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Functional Hypothalamic Amenorrhea (FHA): Time to Think Beyond Polycystic Ovarian Syndrome1Ritu Sharma, 2Aruna Nigam1Associate Professor, 2Professor1Department of Obstetrics and Gynecology, Government Institute of Medical Sciences Noida, Uttar Pradesh, India2Department of Obstetrics and Gynecology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India

Editorial

‘An adolescent girl of 17 years, average built, walking in the clinic with her mother for treatment of amenorrhea, with history of menarche at 11 years and normal menstrual cycle for first 3 years and then gradually decreasing menses: common complaint misdiagnosed as polycystic ovarian syndrome oftenly’

It is the time to think beyond the commonly diagnosed entity polycystic ovarian syndrome in adolescents as amenorrhea can result from interplay of end numbers of factors involving various compartments of hypothalamic-pituitary-ovarian axis and outflow tract. In today’s era, when the adolescents are becoming more conscious of their figures and increasing stress of the competitive examinations, entity called Functional Hypothalamic Amenorrhea (FHA) becomes more evident. It is reversible amenorrhea where no underlying structural or organic cause can be found and the condition is a diagnosis of exclusion. It fits into either type I (hypothalamic causes) or type II (Hypothalamic-pituitary-ovarian axis dysfunction)ovulatory disorder of WHO classification. Previously it was named as ‘hypothalamic hypoestrogenism’ and ‘juvenile hypothalamosis syndrome’. After pregnancy,

FHA contributes to a significant proportion, nearly 20-35%, of secondary amenorrhea.1 FHA can be divided into three types—related to excessive weight loss, excessive exercise and stress (whether physical or mental). Mostly young females are affected although all age groups are susceptible. The condition warrants timely treatment due to associated long-term consequences. FHA results from a complex interaction among neuromodulators, endocrine and metabolic factors as explained in Figure 1. Weight loss, excessive exercise, and stress- all activate hypothalamic-pituitary-adrenal (HPA) axis which via different neuromodulators result in increased cortisol levels. Raised cortisol suppresses Hypothalamic-pituitary-ovarian (HPO) axis by inhibiting gonadotropin-releasing-hormone (GnRH). The important neuromodulators include Kisspeptin, neuropeptide Y and Ghrelin. Kisspeptin, controlled by

ABSTRACTFunctional hypothalamic amenorrhea (FHA) is reversible amenorrhea where no underlying structural or organic cause can be found and the condition is a diagnosis of exclusion. Diagnosing FHA demands complete work up to rule out structural, endocrine, metabolic or systemic causes. Prolonged irregular menstrual cycles can be physiological in the initial 1-2 years of menarche and so diagnosing FHA remains a challenge at puberty. Treatment involves multidisciplinary approach and can be long.Keywords: Amenorrhea, anorexia, estrogen, stress.

To cite: Sharma R, Nigam A. Functional Hypothalamic Amenorrhea (FHA): Time to Think Beyond Polycystic Ovarian Syndrome. Pan Asian J Obs Gyn 2020;3(3):107-112.

Received on: 05-11-2020

Accepted on: 10-12-2020

Address for CorrespondenceAruna Nigam Professor Department of Obstetrics and Gynecology Hamdard Institute of Medical Sciences and Research Jamia Hamdard, New Delhi, Indiaprakasharuna@hotmail.com

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KiSS-1 gene, are secreted from neurons in the arcuate nucleus. It binds with its receptor to form Kisspeptin/ GPR54 complex which stimulates GnRH release.2 Neuropeptide Y (NPY) controls appetite center in hypothalamus and inhibits GnRH secretion at low estrogen levels.3 Ghrelin also affects appetite center and inhibits GnRH secretion.4 Corticotropin-releasing-hormone also increases Beta endorphin secretion

which then inhibits pulsatile release of GnRH.5 Leptin regulates interaction between metabolic and hormonal signals.6 Raised cortisol also suppresses Hypothalamic-pituitary-thyroid (HPT) axis in order to prevent further loss of energy.7 Genetic factors may also play a role in pathogenesis (Fig. 1). Suppression of HPO axis leads to hypoestrogenism which is responsible for long-term sequelae-

Fig. 1: Pathogenesis of functional hypothalamic amenorrhea

Abbreviations: HPA, Hypothalamic pituitary adrenal axis; HPO axis, Hypothalamic pituitary ovarian axis; HPT axis, Hypothalamic pituitary thyroid axis; CRH, Corticotropin releasing hormone; ACTH, adrenocorticotropic hormone; GnRH, Gonadotropin releasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone; TRH, thyrotropin releasing hormone; TSH, thyroid stimulating hormone; T3, Triiodothyronin; T4, thyroxin; IGF-1, Insulin like growth factor-1; BMD, Bone mineral density

