BENIGN PROSTATIC HYPERPLASIA (K MCVARY, SECTION EDITOR)

Testosterone Replacement Therapy on the Natural Historyof Prostate Disease

Aaron Moore1,3 & Michael J. Butcher2,3 & Tobias S. Köhler2,3

# Springer Science+Business Media New York 2015

Abstract The physiology of testosterone production andaction are closely related to prostatic disease. An under-standing of the natural history of testosterone and pros-tate growth and development is needed in order to un-derstand this complex relationship. Lower urinary tractsymptoms (LUTS), benign prostatic hyperplasia (BPH),prostate cancer, and sexual function are common disor-ders for which testosterone is thought to play a role.Proposed in this review are some theories as to howtestosterone interacts to potentially ameliorate these con-ditions. Further research is needed, but we feel our pro-posed points are valid given the review of the literature.

Keywords Testosterone . Prostate cancer . Benign prostatichyperplasia . Lower urinary tract symptoms . Sexualmedicine . Prostate

Introduction

Asmen age, they become plagued with more disease. Some ofthese diseases and symptoms arise from male specific organslike the prostate. Indeed, urinary troubles begin shortly afterendogenous testosterone levels begin to decline in the mid 30sto 40s. Some of the most common bothersome signs are lowerurinary tract symptoms (LUTS) which can often be related tobladder outlet obstruction from benign prostatic hyperplasia(BPH). Exploring the physiology of testosterone and LUTS/BPH and how they interrelate is an important part of medicalpractice especially due to recent concerns over safety risks oftestosterone supplementation.

All testosterone products legally must include a safe-ty warnings and black box warning about the product.Specific sections of the warning related to prostate in-clude the following: BPatients with BPH treated withandrogens are at an increased risk for worsening ofsigns and symptoms of BPH. Monitor patients withBPH for worsening signs and symptoms. Patients treat-ed with androgens may be at increased risk for prostatecancer. Evaluation of patients for prostate cancer priorto initiating and during treatment with androgens isappropriate.^ The black box warning is only applicablefor topical testosterone gels which states, BVirilizationhas been reported in children who were secondarily ex-posed to testosterone gel. Children should avoid contactwith unwashed or unclothed application sites in menusing testosterone gel. Healthcare provider’s should ad-vise patients to strictly adhere to recommended instruc-tions for use.^ [1] It is unclear what evidence theserecommendation are based upon except for the clinicaldata pertaining to gels (the black box warning). Thispaper will describe the most recent and rigorous litera-ture on these interactions.

This article is part of the Topical Collection on Benign ProstaticHyperplasia

* Michael J. Butchermbutcher39@siumed.edu

Aaron Mooreamoore2@siumed.edu

Tobias S. Köhlertkohler@siumed.edu

1 School of Medicine, Southern Illinois University, 801 NorthRutledge St., Springfield, IL 62702, USA

2 The Pavilion at St. John’s Hospital, 301 North Eighth Street,Springfield, IL 62701, USA

3 Division of Urology, Illinois University School of Medicine,Springfield, IL, USA

Curr Urol Rep (2015) 16:51 DOI 10.1007/s11934-015-0526-6

In addition, as people age, testosterone decreases andprostate-specific diseases increase. This manuscript seeks toanswer questions pertaining to the relationship of testosteroneuse and sexual function, obstructive uropathy and LUTS, andprostate cancer risk in the context of increasing age. A solidfoundation of testosterone physiology and separate prostatepathologies is essential to answer these questions and helptheorize how testosterone works in concert with other organsystems.

Natural History of Testosterone and Hypogonadism

Testosterone is an important hormone that is first secreted inutero and plays an important role in sexual differentiation.Testosterone is a lipophilic molecule that is 98 % proteinbound in the blood. Albumin and sex hormone binding glob-ulin (SHBG) are the two serum proteins to which testosteroneis bound. Free testosterone and testosterone bound to albuminare biologically active throughout the body. Testosterone ex-erts the majority of its action by binding a nuclear receptorresulting in transcription and protein synthesis, which ac-counts for much of the difference between men and women.

Testosterone is released in a pulsatile manner causing theserum concentration to fluctuate throughout the day, but itgenerally peaks early in the morning [2]. This age attenuationseems to be most relevant in men less than age 45 [3] Inaddition to the diurnal variation of testosterone, there areage-related changes in serum testosterone concentration. Thisdifferentiation of the male reproductive tract occurs at 12–18 weeks of gestation with neonatal imprinting of androgen-dependent tissues around 2 months of age, and then again atpuberty. After the pubertal increase in serum testosterone, tes-tosterone reaches peak level and plateaus during the 2nd to 3rddecade of life. From this point, there is a slow decline in serumlevels [4–10]. Whether the decrease in androgens with age isphysiologic, pathologic or confounded by comorbid condi-tions remains controversial [11]. The leading theory for de-creasing androgen concentration with age is due to an alteredfeed-forward and feedback link between LH and testosterone[12].

In the body, testosterone can be converted to a morepotent androgen from metabolization of bioactive testos-terone via 5-alpha reductase to dihydrotestosterone(DHT). This more potent form of testosterone concen-trated in the prostate has been the premise behind theproposed pathophysiology of BPH via activation ofprostatic androgen receptors [13••]. Increases in DHTequate to increased prostate volume resulting in LUTS.Medications focusing on blocking 5-alpha reductasehave been used to help inhibit this conversion and de-crease the symptoms and volume of the prostate byabout 25 % [14]. However, more recent research has

proposed a different mechanism of DHT; one that isprotective rather than pathologic when sufficient levelsof testosterone is present [15] (see Fig. 1 for physiolog-ic effects of DHT)

Late onset hypogonadism is a burgeoning health topic be-cause of the aging population and due to increased awareness.With the steady age-related decline of serum testosterone, theprevalence of hypogonadism increases [4, 16]. SHBG alsoincreases with age which limits the bioavailable testosterone[9]. Using the Boston Area Community Health survey in2007, Araujo et al. estimated that 5.6 % of men between theages of 30 to 79 met the criteria for symptomatic androgendeficiency defined by one specific symptom for androgen de-ficiency or two non-specific symptoms and total T<300 ng/dLor free T<5 ng/dL [4].

