 months if required

2 mg daily, increase by 2 mgevery 6 months until 10 mgThen maintenance with adultCOCP or HRT

High cost Liver toxicity,increased levels of someplasma-binding proteinsPotential increased riskof hypertension and VTEWorse growth profile

Progestins Not applicable Introduced once breakthroughbleeding or 2 þ yrs ofcontinuous estrogen

Norethisterone 5 mg More androgenic, increasedrisk of dysmenorrhoea

Utrogestan 200 mg once dailyMedroxyprogesteroneacetate

5 mg once daily

Combinationpreparations

e.g. Evorel sequi, Elleste-Duet

Treatment of Fertility in WomenPulsatile GnRHs.c. pump

Not applicable Requires extensive experience,treatment only within specialistcentres. Most physiologicalform of replacement.

hCG (SC or IM) plusrecombinant FSH (SC).

Not applicable Requires extensive experience,treatment only within specialistfertility centres

a Adjustments for body weight may be required, published advice on cutting patches available [106].b Once changed from overnight to all day use, patches to be changed twice weekly COCP e combined oral contraceptive pill,

HRT, hormone replacement therapy, VTE e venous thromboembolism.




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Conclusion

There are multiple genetic and environmental influences on the timing of puberty in the generalpopulation, and appropriate age cutoffs for delayed puberty in different ethnic groupsmay vary. DP is afrequent problem, and the most common underlying condition is self-limited (or constitutional) DP.However, the differential diagnoses include hypogonadotropic hypogonadism and primary hypo-gonadism, and these conditions must be considered in young people with pubertal delay. Additionally,both of these forms of non-self-limiting hypogonadism may be diagnosed in infancy if the suspicionarises. Distinguishing between self-limited DP and permanent hypogonadotropic hypogonadism inadolescence remains difficult.

Management of adolescents with DP is dependent on the underlying cause. Treatment of isolatedDP involves expectant observation or short courses of sex steroids in low doses, whilst more complexand involved management is required in patients with permanent hypogonadism. Achievement offertility in patients with central hypogonadism requires therapy with gonadotropins. The managementof infants diagnosed with permanent central hypogonadism is an area of future research.

Practice points

� The mini-puberty is an important window of opportunity for the evaluation of suspectedhypogonadism in an infant, and diagnosis during themini-pubertymay aidmanagement andfuture outcomes.

� It is very important to diagnose the underlying cause of delayed puberty, especially todistinguish between self-limited DP and IHH in adolescents, as treatment aims, options andduration are very different in these two patient groups.

� The consideration of fertility in hypogonadic males, even in adolescence, should be para-mount for clinicians, as appropriate treatment may optimize future fertility potential in thesepatients in a time-sensitive manner that may not be possible later in life.

� We have highlighted the need for an awareness of the clinical spectrum in IHH, and thediffering requirements of patients with severe congenital HH versus partial or indeedreversible HH.

Research agenda

� Because of the secular change in the timing of puberty, traditional limits which definedelayed puberty may need moderating in particular environments and ethnic groups.

� Because of the lack of controlled trials, it remains unclear what the optimal management ofmales with severe hypogonadotropic hypogonadism (cryptorchidism,micropenis and lack ofspontaneous increase in testicular size in puberty) should entail. Whether such patientswould benefit from prepubertal (or even neonatal) FSH treatment to improve potential forfuture fertility is an unanswered question.

� The genetic and environmental basis for both DP and IHH is an area of research where thereis still much to be discovered, and one that may bring future benefits for informed man-agement of these patients. Our understanding of the key controllers of pubertal onset and itstiming is advancing, but it is still a complex puzzle to be unlocked.

� In self-limited DP low dose sex steroid treatment is adequate for the majority of patients whorequire intervention. However, a proportion of young men will remain adversely affected bytheir delayed pubertal development and/or short stature in adolescence, which may havelong-term consequences. It is not known whether pubertal delay has a negative impact onadult bone mass and whether potentially compromised bone health is a reason to initiatesex-steroid replacement.




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[77] Bryant J, Baxter L, Cave CB, et al. Recombinant growth hormone for idiopathic short stature in children and adoles-cents. Cochrane Database Syst Rev 2007;(3). PMID: 17636758. https://doi.org/10.1002/14651858.CD004440.pub2.

[78] Hero M, Norjavaara E, Dunkel L. Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increasespredicted adult height in boys with idiopathic short stature: a randomized controlled trial. J Clin Endocrinol Metab2005;90(12):6396e402.

*[79] Wickman S, Sipila I, Ankarberg-Lindgren C, et al. A specific aromatase inhibitor and potential increase in adult heightin boys with delayed puberty: a randomised controlled trial. Lancet 2001;357(9270):1743e8.

[80] Hero M, Toiviainen-Salo S, Wickman S, et al. Vertebral morphology in aromatase inhibitor-treated males with idio-pathic short stature or constitutional delay of puberty. J Bone Miner Res 2010;25(7):1536e43.

[81] Mauras N, Ross JL, Gagliardi P, et al. Randomized trial of aromatase inhibitors, growth hormone, or combination inpubertal boys with idiopathic, short stature. J Clin Endocrinol Metabol 2016;101(12):4984e93.

[82] Pitteloud N, Hayes FJ, Boepple PA, et al. The role of prior pubertal development, biochemical markers of testicularmaturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism.J Clin Endocrinol Metab 2002;87(1):152e60.

[83] Pitteloud N, Hayes FJ, Dwyer A, et al. Predictors of outcome of long-term GnRH therapy in men with idiopathichypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002;87(9):4128e36.

[84] Warne DW, Decosterd G, Okada H, et al. A combined analysis of data to identify predictive factors for spermatogenesisin men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone andhuman chorionic gonadotropin. Fertil Steril 2009;92(2):594e604.

[85] Liu PY, Baker HW, Jayadev V, et al. Induction of spermatogenesis and fertility during gonadotropin treatment ofgonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab 2009;94(3):801e8.

[86] King TF, Hayes FJ. Long-term outcome of idiopathic hypogonadotropic hypogonadism. Curr Opin Endocrinol DiabetesObes 2012;19(3):204e10.

[87] Caron P, Chauvin S, Christin-Maitre S, et al. Resistance of hypogonadic patients with mutated GnRH receptor genes topulsatile GnRH administration. J Clin Endocrinol Metabol 1999;84(3):990e6.

[88] Pitteloud N, Boepple PA, DeCruz S, et al. The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism:spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J ClinEndocrinol Metabol 2001;86(6):2470e5.

[89] Zacharin M, Sabin MA, Nair VV, et al. Addition of recombinant follicle-stimulating hormone to human chorionicgonadotropin treatment in adolescents and young adults with hypogonadotropic hypogonadism promotes normaltesticular growth and may promote early spermatogenesis. Fertil Steril 2012;98(4):836e42.

[90] Barrio R, de Luis D, Alonso M, et al. Induction of puberty with human chorionic gonadotropin and follicle-stimulatinghormone in adolescent males with hypogonadotropic hypogonadism. Fertil Steril 1999;71(2):244e8.

[91] Dwyer AA, Sykiotis GP, Hayes FJ, et al. Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metabol 2013;98(11):E1790e5.

[92] Sato N, Hasegawa T, Hasegawa Y, et al. Treatment situation of male hypogonadotropic hypogonadism in pediatrics andproposal of testosterone and gonadotropins replacement therapy protocols. Clin Pediatr Endocrinol 2015;24(2):37e49.




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[93] Raivio T, Wikstrom AM, Dunkel L. Treatment of gonadotropin-deficient boys with recombinant human FSH: long-termobservation and outcome. Eur J Endocrinol Eur Fed Endocrine Soc 2007;156(1):105e11.

[94] Petak SM, Nankin HR, Spark RF, et al. American Association of Clinical E. American Association of Clinical Endocri-nologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult malepatientse2002 update. Endocr Pract 2002;8(6):440e56.

[95] Han TS, Bouloux PM. What is the optimal therapy for young males with hypogonadotropic hypogonadism? ClinEndocrinol 2010;72(6):731e7.

[96] Juul A, Aksglaede L, Bay K, et al. Klinefelter syndrome: the forgotten syndrome: basic and clinical questions posed toan international group of scientists. Acta Paediatr 2011;100(6):791e2.

[97] Blevins CH, Wilson ME. Klinefelter's syndrome. BMJ 2012;345. e7558.[98] Mehta A, Bolyakov A, Roosma J, et al. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome

treated with at least 1 year of topical testosterone and aromatase inhibitor. Fertil Steril 2013;100(4):970e4.[99] Rives N, Milazzo JP, Perdrix A, et al. The feasibility of fertility preservation in adolescents with Klinefelter syndrome.

Hum Reprod 2013;28(6):1468e79.[100] Matthews D, Bath L, Hogler W, et al. Hormone supplementation for pubertal induction in girls. Arch Dis Child 2017;

102(10):975e80.[101] Saenger P, Wikland KA, Conway GS, et al. Recommendations for the diagnosis and management of Turner syndrome.

J Clin Endocrinol Metabol 2001;86(7):3061e9.[102] Ross JL, Quigley CA, Cao D, et al. Growth hormone plus childhood low-dose estrogen in Turner's syndrome. N Engl J

Med 2011;364(13):1230e42.[103] Bondy CA. Turner syndrome study G. Care of girls and women with turner syndrome: a guideline of the turner

syndrome study group. J Clin Endocrinol Metabol 2007;92(1):10e25.[104] Bakalov VK, Shawker T, Ceniceros I, et al. Uterine development in Turner syndrome. J Pediatr 2007;151(5):528e31. 31

e1.[105] Doerr HG, Bettendorf M, Hauffa BP, et al. Uterine size in womenwith Turner syndrome after induction of puberty with

estrogens and long-term growth hormone therapy: results of the German IGLU Follow-up Study 2001. Hum Reprod2005;20(5):1418e21.

[106] Ankarberg-Lindgren C, Kristrom B, Norjavaara E. Physiological estrogen replacement therapy for puberty induction ingirls: a clinical observational study. Horm Res Paediatr 2014;81(4):239e44.

[107] van Buuren S. Growth charts of human development. Stat Meth Med Res 2013;23(4):346e68.




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e16 Copyright © SLACK Incorporated

SPECIAL ISSUE ARTICLE

Delayed PubertyAlyssa M. Dye, MD; Grace B. Nelson, MD; and Alicia Diaz-Thomas, MD, MPH

ABSTRACTDelayed puberty is defined as the absence of physical signs of puberty 2 to 2.5 standard

deviations above the mean age and affects approximately 2% of adolescents. Causes of de-

layed puberty are broadly divided into two categories: hypergonadotropic hypogonadism

and hypogonadotropic hypogonadism. One exception to this classification system is con-

stitutional delay of growth and puberty, the most common cause of delayed puberty. For

the general pediatrician, knowledge of the different causes and initial steps to evaluation is

crucial when a patient with delayed puberty presents. [Pediatr Ann. 2018;47(1):e16-e22.]

Puberty is the universal process of maturation to reproductive capacity. The mechanisms that

initiate puberty are an area of active research. Once the process initiates, the hypothalamus begins to secrete go-nadotropin-releasing hormone (GnRH) in a pulsatile fashion with increas-ing amplitude and frequency. GnRH stimulates pituitary gonadotropins, lu-teinizing hormone (LH), and follicle-stimulating hormone (FSH). These gonadotropins in turn act at the level of the gonad, causing release of estro-gen and progesterone or testosterone. These sex steroids are responsible for the development of secondary sexual characteristics that we associate with puberty.