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compromised cardiovascular function, compromised bone and mental health. Estrogen stimulates bone formation and remodeling while inhibiting bone resorption, thereby maintaining bone health. Optimum estrogen level to maintain bone health is > 50 pg/mL. Estrogen also stimulates synthesis of Insulin like growth factor (IGF-1) which exerts positive impact on bone mineral density (BMD). Eating disorders suppress bone formation, bone remodeling and repair and hence peak bone mass cannot be achieved. Young amenorrheic females with eating disorders have 7 times increased risk of fracture. Due to this reason BMD should be measured by DEXA if female is amenorrheic for > 6 months or earlier if energy deficit or skeletal fragility is suspected.

ConSequenCeSFunctional hypothalamic amenorrhea has short-term and long-term effects on female reproduction as well as bone, cardiovascular and mental health. Suppression of HPO axis leads to delayed puberty in adolescents, secondary amenorrhea and rarely primary amenorrhea as well. Anovulation and hypoestrogenism are responsible for infertility. Excessive exercise and altered diet leaves behind negative energy balance which reduce BMD. Also ideal energy requirement is 30 kcal/Kg and below this Luteinizing hormone (LH) release is affected. Female athletes should be screened for female athlete triad (abnormal menstruation, reduced energy availability with or without eating disorder and reduced BMD)8 and exercise should begin only when a certain threshold for energy availability is met.9 Chronic hypoestrogenism further impairs bone health increasing osteopenia, osteoporosis and risk of spontaneous fractures. Further estrogen is cardioprotective; hence hypoestrogenism is associated with hyperlipidemia, endothelial and vascular dysfunction. Estrogen via various neuromodulators-serotonin, dopamine and cortisol, is responsible for stabilizing mood. Hypoestrogenism has shown association with depression and anxiety; can lead to sexual dysfunction as well. Pregnancy in patients with FHA, due to associated energy deficit, is susceptible to increased incidence of abortion, intrauterine growth retardation, preterm labor and increased cesarean rate.

AppRoACh To pATienT wiTh SuSpeCTed FhA10,11

Diagnosing FHA demands complete work up to rule out structural, endocrine, metabolic or systemic causes. Prolonged irregular menstrual cycles can be physiological in the initial 1-2 years of menarche and so diagnosing FHA remains a challenge at puberty. However, all females with > 3 months of amenorrhea or having persistent prolonged cycles of > 45 days need evaluation for FHA.11

A detailed history and thorough examination can exclude other causes. Particular focus should be laid on personal history directed towards diet, exercise, weight fluctuations and mental status. Signs suggestive of systemic, endocrine or genetic anomalies should be looked for. Needless to say that exclusion of pregnancy remains the first step as in any other case of amenorrhea. This should be followed by other investigations relevant with respect to history and examination findings—baseline investigations, endocrine and radiological investigations in order to rule out the systemic, hormonal, structural or organic causes responsible for primary and secondary amenorrhea (Fig. 2; Table 1). LH and FSH levels are low in hypothalamic amenorrhea and levels may even be undetectable when the underlying cause is organic. If estradiol levels are also low, we can go for Gonadotropin stimulation test which results in positive response (2-3 times rise in gonadotropin levels) in hypothalamic amenorrhea and not in others. Once organic and genetic causes of hypothalamic amenorrhea are excluded, FHA is diagnosed. Testosterone levels are raised in PCOS. Adrenal pathology may be associated with raised DHEA-S levels. Presence of raised testosterone and DHEA-S along with virilizing signs is an indication for 17-hydroxyprogesterone assay at 8 AM and the levels will be raised in non-classic congenital adrenal hyperplasia which can be confirmed with high dose ACTH stimulation test. For raised cortisol levels, 24 hour urinary cortisol levels and 1mg dexamethasone suppression test may be done to differentiate Cushing’s syndrome from FHA where circadian rhythm is preserved. Abnormal TSH and raised prolactin levels suggest thyroid disorders and hyperprolactinemia which require further evaluation. In patients with normal uterus, positive progesterone challenge test and positive estrogen-progesterone

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Fig. 2: Algorithm for clinical approach to FHA (functional hypothalamic amenorrhea)10,11

challenge test indicate estrogen-primed endometrium

and estrogen-deficient endometrium respectively.

Negative estrogen-progesterone challenge test suggests

investigating for outflow tract obstruction.