Diagnosis of hypogonadism requires clinical symptomsand biochemical evidence [17•, 18, 19••]. The InternationalSociety of Andrology (ISA) and Endocrine Society ClinicalPractice Guidelines state that these symptoms can be eithersexual or the less specific symptoms associated with androgendeficiency such as fatigue [17•, 18]. Diagnosis of late onsethypogonadism remains challenging due to controversy re-garding the criteria for diagnosis. This ambiguity is in partdue to differing sensitivities to androgen concentrations be-tween individuals [20]. There is also an issue of increasingandrogen resistance with age [21], difficulty to accurately as-say testosterone [22], and the wide variations of serum testos-terone dependent on collection time [2]. With so many vari-ables, it is difficult to obtain a consensus of defininghypogonadism and the association with LUTS especially inthe aging population.

Current studies have not established a link between testos-terone therapy and increased incidence of prostate cancer orbenign prostatic hyperplasia (BPH) [23]. Despite the lack ofevidence on testosterone therapy’s effect on BPH, clinicalguidelines from the ISA and Endocrine Society still recom-mend against initiating testosterone therapy in the presence ofsevere lower urinary tract symptoms without proper evalua-tion by urologist [17•, 18].

In individual studies, higher serum testosterone levelshave occasionally been linked to an increased risk ofoverall prostate cancer [24], or an aggressive prostatecancer [25]. However, a previous meta-analysis, whichincluded 6438 men from 18 studies, refuted the notionthat serum androgen concentrations are associated withany form of prostate cancer [26]. Current data on tes-tosterone therapy has not suggested an increased risk ofprostate cancer [27]. These findings correspond with thecurrent theory of the androgen saturation model and thedata on serum testosterone concentrations effect onprostate cancer risk. To definitively dispel the notionthat testosterone therapy may increase prostate cancerrisk, future large-scale long-term trials are required.

51 Page 2 of 10 Curr Urol Rep (2015) 16:51

Natural History of BPH

BPH is a common diagnosis especially in the aging populationand accounts for a significant amount of morbidity in men.Strictly speaking, BPH is a histologic diagnosis, but it is oftenmade with clinical or radiographic data. The development of anormal prostate ends between 21 and 30 years of age as itreaches around 20 g and remains constant unless BPH de-velops. In a meta-analysis of autopsy studies, the prevalenceof histologically identified BPH increased with age from 8 %of men 31–40 years old to 42 % of men 51–60 and 90 % ofmen older than 90 [28]. Clinically, BPH is associated withLUTS, sexual dysfunction, and found concurrently with pros-tate cancer at times. Despite the seemingly simple anatomicalconnection, pathology other than obstruction appears to play asignificant role in the development of LUTS in men with BPH[29] and may be linked with the sexual dysfunction affiliatedwith BPH.

Even with the prevalence of LUTS/BPH, much remainsunknown about its etiology and clinical progression. Histori-cally, it was thought to be an androgen driven disease, but it isnow recognized that androgens are necessary for but not caus-ative of BPH. There are many theories as to LUTS/BPH eti-ology, which are listed here: increased autonomic tone; oxida-tive stress causing benign proliferation of prostatic tissue; andembryonic reawakening of prostatic tissue and growth. LUTS/BPH is also associated with age, obesity, metabolic syndrome,hypogonadism, and physical inactivity. Although links in the-se cases exist, a true etiology is not fully understood nor uni-versally accepted.

Obesity and metabolic syndrome are risk factors for LUTS/BPH [30]. Similarly, obesity is a definitive risk factor for lowtestosterone [31, 32]. In a meta-analysis, it was found that menwith metabolic syndrome were at an 80 % increased risk forLUTS and had significantly larger prostates than men withoutmetabolic syndrome [33]. Men with a BMI>35 kg/m2 werefound to have a 3.5-fold increase in risk for prostate enlarge-ment. It was also shown that for each 1 kg/m2 increase in BMI,there was an increase in prostate size by 0.41 mL via magneticresonance imaging and 0.45 g on post-prostatectomy speci-men [34, 35]. Those men with larger prostates and metabolicsyndrome have more LUTS [36, 37]. Several mechanismsinvolved in metabolic syndrome that may increase the inci-dence and severity of BPH/LUTS may be due tohyperinsulinemia, decreased sex steroids, prostatic and blad-der inflammation, and vascular disease and/or micro-ische-mia. The morbidity of LUTS/BPH increases with age andresults from voiding dysfunction, which can lead to seriousconditions such as urinary tract infections, acute urinary reten-tion, hydronephrosis, and renal failure. These points are illus-trated in Fig. 2a, b.

Another domain that is linked with LUTS/BPH is sexualfunction. A number of cross sectional epidemiological studieshave found a strong link between LUTS severity and sexualdysfunction [38–41]. In theMultinational Survey of the AgingMale-7, LUTS was found to be an independent risk factor forall domains of the International Index of Erectile Function(IIEF) and was actually a stronger predictor for sexual prob-lems than diabetes, hypertension, hypercholesteremia, andcardiac disease [38]. Despite the strong link between LUTS

Fig. 1 Physiologic effects of DHT

Curr Urol Rep (2015) 16:51 Page 3 of 10 51

and sexual dysfunction, prostate enlargement and urinaryflow rate, objective measures of BPH, have no indepen-dent effect on erectile dysfunction [42]. These observationslinking urinary symptoms and sexual function, withoutassociated prostate enlargement support the theories indi-cating other pathology besides obstruction is contributingto LUTS.

The pathophysiology of the connection of sexual dysfunc-tion and LUTS is uncertain; however, there are four

hypotheses: (1) decreased nitric oxide levels in prostatic andpenile smooth muscle, (2) autonomic hyperactivity effect onLUTS, prostate growth and ED, (3) increased Rho-kinase ac-tivation and endothelin activity, and (4) prostate and penileischemia [43]. Testosterone has been implicated in three ofthe four mechanisms cited as influences on autonomic ner-vous system remodeling, increased expression of nitric oxide,and modulation of the Rho-kinase system [44] which all allowfor better pelvic organ blood flow.