Delayed puberty is defined as the absence of physical signs of puberty by

a certain age (2 to 2.5 standard devia-tions above the mean age) in the popu-lation and affects approximately 2% of adolescents.1 In girls, this is charac-terized as lack of breast development by age 13 years, or more than 4 years between physical signs of thelarche (initiation of breast development) and menarche. In boys, lack of testicular enlargement by age 14 years or more than 4 years between the onset of testic-ular development and the completion of puberty defines delayed puberty.2,3 De-layed puberty most commonly presents in boys and most cases are a variant of normal pubertal maturation called con-stitutional delay of growth and puberty (CDGP). However, for children lacking secondary sexual characteristics by the aforementioned-time points, evaluation is necessary.

Pubertal delay itself can present sig-nificant stressors for both the patient and their parents. One study found that in untreated CDGP, over one-half of the boys felt that their growth delay af-fected their social and scholastic suc-cess.2-4 Girls were affected to a lesser extent, although still reported negative effects of growth delay on perceived success.5 Unwanted long-term physi-cal sequelae of delayed puberty can include impaired fertility and com-promised bone health. For the primary care pediatrician, knowledge of steps initial evaluation and when to refer for further evaluation is crucial to timely and effective management of these adolescents.

DIFFERENTIAL DIAGNOSISCauses of delayed puberty are

broadly divided into two categories, based on where the hypothalamic-pituitary-gonadal (HPG) axis failure has occurred (Figure 1). Hypergo-nadotropic hypogonadism is character-ized by an appropriate activation of the hypothalamic-pituitary component, but failure of gonadal sex steroid produc-tion. Conversely, hypogonadotropic hypogonadism (HH) is secondary to delay or failure of the hypothalamic/pituitary portion of the HPG axis. Clas-sification of pubertal delay can proceed along these lines except for two etiolo-gies: CDGP and complete androgen in-sensitivity syndrome (CAIS).

The most common cause of puber-tal delay is CDGP, a delay of pubertal signs and symptoms but with eventual

Alyssa M. Dye, MD, is a Pediatric Resident. Grace B. Nelson, MD, is a Pediatric Endocrinology Fellow.

Alicia Diaz-Thomas, MD, MPH, is an Associate Pediatric Endocrinology Fellowship Program Director. All

authors are affiliated with the University of Tennessee Health Science Center, Graduate Medical Educa-

tion, Department of Pediatrics, Le Bonheur Children’s Hospital.Address correspondence to Grace B. Nelson, MD, 51 N. Dunlap Street, Memphis, TN 38104; email:

[email protected]: The authors have no relevant financial relationships to disclose.doi:10.3928/19382359-20171215-01



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progression to normal puberty.1 This is difficult to distinguish from isolat-ed hypogonadotropic hypogonadism (IHH), a pathologic condition that re-quires treatment.2 Finally, AIS, a cause of delayed menarche after breast devel-opment, fits into neither classification, as both the hypothalamus and gonads function appropriately, but there is end-organ resistance to androgens. Un-derstanding the various causes and dif-ferential diagnosis of delayed puberty can assist the general pediatrician with initial evaluation.

HYPERGONADOTROPIC HYPOGONADISM

Hypergonadotropic hypogonadism, also known as primary gonadal failure, is always a pathologic state. Levels of LH and FSH are elevated, indicating appropriate maturity of the HPG axis but failure of gonadal sex steroid pro-duction to provide negative feedback. One study showed that in boys, this is uncommon (7%), but for girls, 26% of those presenting for delayed puberty were found to have primary ovarian failure.6 Chromosomal abnormalities, other congenital disorders, and ac-quired injuries can all lead to gonadal failure.

FemalesAlthough there are many potential

causes of primary ovarian failure, Turn-er’s syndrome is the most common.6 Turner’s syndrome occurs in 1 in 2,500 females and can be diagnosed during in-fancy and childhood. This is a primary chromosomal disorder caused by lack of sufficient X chromosome dosage, ie, 45,X or 45,X/46,XX. Short stature is a characteristic finding, along with congenital lymphedema (webbed neck, low posterior hairline), facial dysmor-phism with high arched palate, skel-etal anomalies, and associated cardiac

abnormalities including coarctation of the aorta.6,7 Females with Turner’s syn-drome will develop pubic hair, and 15% to 30% will have breast development. Some cases of Turner’s syndrome will not be noted until there is lack of de-velopment of secondary sexual charac-teristics, lack of menarche, or less com-monly, abnormal menses and infertility.

A less common cause resulting in ovarian failure is autoimmune ovarian failure, which has been reported in both type I and type II autoimmune poly-glandular syndromes. This should be suspected in females with other auto-immune conditions, such as Addison’s disease, type 1 diabetes mellitus, and hypoparathyroidism.3 One-half of fe-males with galactosemia will develop ovarian failure, thought to be secondary to the toxicity of galactose metabolites and resulting in atresia of the primary follicles.3,8

MalesTesticular failure is rare, but is

most commonly secondary to chromo-

somal anomalies such as Klinefelter’s syndrome (47,XXY) or multiple X syndrome (48,XXXY; 48,XXYY; 49,XXXYY). Klinefelter’s syndrome has an incidence in males of 1 in 500 to 1 in 1,000 and rarely presents as pubertal delay, instead presenting as lack of completion of puberty. Males have small testes, tall stature, feminine fat distribution (gynecomastia), and behavioral problems noted most com-monly in school.3,7

History of prenatal or acquired tes-ticular damage is another potential cause of testicular failure in males. Testicular regression syndrome, or van-ishing testes, is seen in less than 5% of cryptorchidism cases. This is thought to be the result of antenatal or perinatal thrombosis or torsion.9 Bilateral testic-ular torsion at any age, damaged paren-chyma secondary to sickle cell disease or trauma, or surgical attempt of cor-rection of cryptorchidism can also be causes of testicular failure.

Of note, genetic associations with testicular failure include myotonic

Figure 1. Expected levels of gonadotropins and sex hormones in normal development, both types of hypogonadism and androgen insensitivity syndrome.



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dystrophy, Noonan’s syndrome, and changes in the LH receptor on the testes (LH beta-receptor mutations). These are associated with pubertal delay secondary to gonadal failure.

Conditions Affecting Both SexesHistory of irradiation and chemo-

therapy can result in gonadal failure in both sexes. One-half of females who receive pelvic irradiation devel-op primary ovarian failure, the likeli-hood dependent on the dose given and age of the patient.3 A study performed in male childhood cancer survivors found that gonadal failure was present in 25% of those patients.10 Cytotoxic chemotherapy agents, like cyclophos-phamide, busulfan, procarbazine, and etoposide, have been shown to lead to gonadal failure, but are particularly devastating to the actively proliferat-ing cells of the mature ovary.3 His-tory of infections, including mumps, shigella, malaria, varicella, and cox-sackie viruses, is also associated with ovarian and testicular failure.

HYPOGONADOTROPIC HYPOGONADISM

HH indicates either immaturity or failure of gonadotropin production, or the failure of activation of the hy-pothalamic portion of the HPG axis. Low plasma gonadotropin levels and low testosterone levels (males) or lack of pubertal signs (females and males) indicate this as a diagnosis.11 Differ-entiating immaturity versus failure of the HPG axis presents a challenge and can be confirmed only by the onset of puberty.

Self-Limited CausesCDGP is the most common cause

of HH in males (63%) and in females (30%).6 Constitutional delay of pu-berty is a diagnosis of exclusion and

represents an exaggerated delay of puberty. Patients present with short stature, delayed skeletal age (young-er than age 11 years in females and younger than age 13 years in males) and pubertal delay. In one-half of the CDGP cases, a family history of delayed puberty is present.11 Males present more frequently than females due to the negative psychosocial ef-fects that arise with short stature and pubertal delay.12 Patients will begin puberty spontaneously, and sexual maturity and growth potential are not affected, as adult height is consistent with genetic potential.3

Functional hypogonadotropic hy-pogonadism or hypothalamic dys-function can occur due to systemic illnesses. The HPG axis has normal potential, but is disrupted second-ary to inflammation, poor nutrition, and chronic pain. Some patients may present with stunted growth as well as delayed puberty. Hypothyroidism, diabetes mellitus, growth hormone deficiency, cystic fibrosis, inflam-matory bowel disease, celiac disease, juvenile rheumatoid arthritis, hemo-chromatosis, sickle cell disease, and systemic therapy for chronic condi-tions (long-term glucocorticoids) have all been associated with puber-tal delay. Similarly, intense exercise and undernutrition are known causes of amenorrhea and HH. Although ge-netic height potential might not be achieved in all cases, aggressive man-agement of the underlying condition is the first method of prevention and treatment for pubertal delay.3,12

Pathologic CausesIsolated gonadotropin-releasing

hormone deficiency (IGD) repre-sents a heterogenous group of condi-tions. Males and females with IGD can have an intact smell mechanism

(normosmic) or have variable degree of impairment ranging from impaired smell (hyposmic) to absent smell (an-osmic) mechanism. People with IGD and either hyposmia or anosmia are diagnosed with Kallmann’s syndrome (KS), whereas those with normal ol-factory function are diagnosed with normosmic IGD (nIGD).13 KS is more frequently seen in males with an in-cidence of 1 in 8,000.11 Most cases are sporadic and result from a genetic defect in the KAL-1 gene, which en-codes the protein anosmin-1 that is involved in fetal GnRH neuronal mi-gration.12 KS can also be associated with renal anomalies and midline fa-cial defects. There are other genetic defects that can cause KS, and skel-etal anomalies can be associated with these mutations. nIGD can be spo-radic (66%) or familial (33%) and is caused by congenital dysfunction of the hypothalamic-pituitary struc-ture.3,11 To date, there are more than 20 genetic defects leading to nIGD that have been identified, although many more are expected.14

HH can also be seen as a feature of some genetic syndromes such as Prader-Willi syndrome, Noonan’s syndrome, CHARGE syndrome, and Laurence-Moon-Bardet-Biedel syn-drome. Additionally, leptin deficien-cy or resistance syndromes may have HH as a feature.

Central nervous system lesions and tumors are another potential cause of HH. In patients of pubertal age, delayed puberty can be one of the presenting symptoms of cranio-pharyngioma or other mass lesions in the hypothalamic-pituitary region.3,7 Prolactinomas, resulting in pubertal delay or secondary amenorrhea, pres-ent with galactorrhea without gyneco-mastia.7 It is important for the general pediatrician to inquire about head-



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aches and visual disturbances to rule out these conditions. Pituitary gland hypoplasia, associated with septo-op-tic dysplasia spectrum disorders, can also have pubertal delay from HH.

EUGONADOTROPIC EUGONADISM

Physicians should consider ana-tomical defects in females who present with normal levels of gonadotropins and sex steroids based on age and Tan-ner stage, along with normal develop-ment of secondary sexual characteris-tics. Imperforate hymen or incomplete or partial canalization of the vagina will result in amenorrhea with cyclical abdominal pain.3

OTHER FORMS OF DELAYED PUBERTY

Patients with CAIS do not fit into the previously mentioned classifica-tions. People with CAIS typically pres-ent with high levels of LH/FSH and testosterone, have female breast devel-opment, and lack of pubic hair (signs of androgen activity).15

EVALUATIONFor patients who present with de-

layed puberty, a thorough history and physical examination is key to guide further evaluation and development of diagnostic possibilities. For females and males who meet criteria for de-layed puberty, evaluation of body mass index, history of intense exercise, and laboratory assessment (complete blood count, liver function test, erythrocyte sedimentation rate, thyroid-stimulating hormone (TSH), free T4, hemoglobin A1c) may be necessary to evaluate for secondary causes of delayed puberty. If delayed puberty is secondary to a chronic disease, management focuses on aggressive treatment of the chronic disease to allow the HPG axis to mature

appropriately. Similarly, if a patient is presenting due to malnutrition or an-orexia, nutritional management is the most important first step in treatment.