MAnAgeMenT11,12

Management of FHA needs multidisciplinary approach-

dietician or nutritionist, endocrinologist, gynecologist,

psychiatrist and sports trainer. Counsel and educate

the patient regarding FHA, its consequences if not

intervened timely and the various management

options. Initial step involves excluding pregnancy.

Further management should target the underlying

cause.

Negative energy balance needs correction by life-

style modifications—increasing the calorie intake,

including balanced diet rich in nutrients (400-1000

IU of vitamin D and 1200-1500 mg of calcium) as per

individual requirement and reducing the exercise.

This will help in normalizing weight and spontaneous

resumption of menstruation and ovulation once weight

remains stabilized for > 6 months. It has been noted

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that 5% increase in weight or an absolute weight gain

of 1-2 kg may spontaneously resume periods. Reassess

the patient at 2-3 months intervals.11-13

If stress is the underlying cause or if correcting

negative energy balance fails to treat amenorrhea, refer

to psychiatrist. Aim should be to avoid the stressor and

reduce the stress. Cognitive behavioral therapy (CBT)

improves hormonal profile (cortisol, TSH, leptin) and

may restore ovulation.11,14

Since oral contraceptive pill (OCP) trials in FHA

patients revealed conflicting results, its use in FHA

for regularizing menstrual cycles and improving

BMD is not recommended. If OCP are being used for

contraception, the resultant chronic anovulation will

prevent return of spontaneous menstruation; hence

should be immediately stopped once FHA is diagnosed

and alternative contraceptive method should be

offered.11

If correcting negative energy balance and psycho-

logical treatment fails to treat FHA within a period of

6-12 months, hormonal therapy should be introduced

so as to prevent the long-term consequences on bone

health and cardiovascular function. Since transdermal

estradiol has positive effect on BMD as it does not down

regulate IGF-1 (Insulin like growth factor 1); hence

combination of transdermal estrogen (100 µg patch of

17 β estradiol twice weekly) with cyclic oral progestogen

(micronized progesterone 200 mg daily for last 12 days

of estradiol) is recommended.11,15,16 In patients with

FHA with grossly reduced BMD and delayed fracture

healing short-term recombinant parathyroid hormone

may be prescribed.11

For infertility first line treatment targets the basic

etiology of FHA-suppressed GnRH secretion; hence,

the treatment includes pulsatile GnRH, which if

not available is to be followed by cautious use of

gonadotropin (both LH & FSH) and ovulation induction

with 10 days therapy of clomiphene provided estrogen

levels are normal. CBT acts as a good alternative/

adjuvant therapy for infertility. Pregnancy should

be desired once the BMI reaches at least 18.5 kg/m2;

otherwise one cannot reduce the associated adverse

obstetrical outcome.11,17,18

Though recombinant human Leptin decrease cortisol

levels with resultant increase in estrogen levels, Leptin,

at present is neither recommended for improving

BMD nor for treating infertility because of associated

weight loss and fat reduction. Biphosphonates have the

potential of getting deposited in the bones and being

transferred to fetus and so are contraindicated for

improving BMD in young females. Kisspeptin stimulates

LH and FSH release but associated tachyphylaxis

warrants further research.11,12

To conclude FHA, one of the main contributors of

amenorrhea, is a diagnosis of exclusion with complex

underlying pathogenesis. Management is multimodal

Table 1Endocrine profile in FHA, PCOS and ovarian insufficiency

FHA PCOS Ovarian insufficiencyLH (IU/mL) Low/low normal (<10) < 15 >15FSH (IU/mL) Low/low normal (<10) < 10 >15 (more than LH)LH/FSH ~1 >1 < 1E2 (pg/mL) < 50 < 50 < 50 (usually < 20)P (ng/mL) < 1 < 1 < 1TSH (µU/mL) Low normal Normal Normal/ raisedFree T4 (µg/dL) Low normal Normal Normal/ raisedTestosterone (ng/dL) Low normal High normal/ raised Low normalDHEA-S (µg/dL) Normal High normal Normal PRL (ng/mL) Low normal High normal Normal AMH (ng/mL) >1 Normal/ raised < 0.5

Abbreviations: FHA, functional hypothalamic amenorrhea; PCOS, polycystic ovarian syndrome; LH, luteinizing hormone; FSH, follicle stimulating hormone; E2, estradiol; P, progesterone; TSH, thyroid stimulating hormone; T4, thyroxin; DHEA-S, Dehydroepiandrosterone sulphate; PRL, prolactin; AMH, anti-mullerian hormone

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requiring multidisciplinary approach. Main aim is resumption of menses and prevention of long-term negative impact on bone health by targeting the basic underlying cause.

Source of SupportNil

Conflict of InterestNone to declare.

Financial disclosureNil

AcknowledgmentNil

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