Fig. 2 a The role of metabolicsyndrome and obesity in LUTS/BPH pathology. b The role of in-flammation on LUTS/BPHpathology

Fig. 3 Relationship of Low DHTto the prostate pathologies(theory)

51 Page 4 of 10 Curr Urol Rep (2015) 16:51

BPH is a comorbid condition associated with an increasedrisk of prostate cancer. This association began when BPH wasfound in 80 % of cadavers with prostate cancer and 45 % ofthe control group [45] and has been supported by large-scalepopulation studies [46, 47]. BPH is not considered a prema-lignant lesion because the majority of prostate cancers areadenocarcinomas from epithelial cells in the peripheral zoneof the prostate, while BPH is caused by epithelial hyperplasiain the transitional zone [48]. The cause for increased risk ofprostate cancer in men with BPH could be due to detectionbias, causal link, pathophysiologic mechanism, or shared riskfactors [49]. Risk factors for both BPH and prostate cancerinclude the following: inflammation, hormonal factors, genet-ic factors, and metabolic factors such as obesity. How testos-terone influences are related to LUTS/BPH and prostate can-cer has been studied with no direct causal relationships.

Testosterone and the Prostate

There has been great concern about the effect of testosteronereplacement therapy on prostate disease. This concern comesfrom the dependence of prostate growth on androgens and theuse of 5-alpha reductase inhibitors and castration as effectivetherapies for BPH and prostate cancer, respectively. However,androgen therapy and androgen depletion do not have inverseeffects because of two mechanisms occurring in the prostate.First, it appears that the prostate’s androgen receptor saturatesjust above castrate concentration of testosterone (T~50 ng/mL), meaning variations in androgen concentration inhypogonadal to normal men would not affect binding [50].Second, the hormonal milieu of the prostate does not mirrorthe serum, as intraprostatic concentration of androgens ap-pears to be buffered from exogenous androgens or castration[51, 52].

There is one theory that testosterone concentration is higherin the prostate and that is a cause of pathology. An anatomicstudy was done to identify the flow of free testosterone to theprostate based on super selective interventional radiologysampling, which suggests the theory of concentrated testoster-one delivery directly from testicular arteries and testicular ve-nous flow/back flow to the prostate at concentrations of 130times that of physiologic serum levels, bypassing the systemiccirculation [53]. With time, more venous anomalies and in-competent valves occur which could, therefore, result in morepotent testosterone delivered to the prostate causing over stim-ulation and prostate pathology (cancer and/or BPH). Howev-er, intraprostatic concentration of DHT appears to be stable inboth the presence of high testosterone and at castrate testos-terone levels [54••, 55].

Testosterone and DHT levels in normal prostatic tissuevary between 0.26 to 1.8 ng/g tissue for testosterone and 0.7to 9.3 ng/g for DHT, and no difference in the prostatic

concentration in patients with BPH has been demonstrated[55]. In a randomized controlled trial where Page et al. gavemen varying doses of DHTand noted serum DHT levels up toseven times normal, prostatic concentrations of testosteroneand DHT were not significantly different between the DHTtherapy and placebo group [52]. Furthermore, in a studywhere Marks et al. gave hypogonadal men testosterone, theywere able to normalize the serum concentrations, but the pros-tatic concentrations of DHT remained unchanged from base-line values with no change in prostatic histology or tissuebiomarkers [56].

The growth of the prostate in BPH is temporally related tothe observed decline in circulating testosterone as both occurduring middle age [7, 28]. These observations were supportedby St. Sauver et al. when it was noted that a rapid decrease inthe bioavailable testosterone was associated with a rapid in-crease in prostate volume [57]. Therefore, if testosterone de-creases with age and prostates grow with age, testosterone isunlikely to be the only cause of BPH (see Graph 1).

Serum concentrations of androgens have been shown tohave a relation with LUTS/BPH. In a prospective study, tes-tosterone, estradiol, DHT, and dehydroepiandrosterone weremeasured at the beginning of the study, and 340 respondentswere evaluated for clinical BPH 8 years later. The study foundan increased risk of BPH development with higher midlifeDHT concentration, but did not look into the relationship ofbioavailable testosterone [58]. Bioavailable testosterone andDHT levels were followed on these men and after 20 yearsdemonstrated to have protective effects against LUTS in thosewith higher midlife DHT and bioavailable testosterone levels[59].While other studies did not investigate the relationship ofserum DHT concentration and LUTS, they consistently foundthat higher serum testosterone concentrations were inverselyassociated with LUTS [57, 60, 61]. Studies that measure bothprostate volume and serum sex hormones have largely foundno association [62–64]. While serum sex hormones do notplay a clear role in determining prostate size, it appears thatmen with higher serum testosterone and bioavailable testos-terone have fewer LUTS.

The effects of testosterone therapy in short-term studieshave found that testosterone therapy does not affect LUTSor at least does not worsen LUTS. A retrospective study of120 men with hypogonadism treated with testosterone over2 years demonstratedmild improvement in LUTS. In addition,those with worse symptoms at baseline had a 3 point or greaterimprovement in their symptom scores [65•]. Other studiesfound that LUTS improved with testosterone therapy inhypogonadal men with moderate LUTS followed for about ayear [66–72]. In a randomized controlled study by Shigerharaet al., 46 patients with biochemical hypogonadism, moderateLUTS, and a prostate volume of greater than 20 mL wererandomized to receive 250 mg of intramuscular testosteroneenanthate or placebo for 1 year. The group receiving

Curr Urol Rep (2015) 16:51 Page 5 of 10 51

testosterone therapy demonstrated a clinically significant (3.2point) improvement in the International Prostate SymptomScore (IPSS), had higher maximum urine flow rates and in-creased voided volume versus placebo [71]. Two long-termstudies lasting 3 and 5 years respectively also did not showprogression of LUTSwith prolonged testosterone therapy [73,74]. These studies indicate that the testosterone therapy is safein men with moderate LUTS (IPSS of 8–19) and may evenprovide those with moderate LUTS some relief. These studiesalso demonstrated improvement of LUTS in those with meta-bolic syndrome [73]. Weight loss or phosphodiesterase inhib-itor use also had improvement of LUTSwhen co-administeredwith testosterone [74].