FemalesFor the general pediatrician, evalua-

tion with karyotype to rule out Turner’s syndrome is the next appropriate step in management. If the karyotype sug-gests Turner’s syndrome, referral for endocrine evaluation and treatment is necessary. Guidelines for management of patients with Turner’s syndrome have been developed and recommend the following evaluations: renal ultra-sound, cardiac, audiology, scoliosis/kyphosis, baseline laboratory, includ-ing TSH and total or free T4. The fam-ily and patient should be offered refer-ral to support groups.16 If karyotype is normal, referral to an endocrinologist for further testing and possible in-duction of puberty is the next step in management7 (Figure 2).

MalesEvaluation of karyotype to look for

Klinefelter’s syndrome or multiple X syndrome should be the next step. For males who have a 46,XXY karyo-type, referral for endocrine evaluation should be performed. Patients will also need evaluation by urology, psychol-ogy, neuropsychology for possible speech delays and learning disabilities, and referral for patients and families to support groups.17 For patients with a normal male karyotype, endocrine evaluation of gonadotropin and go-nadal status prior to possible trial of testosterone therapy is the next step. For patients with CDGP, reassurance and waiting is appropriate, however, many patients may wish to proceed with short-term hormonal therapy to start puberty, especially when psycho-social dysfunction is present, or when

there is uncertainty between IHH and CDGP.12,18 Referral to an endocrinolo-gist would also be appropriate for these patients (Figure 3).

MANAGEMENT Males

Replacement of sex steroids (tes-tosterone) can begin between ages 12.5 and 13 years. For patients receiv-ing growth hormone, delay of sex ste-roid replacement may be considered to allow for growth catch-up. Patients who have pubertal bone age do not need delay in hormonal treatment, as studies have shown that therapy in boys age 14 years and older has no ef-fect on adult height.3,7

Differentiation between pubertal delay and permanent gonadotropin deficiency is often not made before sex steroid therapy is started. After treatment for 6 months, males with CDGP should progress to subsequent pubertal testosterone levels and see an increase in size of the testes (a go-nadotropin-dependent process). This confirms that the HPG axis is normal and puberty should progress without intervention.3,7,18 Testosterone helps to start the pubertal progress as sex steroids have a direct permissive ef-fect at the level of the hypothala-mus.19 In males with IHH, testicular enlargement will not be apparent and testosterone levels will remain low; androgen replacement should con-tinue. Testosterone replacement, typi-cally provided via injection, is slowly increased over 3 to 4 years until adult levels are reached. Once adult re-placement levels are reached, patients may opt for other methods of testos-terone delivery such as gels or sprays. Testosterone is continued until a male desires fertility, then FSH and LH an-alogs may be administered to induce adequate spermatogenesis.



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In males who have primary gonad-al failure, hormone replacement will only achieve pubertal maturation and change in physical appearance. Sper-matic production and fertility will still be absent, and counseling for families and patients is indicated. For males without testes, prosthetic testes can be placed for physical appearance.3

FemalesUnlike males, treatment to dif-

ferentiate between CDGP and HH is

usually ineffective, and when therapy is started, it is usually continued un-til completion of puberty.18 Induction of puberty with low-dose estrogen therapy starting at age 10 to 12 years can begin the process of thelarche. Es-trogen can be administered via daily pill or transdermal preparations twice weekly. Transdermal patches may be more metabolically favorable.20 Dos-age is increased slowly to allow for appropriate breast development, with a goal of reaching full dosage in 3 to 4

years. Once the patient reports vaginal spotting, cyclical estrogen-progester-one therapy to begin regular menses is added.3,18

In females with gonadotropin de-ficiency that is permanent, pulsatile GnRH can help achieve fertility. In females with primary ovarian failure, fertility is compromised. Referral to a fertility specialist to advise patients about their options including in vitro fertilization is indicated for these patients.

Figure 2. Algorithm for delayed puberty evaluation in females. CAIS, complete androgen insensitivity syndrome; BMI, body mass index; BP, blood pressure; CDGP, constitutional delay of growth and puberty; EKG, electrocardiogram; FSH, follicle-stimulating hormone; LH, luteinizing hormone.



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NEW HORIZONSCurrent research has focused on

understanding the mechanisms behind pubertal initiation and identifying the different signaling pathways that are involved in the control of puberty. Kisspeptin, a puberty-regulating neu-ropeptide, has emerged as a central factor in control of GnRH release; research is underway to understand if kisspeptin replacement may hold val-ue in the treatment of HH.21,22 Other researchers are investigating whether exposure to environmental endocrine disruptors may interfere with puber-tal timing. Substances such as dioxin

and dioxin-like compounds, lead, and polybrominated biphenyls have been identified as possible causative agents of delayed puberty in girls.23 Research also continues in understanding best prac-tices in pharmacological pubertal ini-tiation and management with emphasis on fertility preservation and discussion of reproductive options for children and families. Finally, understanding whether there are long-term health or psychoso-cial risks associated with delayed puber-tal development will also be important.

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Figure 3. Algorithm for delayed puberty evaluation in males. BMI, body mass index; CDGP, constitutional delay of growth and puberty; FSH, follicle-stimulating hormone; LH, luteinizing hormone.



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19. Dungan HM, Clifton DK, Steiner RA. Minireview: kisspeptin neurons as central processors in the regulation of gonadotro-pin-releasing hormone secretion. Endocrinol-ogy. 2006;147(3):1154-1158. doi:10.1210/en.2005-1282.

20. Jospe N, Orlowski CC, Furlanetto RW. Com-parison of transdermal and oral estrogen ther-apy in girls with Turner’s syndrome. J Pedi-atr Endocrinol Metab. 1995;8(2):111-116.

21. Francou B, Paul C, Amazit L, et al. Preva-lence of KISS1 Receptor mutations in a se-ries of 603 patients with normosmic congeni-tal hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study. Hum Reprod. 2016;31(6):1363-1374. doi:10.1093/humrep/dew073.

22. Manfredi-Lozano M, Roa J, Ruiz-Pino F, et al. Defining a novel leptin-melanocortin-kiss-peptin pathway involved in the metabolic con-trol of puberty. Mol Metab. 2016;5(10):844-857. doi:10.1016/j.molmet.2016.08.003.

23. Lee Y, Styne D. Influences on the onset and tempo of puberty in human beings and impli-cations for adolescent psychological devel-opment. Horm Behav. 2013;64(2):250-261. doi:10.1016/j.yhbeh.2013.03.014.


implicações na fertilidade no feminino e no masculinoMARiA MiGueL GoMeS

Bibliografia:

Boehm u, Bouloux PM, Dattani MT, de Roux n, Dodé C, Dunkel L, et al. european Consensus Statement on congenital hypogonadotropic hypogonadism - pathogenesis, diagnosis and treatment. nature Reviews – endocrinology (2015). 11:547-564.

atraso pubertÁrio


ATrAso PuBerTário | imPliCAções nA ferTilidAde no feminino e no mAsCulino | mAriA miguel gomes

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NATURE REVIEWS | ENDOCRINOLOGY VOLUME 11 | SEPTEMBER 2015 | 547

University of Saarland School of Medicine, Germany (U.B.). University College London, UK (P.‑M.B., M.T.D.). Université Paris Diderot, France (N.d.R.). Université Paris Descartes, France (C.D.). William Harvey Research Institute, UK (L.D.). Endocrinology, Diabetes and Metabolism Sevice of the Centre Hospitalier Universitaire Vaudois (CHUV), du Bugnon 46, Lausanne 1011, Switzerland (A.A.D., N.P.). University of Lille, France (P.G., V.P.). Institut Pasteur, France (J.‑P.H.). University of Copenhagen, Denmark (A.J.). University of Genova, Italy (M.M.). University of Helsinki, Finland (T.R.). University of Cordoba, Spain (M.T.‑S.). Newcastle University, UK (R.Q.). Bicêtre Hospital, France (J.Y.).

Correspondence to: N.P. [email protected]

EXPERT CONSENSUS DOCUMENT

European Consensus Statement on congenital hypogonadotropic hypogonadism —pathogenesis, diagnosis and treatmentUlrich Boehm, Pierre-Marc Bouloux, Mehul T. Dattani, Nicolas de Roux, Catherine Dodé, Leo Dunkel, Andrew A. Dwyer, Paolo Giacobini, Jean-Pierre Hardelin, Anders Juul, Mohamad Maghnie, Nelly Pitteloud, Vincent Prevot, Taneli Raivio, Manuel Tena-Sempere, Richard Quinton and Jacques Young

Abstract | Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRH-synthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10–20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

Boehm, U. et al. Nat. Rev. Endocrinol. 11, 547–564 (2015); published online 21 July 2015; doi:10.1038/nrendo.2015.112

IntroductionCongenital hypogonadotropic hypogonadism (CHH) is caused by deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), a key neuro peptide that orchestrates mammalian reproduc-tion.1 CHH is characterized by incomplete or absent puberty and infertility in the setting of isolated hypo-gonadotropic hypogonadism (that is, otherwise normal anterior pitui tary function). CHH can present solely as congenital GnRH deficiency or be associated with other develop mental anomalies such as cleft lip or palate, dental agenesis, ear anomalies, congenital hearing impairment, renal agenesis, bimanual synkinesis or skel-etal anomalies. When associated with anosmia or hyp-o s mia, CHH is termed Kallmann syndrome, which results from abnormal embryonic migration of GnRH neurons from their origin in the olfactory placode to the forebrain.2,3 CHH has a male predominance of 3–5 to 1.4,5 Most patients with CHH are diagnosed late in adolescence or early in adulthood as CHH is challen ging to differentiate from other causes of delayed puberty. Effective therapies in both men and women are available for the development of secondary sexual characteristics

(virilization and/or estrogenization) and induction of fertility.

A number of important developments in the field have emerged over the past decade. Reversal of CHH occurs in ~10–20% of patients,6,7 which challenges the dogma that the condition is lifelong. These data have implications for the management of CHH and suggest a plasticity of the GnRH neuronal system. Furthermore, inhibin B, insulin-like 3 (INSL3), anti-Müllerian hormone (AMH) and kisspeptin have emerged as biomarkers for use in the diagnosis and treatment of CHH.8,9 In addition, hor-monal therapies are being personalized to maximize fer-tility outcomes.10 Over the past few years, the traditional Mendelian view of CHH as a monogenic disorder has been revised following the identification of oligogenic forms of CHH,11 which has altered the approach adopted for genetic testing and genetic counselling of patients with CHH. Finally, the availability of next-generation sequencing has started to unravel the complex molecular basis of CHH. This Consensus Statement focuses on the pathogenesis, diagnosis and treatment of CHH in light of recent discoveries and differs from existing guidelines for the treatment of hypogonadism12–14 as it focuses exclu-sively on CHH. Definitions of several key terms used in this article are presented in the glossary (Box 1).

Competing interestsThe authors declare no competing interests.