Testosterone can be used to treat some of the other pro-posed mechanisms of LUTS/BPH. Obesity is often linked tometabolic syndrome and increased estrogen levels as a resultof testosterone metabolization to estradiol in adipose tissue.Treatment of obesity, therefore, would indirectly treat LUTS/BPH [31, 75, 76]. A meta-analysis by A. Traish clearly dem-onstrated an increase of lean body mass, decreased body fat,decreased waist circumference, and BMI along with moresustained weight loss in hypogonadal men treated with testos-terone [77]. Testosterone plays a role in increasing the sensi-tivity of insulin, increased muscle mass which helps protectfrom bone demineralization, improved hemoglobin A1clevels, and significantly decreases metabolic syndrome [78].Metabolic syndrome is related to overall obesity which carrieswith it increased estradiol levels and inflammation. Together,these can contribute to LUTS/BPH for which testosteronecould be used to treat both entities; however, testosterone isnot indicated for any of these reasons.

The role of chronic inflammation and its effect on BPH hasbeen demonstrated in several papers [79]. Recently, it has alsobeen suggested that testosterone has an anti-inflammatory ef-fect on tissue and that this effect may be augmented with more

potent androgens such as with DHT, which is highly concen-trated in the prostate. DHT is thought to cause reduced inflam-mation and inhibition of autoimmunity leading to decreasedfibrosis and chronic inflammation [80•]. Hypogonadism cantherefore be considered a proinflammatory state leading toLUTS. Lower testosterone levels may lead to lower levels ofDHT (see Fig. 3).

We propose three possible theories of how hypogonadalstates (low testosterone and/or low DHT) may promoteLUTS. The saturation of androgen receptors in the prostaterequires relatively low levels of testosterone (approximately50 ng/dl as measured in the serum). (1) It could be, that levelsbetween 50 and 300 ng/dl (above prostate saturation but be-low eugonadal states) promote prostatic pathology due to thelack of anti-inflammatory action and/or increased autoim-mune activity of low testosterone on specific organs (prostate,bladder, penis, etc.). (2) Higher saturation levels of androgenreceptors elsewhere in the body may be needed to mitigate thedeleterious effects of this proinflammatory/hypogonadal state.Different organs in the body may have a set threshold ofeugonadal states which may be different than what is mea-sured in the serum (although unknown, hypothetically thebrain may need serum levels of 250 ng/dl or more vs musclewhich may need more or less than that) (3) Another theorycould be that the comorbidities associated with hypogonadisminterfere with testosterone receptor binding or productionwhich may be reversible with comorbidity treatment. Thistheory highlights the complex interaction that disease statescan have on the body which may be unknown. Diabetes, hy-pertension, obesity, high stress states, and pharmacologicalstates could all contribute to faulty receptors or receptor bind-ing or even production of testosterone. The lack of testoster-one, and potentially DHT, could then act as promoters of thedisease states or have synergistic effects to these disease states(co-morbidities) and further perpetuate declines in

Graph 1 Prostate growth andbioavailable testosterone as afactor of time. This informationcomes from St. Sauver et al. dataas they looked at the effects ofbenign urologic outcomescompared to testosterone andestrogen in the Olmstead Countylongitudinal cohort study. Weused their raw data (their Table 1)to illustrate some of our findingsreflected in this graph (57)

51 Page 6 of 10 Curr Urol Rep (2015) 16:51

testosterone. Indeed, testosterone has many effects in the bodyand appropriate supplementation may help in treatment ofthese causative comorbid states.

The proinflammatory state caused by hypogonadism canalso result in overall autonomic hyperactivity and micro-tissuehypoxia resulting in increased fibroblasts, reactive oxygenspecies/oxidative stress, and stimulation of vascular endothe-lial growth factors which all increase prostate volume anddirectly contribute to LUTS [29, 80•]. Testosterone as ananti-inflammatory is the mechanism that would then preventthis chronic inflammation and decreased prostatic growth andLUTS in a more organ specific way.

The most specific symptoms of hypogonadism are sexualaccording to the validated Androgen Deficiency in the AgingMale questionnaire which is commonly used to screen forhypogonadal states [18]. Wu et al. found that with an increas-ing number of sexual symptoms, there was an associated de-crease in the serum testosterone level [19••]. We also knowthat in those with hypogonadism, 18.5–23 % will have con-current ED which can and does improved with testosteronereplacement [81, 82]. Likewise, libido loss plays an integralrole in sexual dysfunction and can be a major sign of lowtestosterone. Replacement of testosterone is known to increaselibido in most men barring other psychosocial and/or medicalabnormalities [83].

The effect of testosterone therapy on sexual function has adose response and has been demonstrated to help in late onsethypogonadism as well. This dose response was proven bysuppressing endogenous testosterone production with aGnRH agonist and giving injections of different doses of tes-tosterone. Changes in overall sexual function and wakingerections differed by dose given and libido varied by doseonly among men who were sexually active at the beginningof the study [84]. In addition, multiple meta-analyses demon-strated a significant improvement in sexual function in studiesperformed on men with low to low-normal (<12 nmol/L)baseline testosterone levels [85, 86]. Isdori et al. also foundthat the amount of erectile function improvement after testos-terone therapy was inversely related to the baseline testoster-one levels [86].

Conclusion

There has been controversy about the effect of testosteronereplacement therapy on prostate disease. Despite, the use ofandrogen depletion as a mainstay for prostate diseases, currentdata has not linked testosterone therapy to increased risk ofprostate disease. Furthermore, testosterone replacement thera-py in hypogonadal men may have beneficial effects on theurinary and sexual symptoms associated with BPH. Testoster-one and DHT as anti-inflammatory mediators may help in thetreatment of LUTS/BPH directly in hypogonadal men or

indirectly based on other comorbid diseases. Increased longi-tudinal research will be needed along with bench studies tohelp identify firm pathophysiologic models as they pertain toLUTS/BPH.

Compliance with Ethics Guidelines

Conflict of Interest Aaron Moore and Michael J. Butcher each declareno potential conflicts of interest.

Tobias S. Köhler reports grants and personal fees from AMS, grantsand personal fees from Coloplast, and personal fees from Auxilium.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

References

1. AndroGel 1.62% Product Insert. North Chicago, IL: AbbVie Inc.2. Brambilla DJ, Matsumoto AM, Araujo AB, McKinlay JB. The

effect of diurnal variation on clinical measurement of serum testos-terone and other sex hormone levels in men. J Clin EndocrinolMetab. 2009;94(3):907–13. doi:10.1210/jc.2008-1902.