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MethodsThis Consensus Statement is the work of the European consortium studying GnRH biology (COST Action BM1105, http://www.gnrhnetwork.eu/). The COST network includes clinician investigators, geneticists, bio-informaticians, basic scientists and patient advocates from 28 countries. Our recommendations are based on a review of the literature published in the English language between 1990 and 2015 using the following search terms: “congeni-tal hypogonadotropic hypogonadism”, “idiopathic GnRH deficiency”, “central hypogonadism” and “Kallmann syndrome”. The reference lists of identified papers were searched for additional relevant articles. A series of meet-ings and focused discussions with expert clinicians (spe-cialized in paediatric and adult CHH) were conducted, with a final vetting process involving experts partici-pating in the network from the fields of endo crinology, andrology, genetics and reproductive medicine.

Biology of the GnRH neuronal systemGnRH neurons are unusual neuroendocrine cells as they originate outside the central nervous system in the olfactory placode and then migrate into the brain during embryonic development.2,3 This route provides a developmental link between the central control of repro-duction and the sense of smell, which are both affected in Kallmann syndrome. Data from the past few years

suggest that GnRH neurons originate from both the neural crest and ectodermal progenitors, and migrate in close association with growing axons of olfactory and/or terminal nerves.15,16 Once in the hypothalamus, GnRH neurons detach from their axonal guides, disperse further into the brain parenchyma and stop migrating. At birth, GnRH neurons have reached their final destination in the brain and many of them project into the median eminence, where they release the GnRH decapeptide from their axon terminals into the hypophyseal portal vasculature.1 GnRH acts via the GnRH receptor, which is expressed on gonadotropic cells in the anterior pituitary gland. This action regulates both synthesis and release of gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which control gonadal maturation and adult reproductive physiology via the hypothalamic–pituitary–gonadal (HPG) axis.

Several genes mutated in Kallmann syndrome affect the fate and migration of GnRH neurons. Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway pro-teins,17–22 chromodomain helicase DNA-binding protein 7 (CHD7)23–27 and sex determining region Y-Box 10 (SOX10)28,29 affect the neurogenic niche in the nasal area and craniofacial development. Conversely, Kallmann syn-drome protein, which is now officially known as anosmin 1 (encoded by KAL1; following nomenclature change, the gene is now denoted as ANOS1),2 prokineticin- 2 and pro-kineticin receptor 2 (encoded by PROK2 and PROKR2, respectively),30–33 WD repeat domain 11 (encoded by WDR11),34,35 semaphorin 3A (encoded by SEMA3A)36–38 and FEZ family zinc finger 1 (encoded by FEZF1)39 influence migration of GnRH neurons.

Postmigratory GnRH neurons are embedded in a com-plex neuronal network of afferents that send information about permissive reproductive cues such as steroid and metabolic hormones to these cells. Individual components of the underlying neural circuits are beginning to emerge. Some key molecules have been discovered through the study of the genetics of CHH.1 Inactivating mutations in genes encoding kisspeptin-1 (KISS1)40 and its recep-tor (KISS1R)41,42 halt pubertal development in humans. Extensive experimental studies in various species have demonstrated that kisspeptin-producing neurons are major afferents to GnRH neurons and are essential for dif-ferent aspects of GnRH function, ranging from the tonic feedback control of GnRH and/or gonadotropin secre-tion to generation of the pre-ovulatory surge responsible for ovulation.43 Interestingly, although kisspeptins do not seem to be mandatory for proper GnRH neuron migration, compelling experimental work has documented that pop-ulations of kisspeptin neurons undergo a dynamic process of prenatal and postnatal maturation that enables them to establish connections with GnRH neurons early in devel-opment44 (under the control of steroid hormones45–47). Similarly, identification of mutations in TAC3 (encoding tachykinin-3, which is cleaved to form neurokinin- B) and TACR3 (encoding tachykinin receptor 3; also known as neuromedin-K receptor [NKR])48–50 in patients with CHH highlights the important role of members of the tachyki-nin family in the control of GnRH neurons. Furthermore,

Box 1 | Glossary

AnosmiaComplete lack of sense of smell

CryptorchidismMaldescended testes that are not in the scrotum (that is, in the inguinal canal or abdomen); can occur in unilateral or bilateral forms

GnRHGnRH is produced by specialized hypothalamic neurons in a pulsatile manner that stimulates the release of gonadotropins (luteinizing hormone and follicle-stimulating hormone) from the pituitary, which activate gonadal maturation and fertility

OligogenicityMutations in two (or more) CHH genes in one patient

ReversalRecovery of the hypothalamic–pituitary–gonadal axis (normal circulating levels of sex steroids and/or fertility) after treatment discontinuation

Secondary sexual characteristicsPhysical characteristics that result from increased sex hormone production during puberty

Virilization (male)Change in external genitalia with phallic development, appearance of pubic and/or axillary and/or facial hair, enlarged larynx and/or deepening of voice and increased lean body mass

Estrogenization (female)Breast development with prominence of nipples, development of pubic and axillary hair, widening of hips and development of labia minoraAbbreviations: CHH, congenital hypogonadotropic hypogonadism; GnRH, gonadotropin-releasing hormone.

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these findings led to the identification of a subpopula-tion of afferent neurons in the arcuate and/or infundibu-lar hypothalamic region, which co-express kiss peptins and NKB.51 Interestingly, data from the past few years suggest that the actual number of kisspeptin and/or NKB neurons might change during development.52,53 Mutations in proteins that regulate ubiquitination such as OTU domain-containing protein 4 (encoded by OTUD4) and E3 ubiquitin-protein ligase RNF216 (also known as ring finger protein 216; encoded by RNF216),54 as well as in proteins involved in lipid metabolism such as neuropathy target esterase (also known as patatin-like phospholipase domain-containing protein 6; encoded by PNPLA6)55,56 have been identified in patients with Gordon Holmes syn-drome (with associated CHH and ataxia). Thus, mutations in these three genes give rise to a broad and progressive neurodegenerative syndrome that includes CHH. In 2014, haploinsufficiency of DMXL2, which encodes synaptic protein DmX-like protein 2, was shown to cause a complex new syndrome associating CHH with polyendocrine deficiencies and polyneuropathies.57

Peripheral signals that convey information about meta-bolic status indirectly modulate GnRH neuro secretion. This modulation is well illustrated by the reproductive phenotype of absent pubertal development and hypo-gonadotropic hypogonadism in patients with inacti-vating mutations in the genes encoding leptin (LEP) or its receptor (LEPR).58 Exactly how the effects of leptin are transmitted to GnRH neurons is unknown, as this neuro nal population does not express the leptin recep-tor.59 Experimental data suggest that kisspeptin neurons are sensitive to changes in leptin concentrations and metabolic conditions,43 yet they apparently do not express functional leptin receptor, which indicates the mode of action is indirect.60 Primary leptin targets for conduction of its reproductive effects probably include nitric oxide-producing neurons in the pre-optic hypothalamus61 and neuronal circuits in the ventral premammillary nucleus,60 which might transmit metabolic information to GnRH neurons through kiss peptin dependent and/or indepen-dent pathways. Taken together, the identification of genes mutated in the different forms of CHH has facilitated an improved understanding of the neuroendocrine control of reproduction.

Puberty and reproductionPuberty represents a period of transition from child-hood into adulthood during which complete reproduc-tive capacity is attained. Puberty is regulated by the HPG axis. The axis is active in utero and shortly after birth62,63 (a phenomenon referred to as mini-puberty), is subse-quently silenced and remains quiescent for years until reawakening at the onset of puberty. Multiple central and peripheral inputs are integrated into pubertal reacti vation of the GnRH pulse generator.64 At the onset of puberty, GnRH-induced pulses of LH are initially nocturnal and, gradually, the pulsatility extends to the daytime as puberty progresses.65–67

In boys, FSH stimulates proliferation of immature Sertoli cells and spermatogonia, whereas LH stimulates

Leydig cells to produce testosterone. The concerted stimu-lation of Sertoli cells by FSH and intragonadal testos terone levels 50–100-fold higher than in the systemic circulation leads to the initiation of spermatogenesis. In girls, the early stages of follicular growth are primarily driven by intra-ovarian factors. FSH and LH are needed for follicular maturation, which leads to ovulation. More specifically, LH stimulates theca cells to produce androgens and FSH stimulates recruitment of secondary ovarian follicles and the secretion of estradiol from granulosa cells. Inhibin B and AMH are produced by prepubertal Sertoli cells and granulosa cells.68 Circulating levels of inhibin B increase during puberty in girls and boys.69,70 AMH concentrations show only minor fluctuations during female puberty.71 In boys, AMH concentrations fall as Sertoli cells differenti-ate and testos terone production increases.72 In male indi-viduals, INSL3 is secreted by Leydig cells during fetal and immediate postnatal life.8,73 Testicular INSL3 secretion declines during childhood before increasing at the time of puberty and peaking during adulthood.74

Early signs of puberty manifest around the age of 10 years in girls (breast development) and 11.5 years in boys (testicular enlargement and spermarche—appearance of spermatozoa in first morning void).75–77 Considerable interindividual variation in the timing of pubertal onset exists, ranging from 8 years to 13 years in girls and 9 years to 14 years in boys.78,79 Subsequent hallmarks of puberty in boys include deepening of the voice and a growth spurt. In girls, menarche occurs at ~12.5 years of age.78

Clinical presentation of CHHNeonatal and childhoodLack of neonatal activation of the HPG axis can provide early diagnostic cues for identifying CHH at birth or during mini-puberty.80–83 In male infants, crypt orchidism (that is, maldescended testes) and micropenis can be signs of GnRH deficiency (Figure 1), yet these fea-tures are by no means invariable.84–86 As penile growth occurs during infancy and childhood, micropenis can be assessed using available cross-sectional normative data.87,88 These two clinical clues warrant hormonal monitoring during mini-puberty. However, more severe genital anomalies, such as hypospadias, point away from a diagnosis of CHH and, instead, indicate a defect of human chorionic gonadotropin (hCG)-driven androgen secretion and/or action in early fetal life, before the initi-ation of endogenous GnRH activity. No specific clinical signs of CHH present in female neonates. Regardless of sex, when infants are born to parents with CHH, we recommend monitoring reproductive hormones during mini-puberty and performing genetic testing if mutations have been identified in the parents.

AdolescentThe timing and onset of puberty varies widely in the general population.89 Delayed puberty is classically defined as absence of testicular enlargement (volume <4 ml) in boys by the age of 14 years and absent breast development in girls by the age of 13 years.90 In addition, use of the stage-line diagram enables the identification of





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patients with delayed puberty, which is based not only on pubertal onset but also on the tempo of pubertal devel-opment.91 In most of these individuals, puberty is initi-ated and eventually completed (that is, constitutional delay of growth and puberty [CDGP]). By contrast, adolescents with CHH lack pubertal activation of the HPG axis, which leads to absent puberty and infertil-ity (Figure 1). In the majority of patients, puberty never occurs (absent puberty); less commonly, puberty is initi-ated then arrested (partial puberty).92–94 Adolescents with CHH exhibit steady linear growth and thus lack the so-called growth spurt.91,95,96 Given the delayed epiphy-seal closure, these individuals often have eunuchoidal proportions. The most common complaints in male adolescents with CHH include absent and/or minimal viriliza tion, low libido and lack of sexual function. Among female adolescents, lack of breast develop ment and/or primary amenor rhoea by the age of 15 years are frequent complaints. In addition, patients with CHH often have low self-esteem, distorted body image, impaired psychosexual development and, in some cases, problems with sexual identity.97,98 Furthermore, small studies have shown increased anxiety and depres-sion among adolescents with CHH and, as such, these symptoms merit attention.99,100

The clinical heterogeneity of CHH makes differen-tiation from CDGP, which is usually associated with short stature, poor growth velocity and delayed skeletal maturation, difficult.90,95 The presence of micropenis and/or cryptorchidism argues firmly in favour of CHH, as these features are rarely seen in CDPG. Associated congenital phenotypes are also very useful as they indi-cate a syndromic form of CHH. The classic, and by far most frequent, form being Kallmann syndrome, which includes anosmia. Other phenotypes like cleft palate or sensorineural deafness also suggest a syndromic form of CHH,94 most often associated with Kallmann syndrome, but not exclusively so.18 The clinical sign that points away from CDGP is a poor sense of smell, which sug-gests Kallmann syndrome.101–103 Other ‘red flags’ include

congenital hearing impairment with or without pigmen-tation defects, bimanual synkinesia (mirror movements), dental agenesis, cleft lip and/or palate and crypt orchid-ism with or without micropenis.17,28,104–108 Family history indicative of autosomal inheritance cannot be used as a diagnostic tool, as this feature can be observed in both CHH and CDGP.109

AdulthoodCHH might be diagnosed after adolescence, when patients present for evaluation of infertility or even for osteo poro tic fractures. This delay in diagnosis might be related to missed opportunities to diagnose CHH in adolescence or a reluctance of patients to seek medical evaluation.

Genetics of CHHCHH is genetically heterogeneous, with both sporadic and familial cases. Several modes of inheritance have been identified, including X chromosome-linked reces-sive, autosomal recessive and dominant.1 By examining milder phenotypes (such as delayed puberty or isolated anosmia), the frequency of familial cases increases.110,111 Understanding of the molecular genetics of CHH and Kallmann syndrome has advanced tremendously in the past 20 years, since the first gene associated with Kallmann syndrome (KAL1 [ANOS1]) was identified by a positional cloning strategy in 1991 (Table 1).112–115 KAL1 (ANOS1) encodes anosmin-1, a transiently expressed, locally restricted glycoprotein of embryonic extracellu-lar matrices116 that is involved in fibroblast growth factor (FGF) signalling.117,118 To date, >25 different genes have been implicated in Kallmann syndrome and/or CHH, which accounts for ~50% of cases.21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1),17,18 FGF8,19,119 CHD7,23–27 HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1),20 SOX10,28,29 SEMA3A (encoding semaphorin-3A),36–38 WDR11 (encoding WD repeat-containing protein 11)34,35 and IL17RD (encoding interleukin-17 receptor D)21 in the autosomal dominant form; and PROKR2 and/or PROK2,30–33 and FEZF139 in the autosomal recessive form, even though it should be noted that most patients carry-ing mutations in PROKR2 or PROK2 carry these muta-tions in the heterozygous state.120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropin-releasing hormone receptor),122,123 GNRH1 (encoding gonadotropin- releasing hormone 1),124,125 KISS1R,41,42 KISS1,40,126 TACR3 and TAC3.48–50 Other genes such as FGFR1 or PROKR2 can be mutated in patients with either Kallmann syndrome or CHH (Table 1). Remarkably, mutations in each Kallmann syndrome or CHH gene identified so far account for <10% of cases.11,21,127

CHH has classically been categorized as a monogenic disorder, which means that one defective gene is suffi-cient to account for the disease phenotype. As such, CHH and Kallmann syndrome caused by mutations in GNRHR (a recessive gene) and KAL1 (ANOS1; an X-linked gene),

Nature Reviews | Endocrinology

GnRH/LH

CHH

Fetal Neonatal Childhood Puberty Adulthood

■ Cryptorchidism (M) ■ Micropenis (M)

■ Prepubertal testes (M) ■ Undervirilization (M) ■ Absent breast development (F) ■ Primary amenorrhoea (F)

■ Infertility (M and F)

HPG

-axi

s ac

tivity

Figure 1 | Activity of the HPG axis across the lifespan. Normal GnRH and LH secretion from fetal life to adulthood (blue line) compared with non-reversible CHH (red line). Reproductive phenotypes observed in CHH are listed under the respective stage of development. Abbreviations: CHH, congenital hypogonadotropic hypogonadism; F, female; GnRH, gonadotropin-releasing hormone; HPG, hypothalamic–pituitary–gonadal; LH, luteinizing hormone; M, male.





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respectively, are highly penetrant,127 yet such a pattern is not observed for all genes involved in CHH and/or Kallmann syndrome. For instance, the p.Arg622X FGFR1 mutation has been reported in unrelated Kallmann syn-drome and CHH probands (Figure 2). Examination of pedigrees reveals low penetrance for most CHH genes and variable expressivity among affected individuals carry ing the same gene defect. Such an observation led to the hypothesis that multiple gene defects could syner-gize to produce a more severe CHH phenotype (that is, oligo genicity).30,128 Studies in large CHH cohorts indi-cate that at least 20% of cases are oligogenic11,21 (Table 1).

This genetic model might be useful to predict genotype– phenotype correlations.5 Interestingly, genome-wide associ ation studies have identified >100 loci affecting the age of menarche,129 which confirms a genetic con-tribution to pubertal timing. Surprisingly, little overlap exists between the genes implicated in age at menarche and CHH.129

Diagnosis of CHHCentral to the evaluation process for diagnosing CHH is the exclusion of differential diagnoses such as pituitary tumour or functional causes (Box 2).

Table 1 | Genes implicated in CHH

Gene OMIM CTO CHH phenotypes Overlapping syndromes

KS CHH CHH reversal

CPHD CPHD + SOD

WS CHARGE HS SHFM D‑WS MGS PEPNS GHS

KAL1 (ANOS1)

300836 × × × × × × × × × × ×

SEMA3A 614897 × × × × × × × × × × × ×

SOX10 602229 × × × × × × × × × × × ×

OL14RD 606807 × × × × × × × × × × × ×

HESX1 182230 × × × × × × × × × × ×

FEZF1 613301 × × × × × × × × × × × × ×

FGFR1 147950 × × × × × ×

FGF8 612702 × × × × × × × × × ×

CHD7 612370 × × × × × × × × × ×

FGF17 603725 × × × × × × × × × ×

HS6ST1 614880 × × × × × × × × × ×

PROK2 610628 × × × × × × × × × × ×

PROKR2 147950 × × × × × × × ×

SEMA7A 607961 × × × × × × × × × × ×

WDR11 614858 × × × × × × × × × ×

NSMF 614838 × × × × × × × × × ×

AXL 109135 × × × × × × × × × × × ×

GNRH1 614841 × × × × × × × × × × × × ×

GNRHR 146110 × × × × × × × × × × ×

KISS1 614842 × × × × × × × × × × × × ×

KISS1R 614837 × × × × × × × × × × × ×

TAC3 614839 × × × × × × × × × × ×

TACR3 614840 × × × × × × × × × × ×

LEP 614962 × × × × × × × × × × × × ×

LEPR 614963 × × × × × × × × × × × × ×

PCSK1 162150 × × × × × × × × × × × × ×

DMXL2 616113 × × × × × × × × × × × ×

RNF216 609948 × × × × × × × × × × × ×

OTUD4 611744 × × × × × × × × × × × ×

PNPLA6 603197 × × × × × × × × × × × ×

NR0B1 300200 × × × × × × × × × × × × ×

Abbreviations: CHH, congenital hypogonadotropic hypogonadism; CHARGE, coloboma, heart defects, atresia of choanae, retardation of growth and/or development, genital and/or urinary defects, ear anomalies or deafness; CPHD, combined pituitary hormone deficiency; CTO, contributes to oligogenicity; D-WS, Dandy-Walker syndrome; GHS, Gordon Holmes syndrome; HS, Hartsfield syndrome; KS, Kallmann syndrome; MGS, Morning Glory syndrome; OMIN, online Mendelian inheritance in man; PEPNS, polyendocrine deficiencies and polyneuropathies; SHFM, split-hand/foot malformation; SOD, septo-optic dysplasia; WS, Waardenburg syndrome.





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Clinical, biochemical & imaging investigationsThe mini-puberty provides a brief opportunity to iden-tify CHH. For male infants, cryptorchidism with or without micropenis can be suggestive of CHH (Figure 1).

In such cases, hormone profiling at 4–8 weeks of life can be used to make a diagnosis83,85 based on comparisons with established reference ranges for gonadotropins, sex steroids and inhibin B levels.62,63,70,130 Female neonates born to parents with CHH should undergo biochemical evaluation; serum levels of FSH during the mini-puberty seem to be the most sensitive indicator of CHH in this setting.131 During childhood, diagnosis of CHH is very challenging as this interval is a physiologically hypo-gonadal period of development. Undetectable levels of FSH (but not of LH) or absence of response to a GnRH test in childhood might indicate CHH.

CHH diagnosis is typically made during adolescence or early adulthood (Table 2). Approximately half of patients with CHH have Kallmann syndrome.101 Self-report of anosmia is reliable, yet claims of having a ‘good’ sense of smell do not always align with formal smell testing. Most patients with Kallmann syndrome display olfactory bulb hypoplasia and/or aplasia on brain MRI; however, this finding is not fully concordant with sense of smell.102 An assessment of family history is important to identify familial cases. A family history of CDGP does not exclude CHH as pedigrees of patients with CHH seem to be enriched in delayed puberty, subfertility and anosmia or hyposmia.132 A detailed physical examination is needed, with particular atten-tion paid to genitalia (that is, measurement of testicular volume using a Prader orchidometer) and virilization and/or estrogenization (that is, Tanner staging for breast development and pubic hair133,134). Eunuchoidal proportions are often present.135 A stage-line diagram is useful for providing developmental stages ±SD or as percentiles, as well as the tempo of pubertal develop-ment ±SD per year.91 Additionally, signs of associated developmental anomalies such as cryptorchidism with or without micropenis, midline defects or signs sugges-tive of combined pituitary hormone deficiency should be evaluated (Box 2).

Biochemical evaluation includes a variety of tests to exclude other causes of CHH such as pituitary tumour or functional causes (Table 3). Isolated hypogonadotropic


I

II

III

Carrier Proband

Family 4

1 2

21

1 2

Arg622X/+

Arg622X/+

Arg622X/+

Family 3

1 2

2 31

1

Arg622X/+ Arg622X/+

Arg622X/+

Family 1

1 2

21

1 2 3

+/+

Arg622X/+

Arg622X/+ Arg622X/+ Arg622X/+

Family 2

1 2

2 31

1 2

Arg622X/+

Arg622X/+

Arg622X/+ Arg622X/+

Arg622X/+

Cleft palateDelayed pubertyCHH Anosmia

Figure 2 | FGFR1 mutation p.Arg622X in an autosomal dominant form of CHH with incomplete penetrance and variable expressivity. In family 1, the CHH phenotype is fully penetrant.147 In the three other pedigrees, family members carrying the same FGFR1 mutation have variable reproductive and olfactory phenotypes and family 2 includes an asymptomatic carrier.17,148 + denotes wild-type allele. Abbreviation: CHH, congenital hypogonadotropic hypogonadism.

Box 2 | Forms of CHH and differential diagnosis

Forms of CHHGnRH deficiency and defective sense of smell ■ Kallmann syndrome

Isolated GnRH deficiency (normal sense of smell) ■ Normosmic CHH

Complex syndromes including CHH or KS ■ Combined pituitary hormone deficiency ■ Septo-optic dysplasia ■ CHARGE syndrome ■ Adrenal hypoplasia congenita with HH ■ Waardenburg syndrome ■ Bardet–Biedl syndrome ■ Gordon Holmes syndrome ■ Others

Differential diagnosisFunctional causes ■ Malnutrition and/or malabsorption ■ Any chronic disease (for example, IBS or asthma) ■ Coeliac disease ■ Eating disorders ■ Excessive exercise

Systemic causes ■ Haemochromatosis ■ Sarcoidis ■ Histiocytosis ■ Thalassaemia

Acquired causes ■ Pituitary adenomas and/or brain tumours ■ Rathke’s cleft cyst ■ Pituitary apoplexy ■ Radiation (brain or pituitary) ■ Medication induced (such as, by steroids, opiates

or chemotherapy)Abbreviations: CHARGE, coloboma, heart defects, atresia of choanae, retardation of growth and/or development, genital and/or urinary defects, ear anomalies or deafness; CHH, congenital hypogonadotropic hypogonadism; GnRH, gonadotropin-releasing hormone; HH, hypogonadotropic hypogonadism; IBS, irritable bowel syndrome; KS, Kallmann syndrome.