3. Welliver Jr RC, Wiser HJ, Brannigan RE, Feia K, Monga M,Kohler TS. Validity of midday total testosterone levels in oldermen with erectile dysfunction. J Urol. 2014;192(1):165–9. doi:10.1016/j.juro.2014.01.085.

4. Araujo AB, Esche GR, Kupelian V, O'Donnell AB, Travison TG,Williams RE, et al. Prevalence of symptomatic androgen deficiencyin men. J Clin Endocrinol Metab. 2007;92(11):4241–7. doi:10.1210/jc.2007-1245.

5. Gapstur SM, Gann PH, Kopp P, Colangelo L, Longcope C, Liu K.Serum androgen concentrations in young men: a longitudinal anal-ysis of associations with age, obesity, and race. The CARDIA malehormone study. Cancer Epidemiol Biomark Prev: Publ Am AssocCancer Res Cosponsored Am Soc Prev Oncol. 2002;11(10 Pt 1):1041–7.

6. Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease,and changing sex hormone levels in middle-agedmen: results of theMassachusetts Male Aging Study. J Clin Endocrinol Metab.1991;73(5):1016–25. doi:10.1210/jcem-73-5-1016.

7. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR.Longitudinal effects of aging on serum total and free testosteronelevels in healthy men. Baltimore Longitudinal Study of Aging. JClin Endocrinol Metab. 2001;86(2):724–31. doi:10.1210/jcem.86.2.7219.

8. Liu PY, Beilin J, Meier C, Nguyen TV, Center JR, Leedman PJ,et al. Age-related changes in serum testosterone and sex hormonebinding globulin in Australian men: longitudinal analyses of twogeographically separate regional cohorts. J Clin Endocrinol Metab.2007;92(9):3599–603. doi:10.1210/jc.2007-0862.

9. Morley JE, Kaiser FE, Perry 3rd HM, Patrick P, Morley PM,Stauber PM, et al. Longitudinal changes in testosterone, luteinizinghormone, and follicle-stimulating hormone in healthy older men.Metab Clin Exp. 1997;46(4):410–3.

10. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH.Longitudinal relation between endogenous testosterone and cardio-vascular disease risk factors in middle-aged men. A 13-year follow-up of formermultiple risk factor intervention trial participants. Am JEpidemiol. 1997;146(8):609–17.

Curr Urol Rep (2015) 16:51 Page 7 of 10 51

11. Basaria S. Testosterone therapy in older men with late-onsethypogonadism: a counter-rationale. Endocrine Pract: Off J AmCollege Endocrinol Am Assoc Clin Endocrinol. 2013;19(5):853–63. doi:10.4158/ep13318.ra.

12. Mulligan T, Iranmanesh A, Johnson ML, Straume M, Veldhuis JD.Aging alters feed-forward and feedback linkages between LH andtestosterone in healthy men. Am J Physiol. 1997;273(4 Pt 2):R1407–13.

13.•• Jarvis TR, Chughtai B, Kaplan SA. Testosterone and benign pros-tatic hyperplasia. Asian J Androl. 2015;17:212–26. doi:10.4103/1008-682x.140966. This is a great review of the effects oftestosterone on BPH. With the FDA warning on worseiningBPH symptoms with testosteorne supplementation, all patientsshould be warned about this potential complication. The studiesthat show no worsening in LUTS/BPH are not high level evi-dence making clinical decisions difficult.

14. Kaplan SA, Roehrborn CG, McConnell JD, Meehan AG,Surynawanshi S, Lee JY, et al. Long-term treatment with finasterideresults in a clinically significant reduction in total prostate volumecompared to placebo over the full range of baseline prostate sizes inmen enrolled in theMTOPS trial. J Urol. 2008;180(3):1030–2. doi:10.1016/j.juro.2008.05.004. discussion 2–3.

15. Fan Y, Hu S, Liu J, Xiao F, Li X, Yu W, et al. Low intraprostaticDHT promotes the infiltration of CD8+ T cells in BPH tissues viamodulation of CCL5 secretion. Mediat Inflamm. 2014;2014:397815. doi:10.1155/2014/397815.

16. Araujo AB, O'Donnell AB, Brambilla DJ, SimpsonWB, LongcopeC, Matsumoto AM, et al. Prevalence and incidence of androgendeficiency in middle-aged and older men: estimates from theMassachusetts Male Aging Study. J Clin Endocrinol Metab.2004;89(12):5920–6. doi:10.1210/jc.2003-031719.

17.• Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ,Swerdloff RS, et al. Testosterone therapy in men with androgendeficiency syndromes: an Endocrine Society clinical practice guide-line. J Clin EndocrinolMetab. 2010;95(6):2536–59. doi:10.1210/jc.2009-2354. These are clinical guidelines for testosteronereplacement per the Endocrine Society. This is one acceptedway to correctly diagnosis, treat, and follow hypogonadal men.

18. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ,Gooren LJ, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASArecommendations. Eur Urol. 2009;55(1):121–30. doi:10.1016/j.eururo.2008.08.033.

19.•• Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, et al.Identification of late-onset hypogonadism in middle-aged and el-derly men. N Engl J Med. 2010;363(2):123–35. doi:10.1056/NEJMoa0911101. A prospective study of 3,369 men in Europescreened and treated for hypogonadism. The aim was to helpidentify late-onset hypogondism. Erectile dysfunction, poormorning erections, and few thoughts about sex along with totaltestosterone levels of <11nmol/l and free testosterone of<200pmol/l can be diagnostic of late-onset hypogonadsim.

20. Kelleher S, Conway AJ, Handelsman DJ. Blood testosteronethreshold for androgen deficiency symptoms. J Clin EndocrinolMetab. 2004;89(8):3813–7. doi:10.1210/jc.2004-0143.

21. Zitzmann M, Nieschlag E. The CAG repeat polymorphism withinthe androgen receptor gene and maleness. Int J Androl. 2003;26(2):76–83.

22. Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS.Measurement of total serum testosterone in adult men: comparisonof current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab. 2004;89(2):534–43. doi:10.1210/jc.2003-031287.