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hypogonadism is characterized by low serum levels of testosterone in male individuals (usually <2 nmol/l) in the setting of low or normal serum levels of gonado-tropins (LH and FSH) with otherwise normal pituitary function (Figure 3). In female individuals, serum levels of estradiol are often low, sometimes undetectable in the setting of low-normal gonadotropin levels. Serum levels of estradiol seem to correlate with breast development, as most women with absent breast development have very low or undetectable levels, whereas women with breast development exceeding Tanner stage B2 usually have measurable serum levels of estradiol.

In early adolescence (13–16 years), a diagnosis of CHH is challenging to make as isolated hypogonadotropic hypogonadism is common to both CHH and CDGP. In CHH, the GnRH stimulation test has a poor diagnostic value. In the absence of a gonadotropin response, this test can help to confirm severe GnRH deficiency, yet clini-cal signs are often already evident (that is, prepubertal testes or absence of breast development). By contrast, the GnRH stimulation test rarely enables differentiation of CDGP from partial forms of CHH—the most challen-ging differential diagnosis. A number of other tests have been proposed to differentiate between these two enti-ties, including a combination of GnRH and hCG stimu-lation tests, as well as measurement of serum levels of inhibin B, AMH or INSL3.74,136–142 However to date, no gold-standard diagnostic test exists to fully differentiate CHH from CDGP.143

Inhibin B is a marker of Sertoli cell number and cor-relates with testicular volume.92 In men with CHH and severe GnRH deficiency, serum levels of inhibin B are typically very low (<30 pg/ml; Figure 3). However, for partial forms of CHH, inhibin B levels overlap with those in patients with CDGP and in healthy controls.138,139 INSL3 is a good marker of Leydig cell function144 and, as such, levels of INSL3 are typically low in male individuals with CHH (at diagnosis or on testosterone therapy) and increase with LH and/or hCG stimulation.74 However, further studies are needed to identify the potential clini-cal utility of INSL3 measurements, such as differentiating CHH from CDGP or as a predictor of reversible CHH. Kisspeptin is a potent stimulator of GnRH-induced LH secretion.9 Exogenous kisspeptin administration failed to induce a response in patients with CHH regardless of genotype. However, a male individual with revers-ible CHH exhibited a robust response to exogenous kisspeptin145 and continuous kisspeptin infusion was demonstrated to overcome genetic defects in the kiss-peptin signalling pathway.146 In terms of clinical applica-tion, kiss peptin has been used with therapeutic effect in women with hypothalamic amenorrhoea,147 as well as for egg maturation during assisted fertility.148 Thus, although still investigational, kisspeptin seems to be emerging as useful in several therapeutic areas.

CHH work-up also includes cranial MRI to assess for tumours and/or space occupying lesions and to visualize inner ear and olfactory structures, bone age in adolescents to compare with chronological age and to assess epiphyseal closure, abdominal and/or pelvic ultra sonography to assess unilateral renal agenesis and to visualize the ovaries and/or uterus or testis, and bone densitometry (dual-energy X-ray absorptiometry) to assess bone density.

Genetic testingGenetic testing is useful for diagnosis, prognosis149 and genetic counselling in CHH.127 The first step in priori-tizing genes for genetic testing is to establish the inheri-tance pattern. Briefly, X-linked inheritance is observed in pedigrees when male-to-male transmission of the disease phenotype does not occur but the disease is observed in male members of the maternal line. This feature is typical for KAL1 (ANOS1) mutations underlying Kallmann syn-drome.150 Autosomal dominant inheritance is observed in a family with vertical transmission of the disease pheno-type across one or more generations. In this setting, male and female individuals are equally affected and male-to-male transmission can be observed. Importantly, incom-plete penetrance and variable expressivity of the disease among people with identical mutations can be observed for most CHH genes (Figure 2).17,151,152 In autosomal recessive inheritance, vertical transmission of the disease phenotype does not occur and ~25% of offspring are affected. Examples of autosomal recessive forms include those involving mutations in GNRHR, KISS1R, TACR3, PROKR2 or FEZF1 (Table 1).

Genetic testing can also be guided by the presence of additional phenotypic features. Cleft lip and/or palate

Table 2 | Clinical evaluation of CHH

Assessment Signs Focus

Growth Evaluation of growth (growth chart) Linear growth, acceleration and/or deceleration in growth

Eunuchoidal proportions Closure of epiphysis

Sexual Cryptorchidism and micropenis Severe CHH in male individuals

Sexual development (Tanner staging of pubic hair, penis and gonads in male individuals and breasts in female individuals)

Puberty (Tanner stage 2 genitalia in male individuals indicates the onset of puberty)

Male individuals: testicular volume (Prader orchidometer) and penile length

Male individuals: at age 14 years, testicular volume <4 ml indicates absent pubertyAssess micropenis (versus cross-sectional normative data)

Female individuals: breast development and age at menarche

Female individuals: at age 13 years, Tanner stage 1 breasts indicate absent pubertyPrimary amenorrhoea by age 15 years

Other Olfaction (using odorant panel and/or olfactometry)

Hyposmia and/or anosmia

Snellen eye chart, ocular fundoscopy Optic nerve hypoplasia

External ear shape and audition Hearing impairment

Number of teeth Cleft lip and/or palate, missing tooth or teeth

Pigmentation of skin and hair Achromic patches

Rapid sequential finger–thumb opposition

Bimanual synkinesisNeurodevelopmental delay

Abbreviation: CHH, congenital hypogonadotropic hypogonadism.





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and skeletal anomalies indicate mutations in genes encoding components of the FGF8 signalling pathway (for example, FGFR1, FGF8 and HS60ST1).17,20,21,104,153 Signs associated with CHARGE syndrome (CHARGE: coloboma, heart defects, atresia of choanae, retardation of growth and/or development, genital and/or urinary defects, and ear anomalies and/or deafness) favour screening for mutations in CHD7.24–26,104 Likewise, the association of CHH with congenital hearing impairment should direct screening towards CHD7, SOX10 and/or IL17RD.21,28,104 Bimanual synkinesia or renal agenesis are important clinical cues suggestive of KAL1 (ANOS1) mutations.101,104,114,154,155 Early onset of morbid obesity associated with CHH suggests mutations in LEP, LEPR or PCSK1.58,156 Indeed, combining CHH with specific associated phenotypes can increase the probability of finding causal mutations by targeted gene sequencing (Figure 4).21,28,104,157 CHH accompanied by other syn-dromic features such as congenital ichthyosis158 or sphero-cytosis159 is suggestive of a contiguous gene syndrome for which a karyotype or comparative genomic hybridization array analysis might be useful for identifying underlying chromosomal abnormalities.159–161

Genetic counsellingA legitimate question often raised by patients with CHH relates to the risk of passing on the disease to their off-spring.26,127,162 When autosomal dominant transmission is suspected, the patient and partner should receive genetic counselling before fertility-inducing treatment. This counselling should include clear explanation of the 50% theoretical risk of transmitting the disease. In such cases, hormonal profiling during mini-puberty should be conducted. In proven autosomal recessive forms, which affect both male and female individuals, the risk of disease transmission to offspring is very low in the absence of consanguinity (that is, inter-related parents). This reduced risk is due to the very low frequency of heterozygous healthy carriers in the general population, which should be reassuring for intended parents. Male individuals with X-linked Kallmann syndrome should be informed of the automatic transmission of the muta-tion to their unborn daughters (obligate carriers) and the necessity for genetic counselling of these girls after the age of puberty. When patients carry several mutations in different CHH or Kallmann syndrome genes (that is, oligogenicity), genetic counselling is difficult and the transmission risk is variable.127 Finally, the advent of next-generation sequencing will probably improve the molecular genetic diagnosis of CHH.163 More spe-cifically, this technology will help identify cases of oligo-genicity and might promote personalized approaches to genetic counselling.

Treatment of CHHNo treatments exist for many of the CHH-associated phenotypes such as anosmia, bimanual synkinesia or renal agenesis. Others phenotypes such as cleft lip and/or palate, hearing loss or various skeletal defects require surgical and/or specialist intervention early in life. The approach to CHH treatment is largely deter-mined by goals such as developing only virilization or estrogenization, or inducing fertility as well.

During infancy and childhoodIn affected boys, the focus of most treatment is on appropriate testicular descent and penile growth. Cryptorchidism (particularly bilateral) can have far reaching negative effects on future fertility potential.164,165 As such, current recommendations advocate surgical correction at 6–12 months.166–168 Micropenis should be treated early using short-term, low-dose testos terone (dihydrotestosterone or testosterone esters) to induce penile growth (Table 4).86,169 Importantly, as the duration of treatment is brief, no major concerns regarding viril-ization or the development of secondary sexual charac-teristics exist; however, erections might be observed. Gonadotropins (LH and FSH) have been used to treat patients with micropenis and evidence of absent mini-puberty.170,171 Such an approach might be beneficial for the additional stimulatory effect on gonadal develop-ment. Indeed, treatment with FSH stimulates prolifera-tion of immature Sertoli cells and spermatogonia in men with CHH before pubertal induction.10 Furthermore,

Table 3 | Biochemical, radiological and genetic evaluation of CHH

Assessment Marker Focus

Biochemical 0800–1000 h hormonal measurements (LH, FSH, testosterone or estradiol, prolactin, free T4, TSH, cortisol, IGF-1 and IGFBP3)

Assess for combined pituitary hormone deficiencyDemonstrate isolated hypogonadtropic hypogonadism

Specialized endocrine tests (serum inhibin B, AMH, INSL3, GnRH and/or hCG stimulation test)

Evaluate the degree of GnRH deficiency and function of the gonads

Spermiogram Assess fertility

Liver and/or renal function and inflammatory markers (LFTs, BUN, lytes, CBC, Ca, CRP, ESR and faecal calprotectin)

Assess systemic and/or inflammatory disease

Screen for coeliac disease Assess malabsorption

Iron overload screen (ferritin, TIBC% saturation)

Assess juvenile haemochromatosis

Radiologic Wrist radiography (bone age) Delayed bone age (chronological age greater than bone age)

Brain MRI Exclude hypothalamo–pituitary lesionAssess olfactory bulbs and sulciVisualize optic nerveAssess inner ear (semicircular canals)

Renal ultrasonography Rule out unilateral renal agenesis

Bone density (DXA) Assess osteopenia and/or osteoporosis

Genetic Comparative genomic hybridization array or karyotype

Large, rare deletions and/or insertions to identify contiguous gene syndromes

Gene screening (Sanger or next-generation sequencing)

Mutations in CHH and/or KS genes

Abbreviations: AMH, anti-Müllerian hormone; BUN, blood urea nitrogen; CBC, complete blood count; CHH, congenital hypogonadotropic hypogonadism; CRP, C-reactive protein; DXA, dual-energy X-ray absorptiometry; ESR, erythrocyte sedimentation rate; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; IGF-1, insulin growth factor 1; IGFBP3, insulin-like growth factor-binding protein 3; INSL3, insulin-like 3; KS, Kallmann syndrome; LFTs, liver function tests; LH, luteinizing hormone; TIBC, total iron-binding capacity.