23. Cooper LA, Page ST. Androgens and prostate disease. Asian JAndrol. 2014;16(2):248–55. doi:10.4103/1008-682x.122361.

24. Parsons JK, Carter HB, Platz EA, Wright EJ, Landis P, Metter EJ.Serum testosterone and the risk of prostate cancer: potential impli-cations for testosterone therapy. Cancer Epidemiol Biomark Prev:Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol.2005;14(9):2257–60. doi:10.1158/1055-9965.epi-04-0715.

25. Pierorazio PM, Ferrucci L, Kettermann A, Longo DL, Metter EJ,Carter HB. Serum testosterone is associated with aggressive pros-tate cancer in older men: results from the Baltimore LongitudinalStudy of Aging. BJU Int. 2010;105(6):824–9. doi:10.1111/j.1464-410X.2009.08853.x.

26. Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hor-mones and prostate cancer: a collaborative analysis of 18 prospec-tive studies. J Natl Cancer Inst. 2008;100(3):170–83. doi:10.1093/jnci/djm323.

27. Fernandez-Balsells MM, Murad MH, Lane M, Lampropulos JF,Albuquerque F, Mullan RJ, et al. Clinical review 1: adverse effectsof testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95(6):2560–75. doi:10.1210/jc.2009-2575.

28. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development ofhuman benign prostatic hyperplasia with age. J Urol. 1984;132(3):474–9.

29. McVary KT, Rademaker A, Lloyd GL, Gann P. Autonomic nervoussystem overactivity in men with lower urinary tract symptoms sec-ondary to benign prostatic hyperplasia. J Urol. 2005;174(4 Pt 1):1327–433.

30. Gacci M, Corona G, Vignozzi L, Salvi M, Serni S, De Nunzio C,et al. Metabolic syndrome and benign prostatic enlargement: a sys-tematic review and meta-analysis. BJU Int. 2015;115(1):24–31.doi:10.1111/bju.12728.

31. Cattabiani C, Basaria S, Ceda GP, Luci M, Vignali A, Lauretani F,et al. Relationship between testosterone deficiency and cardiovas-cular risk and mortality in adult men. J Endocrinol Investig.2012;35(1):104–20. doi:10.3275/8061.

32. Bekaert M, Van Nieuwenhove Y, Calders P, Cuvelier CA, BatensAH, Kaufman JM, et al. Determinants of testosterone levels inhuman male obesity. Endocrine. 2015. doi:10.1007/s12020-015-0563-4.

33. De Nunzio C, Aronson W, Freedland SJ, Giovannucci E, ParsonsJK. The correlation between metabolic syndrome and prostatic dis-eases. Eur Urol. 2012;61(3):560–70. doi:10.1016/j.eururo.2011.11.013.

34. Parsons JK, Carter HB, Partin AW, Windham BG, Metter EJ,Ferrucci L, et al. Metabolic factors associated with benign prostatichyperplasia. J Clin Endocrinol Metab. 2006;91(7):2562–8. doi:10.1210/jc.2005-2799.

35. Kopp RP, Han M, Partin AW, Humphreys E, Freedland SJ, ParsonsJK. Obesity and prostate enlargement in menwith localized prostatecancer. BJU Int. 2011;108(11):1750–5. doi:10.1111/j.1464-410X.2011.10227.x.

36. Kupelian V, McVary KT, Kaplan SA, Hall SA, Link CL, Aiyer LP,et al. Association of lower urinary tract symptoms and themetabolicsyndrome: results from the Boston Area Community HealthSurvey. J Urol. 2009;182(2):616–24. doi:10.1016/j.juro.2009.04.025. discussion 24–5.

37. Rohrmann S, Smit E, Giovannucci E, Platz EA. Association be-tween markers of the metabolic syndrome and lower urinary tractsymptoms in the Third National Health and Nutrition ExaminationSurvey (NHANES III). Int J Obes. 2005;29(3):310–6. doi:10.1038/sj.ijo.0802881.

38. Rosen R, Altwein J, Boyle P, Kirby RS, Lukacs B, Meuleman E,et al. Lower urinary tract symptoms and male sexual dysfunction:the multinational survey of the aging male (MSAM-7). Eur Urol.2003;44(6):637–49.

39. Bozkurt O, Bolat D, Demir O, Ucer O, Sahin A, Ozcift B, et al.Erectile function and late-onset hypogonadism symptoms related to

51 Page 8 of 10 Curr Urol Rep (2015) 16:51

lower urinary tract symptom severity in elderly men. Asian JAndrol. 2013;15(6):785–9. doi:10.1038/aja.2013.44.

40. Macfarlane GJ, Botto H, Sagnier PP, Teillac P, Richard F, Boyle P.The relationship between sexual life and urinary condition in theFrench community. J Clin Epidemiol. 1996;49(10):1171–6.

41. ChungWS, Nehra A, Jacobson DJ, Roberts RO, Rhodes T, GirmanCJ, et al. Lower urinary tract symptoms and sexual dysfunction incommunity-dwellingmen.MayoClin Proc. 2004;79(6):745–9. doi:10.4065/79.6.745.

42. Blanker MH, Bohnen AM, Groeneveld FP, Bernsen RM, Prins A,Thomas S, et al. Correlates for erectile and ejaculatory dysfunctionin older Dutch men: a community-based study. J Am Geriatr Soc.2001;49(4):436–42.

43. McVary KT. Erectile dysfunction and lower urinary tract symptomssecondary to BPH. Eur Urol. 2005;47(6):838–45. doi:10.1016/j.eururo.2005.02.001.

44. Pradidarcheep W. Lower urinary tract symptoms and its potentialrelation with late-onset hypogonadism. Aging Male: Off J Int SocStudy Aging Male . 2008 ;11(2 ) :51–5 . do i :10 .1080/13685530801954026.

45. Sommers SC. Endocrine changes with prostatic carcinoma. Cancer.1957;10(2):345–58.

46. ChokkalingamAP, NyrenO, Johansson JE, GridleyG,McLaughlinJK, Adami HO, et al. Prostate carcinoma risk subsequent to diag-nosis of benign prostatic hyperplasia: a population-based cohortstudy in Sweden. Cancer. 2003;98(8):1727–34. doi:10.1002/cncr.11710.

47. Orsted DD, Bojesen SE, Nielsen SF, Nordestgaard BG. Associationof clinical benign prostate hyperplasia with prostate cancer inci-dence and mortality revisited: a nationwide cohort study of 3,009,258 men. Eur Urol. 2011;60(4):691–8. doi:10.1016/j.eururo.2011.06.016.