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neonatal gonadotropin therapy can increase intra-testicular testosterone concentrations without fear of inducing spermatogenesis or negatively affecting the ultimate number of Sertoli cells (an important deter-minant of fertility), as Sertoli cells do not express the androgen receptor during the first 5 years of life.172,173 Although initial studies involving neonatal administra-tion of gonadotropin have been promising, these studies are limited, both in number of studies and number of participants, and further investigations are needed to examine the effectiveness of gonadotropin and its effect on long-term outcomes such as fertility (Box 3).

During adolescence and adulthoodThe aim of treatment is to induce virilization or estro-genization and normal sexual function, to stimulate statural growth, to promote bone health and to address concerns about future fertility as well as psychological and emotional wellbeing.174,175 Sex steroid therapy (that is, testosterone in male individuals and estradiol before

estradiol + progesterone in female individuals) induces the characteristic changes of puberty, which includes psychosocial development (Table 4).

Induction of male sexual characteristicsVirilization is typically the primary objective of treat-ing CHH174 in order to diminish the psychological suf-fering caused by sexual infantilism.97,98,176 Accordingly, prompt initiation of therapy after diagnosis is important and usually involves an injectable testosterone ester (aromatizable androgen such as enanthate, cypionate or undecanoate) or transdermal testosterone application with the precise protocol depending on the age at diag-nosis and local practice.94,177,178 Paediatric endocrinolo-gists treating young patients (that is, from 12 years of age) usually begin treatment with low-dose testos-terone (for example, 50 mg of testosterone enanthate monthly, 10 mg transdermal testosterone every second day, or 40 mg oral testosterone undecanoate daily) and gradually increase to full adult dosing over the course of 18–24 months, depending on age at the start of treat-ment. Such regimens help mimic natural puberty and maximize statural growth while affording time for psycho sexual development and minimizing the risk of precocious sexual activity.95,174

Adult endocrinologists often see patients with CHH in late adolescence or early adulthood when the main complaint is the lack of pubertal development.94 In such cases, the therapeutic approach is often more incisive than for younger patients, involving higher initial tes-tosterone doses (200 mg testosterone enanthate monthly, then every 2–3 weeks) than those used by paediat-ric endocrinologists to induce more rapid virilization (Box 4). The frequency of injections should be guided by trough serum testosterone measurement targeting the lower end of the normal range to avoid periods of hypogonadism between injections. Of note, testoster-one treatment will not induce gonadal maturation or fertility in these patients.94,177 Importantly, increased testicular volume following testosterone treatment is an indicator of reversal6,7,179–185 and requires re-assessment of the HPG axis in the absence of testosterone replace-ment therapy. An estimated 10–20% of patients with CHH undergo spontaneous recovery of reproductive function,6,7 and this includes patients with mutations in known CHH genes (Table 1). Moreover, reversal is not always lasting7,184 and, as yet, no predictors to identify those who will reverse or relapse exist (Box 3). Ongoing monitoring is thus justified.

Virilization in adolescents or young adults can also be achieved with pulsatile GnRH186–188 or gonadotropin therapy (hCG alone or combined with FSH).189,190 These fertility-inducing treatments stimulate endogenous testosterone (and estradiol) production by testicular Leydig cells and are associated with good physical and psychological outcomes.191 In clinical practice, testos-terone enanthate is the most frequently used treatment for young adults, yet clinicians should avoid adher-ence to an overly dogmatic approach. Few published studies have examined the effects of treatment to induce

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Figure 3 | Hormonal profile of patients with CHH and/or KS compared with healthy controls. a | Serum testosterone levels. b | Serum gonadotropin (LH and FSH) levels. c | Serum inhibin B levels. d | Serum INSL3 levels. Healthy male individuals (controls; aged 17—27 years) versus untreated patients with CHH and/or KS (aged 17–29 years). Abbreviations: CHH, congenital hypogonadotropic hypogonadism; FSH, follicle-stimulating hormone; INSL3, insulin-like 3; LH, luteinizing hormone; KS, Kallmann syndrome. Adapted with permission from The Endocrine Society © Trabado, S. et al. J. Clin. Endocrinol. Metab. 99, E268–E275 (2014) and Young, J. J. Clin. Endocrinol. Metab. 97, 707–718 (2012).





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virilization, as well as fertility treatment, on quality of life and sexuality in men with CHH,97,98,192 particularly in those with severe CHH (micropenis and cryptorchid-ism). Regardless of the therapy considered, patients and their entourage (that is, spouse, partner or family) should be clearly informed that treatment is likely to be lifelong and to require regular monitoring for optimal benefit.

Induction of male fertilityCHH manifests as a lack of gonadal development and infertility. Importantly, CHH is one of the rare treat-able causes of male infertility. Spermatogenesis can be induced either by long-term pulsatile GnRH admin-istration (pump)193 or more commonly by subcutan-eous gonadotropin injections (2–3 times weekly).194–198 These therapies induce both testicular testosterone production by Leydig cells and spermatogenesis in the seminiferous tubules.199–202 The majority of patients with CHH develop sperm in their ejaculate with long-term therapy.149,193,196,197 Although these treatments seem to have similar fertility outcomes,199–202 compar-ing their efficacy is difficult owing to the small numbers of patients studied, heterogeneity in terms of degrees of GnRH deficiency (testicular volume before treatment), prior treatment and a lack of randomized studies performed to date.

A number of predictors of fertility outcome have emerged in CHH. First, cryptorchidism indicates a poor fertility prognosis.193,195 Men with CHH who have cryptor chidism often require extended courses of treat-ment (18–24 months).203,204 Prepubertal testicular volume (<4 ml) and/or low serum levels of inhibin B are also neg-ative determinants of fertility outcome.193–197 Clinicians should be aware that although ~75% of men will develop sperm, counts rarely reach the normal range with long-term therapy. A 2014 meta-analysis identified a mean sperm count of 5.9 × 106/ml (range: 4.7–7.1 × 106/ml) for gonadotropin therapy and 4.3 × 106/ml (range: 1.8–6.7 × 106/ml) for GnRH therapy.200 However, an important feature of patients with CHH is that low sperm concentrations do not preclude fertility.205

In clinical practice, when testicular volume is <4 ml, the classic treatment is either pulsatile GnRH (25 ng/kg every 2 h, titrated for trough serum testosterone level) or com-bined gonadotropin therapy (hCG: 1,000–1,500 IU + FSH: 75–150 IU 2–3 times weekly, based on available formu-lations). In patients with some gonadal development (testicular volume >4 ml) and no history of cryptorchi-dism, induction of spermatogenesis can be achieved with hCG mono therapy.194,206–208 If no sperm is present in the ejaculate after 3–6 months of treatment, FSH can be used to stimulate the seminiferous tubules.198 In the most severely affected men with CHH (testicular volume <4 ml), a sequential treatment has emerged in an attempt to maximize fertility potential.10,209,210 The unopposed FSH treatment before maturation by hCG (or alternatively, GnRH-induced LH) stimulates proliferation of imma-ture Sertoli and germ cells. Outcomes of patients treated with this regimen demonstrate successful induction of tes-ticular development and fertility in men with CHH who have prepubertal testes.10,210 To definitively determine the optimal approach to fertility treatment in men with CHH and severe GnRH deficiency (with or without cryptorchi-dism), an international, multicentre randomized trial is needed (Box 3).

Assessment of the fertility status of the female partner is crucial before induction of spermatogen-esis and includes a detailed reproductive and/or men-strual history and evaluation of the integrity of the uterine cavity and tubal permeability (by use of sono- hysterosalpingography or hysterosalpingography). Anovulation and ovarian reserve can be assessed via a combination of history of menstrual cycle abnormali-ties, laboratory examination and pelvic ultrasonography. Couples should be counselled appropriately on the basis of the identified predictors of CHH fertility-inducing treatment,193–198,200 as well as the partner’s reproductive status and age in order to develop realistic expectations regarding treatment outcome.

For men with CHH who have severely impaired sperm counts (or quality), assisted reproductive technol-ogy (ART) treatments such as in vitro fertilization can be used to improve fertility. More invasive procedures than ART include surgical testicular sperm extraction followed by in vitro intracytoplasmic sperm injection (ICSI). ICSI was initially used in men with CHH as a means to shorten the duration of treatment;211 however, outcomes are improved after maximal testicular volume is attained. Overall, fertilization is achieved in 50–60% of cases of ICSI, with pregnancy occurring in about a third of cycles.212–215 Although a study of sperm quality in men with CHH who received fertility-inducing treat-ment revealed neither altered DNA integrity nor an increased risk of chromosomal abnormalities,216 the possibility of an increased risk of birth defects with ART remains controversial. Once pregnancy is achieved, men with CHH can be transitioned to testosterone replace-ment therapy (injectable or transdermal preparations) for long-term treatment. Our consensus is that treat-ment be continued through the first trimester of preg-nancy, in order to maintain male fertility capability in


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the event of miscarriage. Furthermore, although previous gonadotropin cycles seem to shorten the time to fertility in subsequent treatments,196 fertility in the future is not guaranteed. We, thus, recommend cryopreserving sperm once fertility has been attained.

Induction of female sexual characteristicsPuberty can be induced by oral or preferably transder-mal estradiol administration in girls. The use of specific low-dose estradiol formulations (for example, 0.1 mg daily) are important.174 Transdermal estradiol adminis-tration is started (from age 10 years at the earliest) at low doses (typically 0.05–0.07 μg/kg nocturnally), with the goal of mimicking estradiol levels during gonadarche. In older girls, when breast development is a high pri-ority, the starting dose of transdermal estradiol can be 0.08–0.12 μg/kg.217 The estradiol dose is slowly increased

over 12–24 months, after which time cyclic gestagen is added (or after the first menstrual bleed) in order to max-imize breast development. In adulthood, estradiol is typi-cally given orally (at a dose of 1–2 mg) or transdermally (50 μg daily by patch or 1–2 pumps of 0.06% gel daily) as a maintenance dose with a cyclic progestin regimen (progesterone 200 mg for 14 days of the cycle, depending on formulation) to avoid endometrial hyperplasia. In the majority of women with CHH, estroprogestin therapy is effective in inducing harmonious development of the breasts and genitals, as well as an increased sense of femi-ninity that contributes to a satisfactory emotional and sexual life. Estrogen treatment increases uterine size and combined estrogen and progestin therapy induces monthly withdrawal bleeding, but does not induce ovu-lation. For fertility, gonadotropins or GnRH therapy are necessary and effective.

Table 4 | Approach to treatment of CHH

Target population

Goals Treatment Clinical monitoring Laboratory monitoring

Comments

Neonatal and childhood

Male individuals with cryptorchidism with or without micropenis

Testicular descent

Cryptorchidism: orchidopexy (patients aged <1 year)

Testicular volume Testosterone, LH, FSH, inhibin B and AMH levels

Baseline levels of testosterone, LH and FSH between days 14–90; for later timepoints, measure after GnRH agonist stimulationNo current indication for female individuals

Penis growth Micropenis: testosterone, DHT or gonadotropin therapy (patients aged 1–6 months)

Penile growth

Adolescent

Patients aged 14–15 years (earlier in the presence of specific signs such as anosmia)

Virilization or estrogenizationSexual functionGrowth and bone healthGonadal maturation and future fertilityPsychological wellbeing

Male patients: testosterone (oral, injectable or transdermal)Gonadotropins?