48. Guess HA. Benign prostatic hyperplasia and prostate cancer.Epidemiol Rev. 2001;23(1):152–8.

49. Orsted DD, Bojesen SE. The link between benign prostatic hyper-plasia and prostate cancer. Nat RevUrol. 2013;10(1):49–54. doi:10.1038/nrurol.2012.192.

50. Morgentaler A, Traish AM. Shifting the paradigm of testosteroneand prostate cancer: the saturation model and the limits ofandrogen-dependent growth. Eur Urol. 2009;55(2):310–20. doi:10.1016/j.eururo.2008.09.024.

51. Page ST, Lin DW, Mostaghel EA, Hess DL, True LD, Amory JK,et al. Persistent intraprostatic androgen concentrations after medicalcastration in healthy men. J Clin Endocrinol Metab. 2006;91(10):3850–6. doi:10.1210/jc.2006-0968.

52. Page ST, LinDW,Mostaghel EA,Marck BT,Wright JL,Wu J, et al.Dihydrotestosterone administration does not increase intraprostaticandrogen concentrations or alter prostate androgen action in healthymen: a randomized-controlled trial. J Clin Endocrinol Metab.2011;96(2):430–7. doi:10.1210/jc.2010-1865.

53. Gat Y, Joshua S, Gornish MG. Prostate cancer: a newly discoveredroute for testosterone to reach the prostate: treatment by super-selective intraprostatic androgen deprivation. Andrologia.2009;41(5):305–15. doi:10.1111/j.1439-0272.2009.00972.x.

54.•• van der Sluis TM, Meuleman EJ, van Moorselaar RJ, Bui HN,Blankenstein MA, Heijboer AC, et al. Intraprostatic testosteroneand dihydrotestosterone. Part II: concentrations after androgen hor-monal manipulation in men with benign prostatic hyperplasia andprostate cancer. BJU Int. 2012;109(2):183–8. doi:10.1111/j.1464-410X.2011.10652.x. This reference in part 1 and part 2 bothdemonstrate how DHT in the prostate and testosterone in theserum and prostate are related to each other. Homonalmanipulation with drugs and the physiology of DHT andtestostoerone in the prostate leading to pathology is explored.See Van der Sluis et al. Part I for further details.

55. van der Sluis TM, Vis AN, van Moorselaar RJ, Bui HN,Blankenstein MA, Meuleman EJ, et al. Intraprostatic testosteroneand dihydrotestosterone. Part I: concentrations and methods of de-termination in men with benign prostatic hyperplasia and prostatecancer. BJU Int. 2012;109(2):176–82. doi:10.1111/j.1464-410X.2011.10651.x.

56. Marks LS, Mazer NA,Mostaghel E, Hess DL, Dorey FJ, Epstein JI,et al. Effect of testosterone replacement therapy on prostate tissue inmen with late-onset hypogonadism: a randomized controlled trial.JAMA. 2006;296(19):2351–61. doi:10.1001/jama.296.19.2351.

57. St Sauver JL, Jacobson DJ, McGree ME, Girman CJ, Klee GG,Lieber MM, et al. Associations between longitudinal changes inserum estrogen, testosterone, and bioavailable testosterone andchanges in benign urologic outcomes. Am J Epidemiol.2011;173(7):787–96. doi:10.1093/aje/kwq438.

58. Parsons JK, Palazzi-Churas K, Bergstrom J, Barrett-Connor E.Prospective study of serum dihydrotestosterone and subsequent riskof benign prostatic hyperplasia in community dwelling men: theRancho Bernardo Study. J Urol. 2010;184(3):1040–4. doi:10.1016/j.juro.2010.05.033.

59. Trifiro MD, Parsons JK, Palazzi-Churas K, Bergstrom J, Lakin C,Barrett-Connor E. Serum sex hormones and the 20-year risk oflower urinary tract symptoms in community-dwelling older men.BJU Int. 2010;105(11):1554–9. doi:10.1111/j.1464-410X.2009.09090.x.

60. Kristal AR, Schenk JM, Song Y, Arnold KB, Neuhouser ML,Goodman PJ, et al. Serum steroid and sex hormone-binding glob-ulin concentrations and the risk of incident benign prostatic hyper-plasia: results from the prostate cancer prevention trial. Am JEpidemiol. 2008;168(12):1416–24. doi:10.1093/aje/kwn272.

61. Litman HJ, Bhasin S, O'Leary MP, Link CL, McKinlay JB. Aninvestigation of the relationship between sex-steroid levels and uro-logical symptoms: results from the Boston Area Community Healthsurvey. BJU Int. 2007;100(2):321–6. doi:10.1111/j.1464-410X.2007.06938.x.

62. Lee JH, Kim Y, Park YW, Lee DG. Relationship between benignprostatic hyperplasia/lower urinary tract symptoms and total serumtestosterone level in healthy middle-aged eugonadal men. J SexMed. 2014;11(5):1309–15. doi:10.1111/jsm.12489.

63. Liu CC, Huang SP, Li WM, Wang CJ, Chou YH, Li CC, et al.Relationship between serum testosterone and measures of benignprostatic hyperplasia in aging men. Urology. 2007;70(4):677–80.doi:10.1016/j.urology.2007.05.025.

64. Roberts RO, Jacobson DJ, Rhodes T, Klee GG, Leiber MM,Jacobsen SJ. Serum sex hormones andmeasures of benign prostatichyperplasia. Prostate. 2004;61(2):124–31. doi:10.1002/pros.20080.

65.• Pearl JA, Berhanu D, Francois N, Masson P, Zargaroff S, Cashy J,et al. Testosterone supplementation does not worsen lower urinarytract symptoms. J Urol. 2013;190(5):1828–33. doi:10.1016/j.juro.2013.05.111. Administration of testosterone in 120 hypogondalmen did not cause a worsening in LUTS/BPH per the AUASIvalidated questionaaire in these patients.

66. Haider A, Gooren LJ, Padungtod P, Saad F. Concurrent improve-ment of the metabolic syndrome and lower urinary tract symptomsupon normalisation of plasma testosterone levels in hypogonadalelderly men. Andrologia. 2009;41(1):7–13. doi:10.1111/j.1439-0272.2008.00880.x.

67. Amano T, Imao T, Takemae K, Iwamoto T, Nakanome M.Testosterone replacement therapy by testosterone ointment relieveslower urinary tract symptoms in late onset hypogonadism patients.Aging Male: Off J Int Soc Study Aging Male. 2010;13(4):242–6.doi:10.3109/13685538.2010.487552.

68. Kalinchenko S, Vishnevskiy EL, Koval AN,MskhalayaGJ, Saad F.Beneficial effects of testosterone administration on symptoms of thelower urinary tract in men with late-onset hypogonadism: a pilot

Curr Urol Rep (2015) 16:51 Page 9 of 10 51

study. Aging Male: Off J Int Soc Study Aging Male. 2008;11(2):57–61. doi:10.1080/13685530801953994.

69. Karazindiyanoglu S, Cayan S. The effect of testosterone therapy onlower urinary tract symptoms/bladder and sexual functions in menwith symptomatic late-onset hypogonadism. Aging Male: Off J IntSoc Study Aging Male. 2008;11(3):146–9. doi:10.1080/13685530802290438.

70. Pechersky AV, Mazurov VI, Semiglazov VF, Karpischenko AI,Mikhailichenko VV, Udintsev AV. Androgen administration inmiddle-aged and ageing men: effects of oral testosteroneundecanoate on dihydrotestosterone, oestradiol and prostate vol-ume. Int J Androl. 2002;25(2):119–25.

71. Shigehara K, Sugimoto K, Konaka H, Iijima M, FukushimaM, Maeda Y, et al. Androgen replacement therapy contrib-utes to improving lower urinary tract symptoms in patientswith hypogonadism and benign prostate hypertrophy: arandomised controlled study. Aging Male: Off J Int SocStudy Aging Male. 2011;14(1):53–8. doi:10.3109/13685538.2010.518178.

72. Page ST, Hirano L, Gilchriest J, Dighe M, Amory JK, Marck BT,et al. Dutasteride reduces prostate size and prostate specific antigenin older hypogonadal men with benign prostatic hyperplasia under-going testosterone replacement therapy. J Urol. 2011;186(1):191–7.doi:10.1016/j.juro.2011.03.026.

73. Francomano D, Ilacqua A, Bruzziches R, Lenzi A, Aversa A.Effects of 5-year treatment with testosterone undecanoate on lowerurinary tract symptoms in obese men with hypogonadism and met-abolic syndrome. Urology. 2014;83(1):167–73. doi:10.1016/j.urology.2013.08.019.

74. Yassin DJ, El Douaihy Y, Yassin AA, Kashanian J, Shabsigh R,Hammerer PG. Lower urinary tract symptoms improve with testos-terone replacement therapy in men with late-onset hypogonadism:5-year prospective, observational and longitudinal registry study.World J Urol. 2014;32(4):1049–54. doi:10.1007/s00345-013-1187-z.

75. Aversa A, Bruzziches R, Francomano D, Rosano G, IsidoriAM, Lenzi A, et al. Effects of testosterone undecanoate oncardiovascular risk factors and atherosclerosis in middle-agedmen with late-onset hypogonadism and metabolic syndrome:results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med. 2010;7(10):3495–503. doi:10.1111/j.1743-6109.2010.01931.x.

76. Rosner W, Hryb DJ, KhanMS, Nakhla AM, Romas NA. Androgenand estrogen signaling at the cell membrane via G-proteins andcyclic adenosine monophosphate. Steroids. 1999;64(1–2):100–6.

77. Traish AM. Testosterone and weight loss: the evidence. Curr OpinEndocrinol Diabetes Obes. 2014;21(5):313–22. doi:10.1097/med.0000000000000086.

78. Cunningham GR. Testosterone and metabolic syndrome. Asian JAndrol. 2015;17(2):192–6. doi:10.4103/1008-682x.148068.

79. Ficarra V, Rossanese M, Zazzara M, Giannarini G, Abbinante M,Bartoletti R, et al. The role of inflammation in lower urinary tractsymptoms (LUTS) due to benign prostatic hyperplasia (BPH) andits potential impact on medical therapy. Curr Urol Rep.2014;15(12):463. doi:10.1007/s11934-014-0463-9.

80.• Vignozzi L, Cellai I, Santi R, Lombardelli L, Morelli A, ComeglioP, et al. Antiinflammatory effect of androgen receptor activation inhuman benign prostatic hyperplasia cells. J Endocrinol.2012;214(1):31–43. doi:10.1530/joe-12-0142. This articleconnects hypogonadism and BPH, revealing a 5 fold increasein BPH symptoms and inflammation in vitro due tohypogonadism and low DHT. DHT helps preventautoimmunity and inflmaation.

81. Bodie J, Lewis J, Schow D, Monga M. Laboratory evaluations oferectile dysfunction: an evidence based approach. J Urol.2003;169(6):2262–4. doi:10.1097/01.ju.0000063940.19080.58.

82. Kohler TS, Kim J, Feia K, Bodie J, Johnson N, Makhlouf A, et al.Prevalence of androgen deficiency inmenwith erectile dysfunction.Urology. 2008;71(4):693–7. doi:10.1016/j.urology.2007.11.073.

83. Nieschlag E. Current topics in testosterone replacement ofhypogonadal men. Best Pract Res Clin Endocrinol Metab.2015;29(1):77–90. doi:10.1016/j.beem.2014.09.008.

84. Gray PB, Singh AB, Woodhouse LJ, Storer TW, Casaburi R,Dzekov J, et al. Dose-dependent effects of testosterone on sexualfunction, mood, and visuospatial cognition in older men. J ClinEndocrinol Metab. 2005;90(7):3838–46. doi:10.1210/jc.2005-0247.

85. Corona G, Isidori AM, Buvat J, Aversa A, Rastrelli G, Hackett G, et al.Testosterone supplementation and sexual function: a meta-analysisstudy. J Sex Med. 2014;11(6):1577–92. doi:10.1111/jsm.12536.

86. Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V,Aversa A, et al. Effects of testosterone on sexual function in men:results of a meta-analysis. Clin Endocrinol. 2005;63(4):381–94.doi:10.1111/j.1365-2265.2005.02350.x.

51 Page 10 of 10 Curr Urol Rep (2015) 16:51