Genital developmentGrowth and epiphyseal closureVirilizationSexual functionWellbeingAdherenceReversibility

Morning serum testosterone levels (trough levels for injections), LH, FSH and inhibin B levels, haemocrit

Testosterone treatment will not induce testicular growth or fertility

Female patients:estradiol (oral or transdermal) followed by estradiol + progesterone or progestin

Breast developmentGrowth and epiphyseal closureEstrogenizationFeminized bodyMensesSexual functionBone healthWellbeingAdherenceReversibility

No specific Estradiol must be increased slowly before the combination of estradiol + progesterone or progestin to maximize breast development and avoid areolar protrusion

Adulthood

All patients Sexual functionFertilityLimiting comorbiditiesPsychological wellbeingPuberty induction

Male patients:Testosterone (injectable or transdermal)hCG ± FSHFSH, FSH + hCGGnRH pump

Pubertal developmentSexual function and libidoBone healthWellbeingAdherenceFertilityReversibility

Tough serum testosterone levels, LH, FSH and inhibin B levels, haematocrit, PSA levels

Sex steroid replacement will not induce fertility

Female patients:Estradiol (oral or transdermal)Progesterone or progestinFSH + hCG or GnRH pump

Pubertal developmentSexual function and libidoBone healthWellbeingAdherenceFertilityReversibility

Serum levels of estradiol, LH, FSH, inhibin B and AMH

Sex steroid replacement will not induce fertility

Abbreviations: AMH, anti-Müllerian hormone; CHH, congenital hypogonadotropic hypogonadism; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone; PSA, prostate-specific antigen.





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Induction of female fertilityInfertility in women with CHH is related to insufficient follicular maturation, which leads to chronic anovula-tion.218 GnRH-induced pituitary gonadotropins induce absent or decreased physiological ovarian stimulation; however, no evidence of a decreased follicular reserve exists. This point must be emphasized as decreased circu-lating AMH concentrations observed in female patients with CHH and severe GnRH deficiency could wrongly suggest an alteration in ovarian reserve and therefore a poor fertility prognosis.219 By contrast, women with CHH should be informed that their infertility is treat-able and that their reproductive prognosis is quite good in the absence of a male factor of infertility.

Before considering ovulation induction, sono- hysterosalpingography or hysterosalpingography should be performed to evaluate the integrity of the uterine cavity

and fallopian tubes. One must also ensure regular sexual intercourse takes place and rule-out an associated male factor in infertility by semen analysis.220 Couples should be advised on the optimal timing of sexual intercourse during the ovulation induction as this first-line therapy does not require in vitro fertilization.221 The goal of ovu-lation induction therapy in female patients with CHH is to obtain a single ovulation and to avoid multiple preg-nancies. Ovulation can be achieved either with pulsatile GnRH therapy222–224 or, alternatively, with FSH treatment followed by hCG or LH to trigger ovulation.225 One caveat is that most women with CHH do not secrete endogenous LH and, thus, require a complement of LH to stimulate local production of androgen substrates by theca cells, which facilitates sufficient secretion of estradiol by the dominant follicle.226–228 Physiologic estradiol secretion promotes optimal endometrial development and the cervical mucus production needed for sperm transit and embryo implantation.229 Typically, subcutaneous FSH doses of 75–150 IU per day are sufficient.223–225,229 The usual time required to obtain a dominant mature follicle (>18 mm) is ~12 days.223–225,229 The starting dose of FSH is often increased or decreased depending on the ovarian response, as assessed by repeated serum estradiol meas-urements or by counting maturing follicles (using ultra-sonography) performed approximately every 3–4 days. This regimen helps to minimize multiple pregnancies and the risk of ovarian hyperstimulation syndrome.230 After ovulation, progesterone production can be stimulated by repeated hCG injections or direct administration of pro-gesterone during the postovulatory phase, until embryonic endogenous hCG secretion takes over.

Ovulation induction with a pulsatile GnRH pump can be effective even in the presence of GnRH resistance, such as in women with CHH who have mutations in GNRHR.231 GnRH can be administered at different pulse frequencies across the cycle, mimicking physiological ovarian stimulation.232 Alternatively, pulsatile GnRH at a constant frequency also induces maturation of ovarian fol-licles and triggers an LH peak. The usual doses comprise 3–10 μg per pulse, injected subcutaneously every 90 min. Monitoring ovulation induction with GnRH is useful, as the risk of multiple pregnancy and ovarian hyperstimula-tion syndrome is much lower than that with gonadotropin therapy.233 Once ovulation is obtained, the corpus luteum is stimulated to produce progesterone, which is neces-sary for embryo implantation. Short-term GnRH treat-ment is necessary to induce progesterone release until the endo genous secretion of hCG from the embryo begins.

Reducing long-term health effects of CHHWith appropriate and long-term treatment, many of the long-term effects of hypogonadism can be minimized. Adherence to treatment is key to supporting pubertal development, sexual function and psychological health.234 Patients with psychosexual problems, low self-esteem and distorted body image might require psychological coun-selling and often benefit from peer–peer support.98,192 Bone-health concerns in patients with CHH are well-recognized.235 Lack of sex steroids is the presumed cause

Box 3 | Challenges for management of CHH and goals

Detection and diagnosis of CHH ■ Discover novel biomarkers for CHH diagnosis and

assess the utility of refining the phenotype to enhance genetic testing

Best treatment and timing of initiating treatment ■ Long-term studies evaluating: neonatal gonadotropin

treatment to optimize fertility; gonadotropin treatment during adolescence versus adulthood for fertility optimization; and role of prior androgen treatments on fertility outcomes

Adherence to treatment and transition to adult services ■ Interventions to promote adherence and structured

transitional care from paediatric to adult services

Psychological distress and psychosexual effect ■ Targeted psychosocial interventions and enhanced

peer-to-peer support

Specialized care for fertility induction ■ International, multicentre trials to identify optimal

approach to treatment

Genetic counselling (monogenic versus oligogenic forms of CHH) ■ Personalized counselling of patients using results

obtained by next-generation sequencing technologiesAbbreviation: CHH, congenital hypogonadotropic hypogonadism.

Box 4 | Goals for testosterone replacement therapy*

Promote ■ Virilization (for example, axillary, body and facial hair) ■ Development of muscle mass and strength ■ Pubertal growth spurt ■ Skeletal maturation and bone mass ■ Deepening of voice ■ Growth of penis ■ Libido and sexual function ■ Self-confidence and wellbeing

Monitor and minimize ■ Acne ■ Gynaecomastia ■ Aggressiveness ■ Polycythaemia

*In male patients with congenital hypogonadotropic hypogonadism.





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of osteoporosis in patients with CHH236–238 and although sex steroid treatment typically improves bone density, it does not fully reverse the pheno type. Notably, mutations in FGF8, FGFR1 or SEMA3A might not only cause GnRH deficiency but also directly affect bone.153,239 We recom-mend a baseline bone density measurement in all patients with CHH at final height and after 2 years of treatment. To date, insufficient evidence exists to use the WHO–FRAX risk calculator240 in this population of patients. Long-term effects of hypo gonadism also include an increased risk of developing metabolic problems. Several meta-analyses have demonstrated an association between low testos-terone levels and the metabolic syndrome.241–244 In male individuals, low testosterone levels are also strongly associ-ated with an increased risk of developing type 2 diabetes mellitus.245 However, few studies have examined metabolic risk specifically in patients with CHH. Interestingly, even short-term hypogonadism (such as that resulting from dis-continuation of sex steroids for 2 weeks) induces increased fasting insulin concentrations in young men with CHH,246 which suggests that adherence to treatment is also impor-tant for promoting metabolic health. Accordingly, thera-peutic education is important for promoting adherence in the ongoing management of CHH.

Transitional care for CHHTransition of young adults from paediatric care to adult care is a well-recognized challenge for patients with chronic endocrine conditions247,248 including CHH.175 For patients with CHH, discontinuation of care and resulting gaps in treatment can have considerable health consequences. Several types of model for transition exist from a simple transfer of care to more structured programmes.249 Consensus among paediatric and adult endocrinologists in the European consortium study-ing GnRH biology (COST Action BM1105, http:// www.gnrhnetwork.eu/) is that a structured transition is preferable and the process should include an evaluation of patient readiness, communication between providers and

follow-up to ensure that the initial consultation has been completed. The timing of transition not only depends on structural aspects of a given health-care system but also on the individual patient’s psychological and emotional development and capacity for autonomy and self-care.

ConclusionsCHH is a condition that is clinically and genetically hetero geneous. It is often challenging to diagnose, par-ticularly during adolescence. In male individuals, crypt-orchidism with or without micropenis might suggest neonatal CHH; however, similarly useful signs are lacking for female individuals. During adolescence, the diagnosis of CHH is difficult to discern from constitutional delay of growth and puberty. The presence of anosmia and/or olfactory bulb hypoplasia and/or aplasia (visualized by MRI) points to Kallmann syndrome, yet measurement of levels of serum gonadotropins, sex steroids, AMH and inhibin B are not always fully informative in confirming the diagnosis. At this stage, pubertal induction is com-menced and a clinical and/or biochemical reassessment is conducted following therapeutic pause at final height, thus enabling a definitive diagnosis of CHH. Effective treatment is available not only for inducing virilization or estrogenization, but also for successful development of fertility. Advances in our understanding of the molecular basis of CHH have helped explain the genetic cause in 50% of cases and uncovered a complex model of gen etics (oligo genicity) that might apply to a large proportion of patients. Furthermore, cases of reversal in adulthood point to gene–environment interactions.6,7 To advance the field, identification of novel biomarkers to aid early diagnosis of CHH, assembly of a large CHH population to study the complex molecular basis of the disease, and development of targeted treatments to optimize fertility outcomes are important. The COST network was created to address these issues as well as to promote translational research into human reproduction and improve the manage ment of CHH.

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AcknowledgementsThe authors acknowledge support of COST Action BM1105.

Author contributionsM.T.D., L.D., A.A.D., A.J., N.P., T.R., R.Q. and J.Y. researched data for the article. U.B., M.T.D., L.D., A.A.D., P.G., J.-P.H., A.J., N.P., V.P., T.R., R.Q. and J.Y. wrote the article. All authors provided substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission. The final Consensus statement was approved by the Clinical Working Group (Corin Badiu, Hermann Behre, Marco Bonomi, Claire Bouvattier, Jean-Claude Carel, Sophie Christin-Maitre, Martine Cools, Waljit Dhillo, Jyothis George, Neoklis Georgopoulos, Christina Ghervan, Jörg Gromoll, Michael Hauschild, Sabine Kliesch, Csilla Krausz, Philip Kumanov, Mariarosaria Lang-Muritano, Beatriz L. Santamaria, Juliane Leger, Madalina Musat, Vassos Neocleous, Irene Netchine, Marek Niedziela, Franziska Phan-Hug, Duarte Pignatelli, Michel Polak, Vera Popovic, Nicos Skordis, Vallo Tillmann, Jorma Toppari, Philippe Touraine and Josanne Vasallo) and the Genetic & Bioinformatics Working Group (James Acierno Jr, Magdalena Avbelj-Stefanija, Jérôme Bouligand, Anne Guichon-Mantel, Sabine Heger, Soo-Hyun Kim, Zoltán Kutalik, Manuel Lemos, Ken Ong, Luca Persani, Serban Radian, Tuula Rinne, Manuela Simoni, Brian Stevenson, Gerasimos Sykiotis, Johanna Tommiska and Ionannis Xenarios).

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