Editorial Functional Hypothalamic (FHA): Time to Think Beyond Polycystic To cite: Sharma R, Nigam A. Functional Hypothalamic Amenorrhea (FHA): Time Ovarian Syndrome to Think Beyond Polycystic Ovarian Syndrome. Pan Asian 1Ritu Sharma, 2Aruna Nigam J Obs Gyn 2020;3(3):107-112. Received on: 1Associate Professor, 2Professor 05-11-2020 1Department of Obstetrics and Gynecology, Government Institute of Medical Sciences Accepted on: Noida, Uttar Pradesh, India 10-12-2020 2Department of Obstetrics and Gynecology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India

ABSTRACT Functional 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, , stress.

‘An adolescent girl of 17 years, average built, walking in FHA contributes to a significant proportion, nearly 20- the clinic with her mother for treatment of amenorrhea, 35%, of secondary amenorrhea.1 FHA can be divided into with history of menarche at 11 years and normal three types—related to excessive weight loss, excessive for first 3 years and then gradually exercise and stress (whether physical or mental). Mostly decreasing menses: common complaint misdiagnosed young females are affected although all age groups are as polycystic ovarian syndrome oftenly’ susceptible. The condition warrants timely treatment due to associated long-term consequences. It is the time to think beyond the commonly FHA results from a complex interaction among diagnosed entity polycystic ovarian syndrome in neuromodulators, endocrine and metabolic factors as adolescents as amenorrhea can result from interplay of explained in Figure 1. Weight loss, excessive exercise, end numbers of factors involving various compartments and stress- all activate hypothalamic-pituitary-adrenal of hypothalamic-pituitary-ovarian axis and outflow (HPA) axis which via different neuromodulators result tract. In today’s era, when the adolescents are becoming in increased cortisol levels. Raised cortisol suppresses more conscious of their figures and increasing Hypothalamic-pituitary-ovarian (HPO) axis by stress of the competitive examinations, entity called inhibiting -releasing-hormone (GnRH). Functional Hypothalamic Amenorrhea (FHA) becomes The important neuromodulators include Kisspeptin, more evident. It is reversible amenorrhea where no neuropeptide Y and Ghrelin. Kisspeptin, controlled by 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 Address for Correspondence (Hypothalamic-pituitary-ovarian axis dysfunction) Aruna Nigam Professor ovulatory disorder of WHO classification. Previously Department of Obstetrics and Gynecology it was named as ‘hypothalamic hypoestrogenism’ and Hamdard Institute of Medical Sciences and Research Jamia Hamdard, New Delhi, India ‘juvenile hypothalamosis syndrome’. After pregnancy, [email protected]

Pan Asian Journal of Obstetrics & Gynecology, September-December 2020;3(3):107-112 107 Ritu Sharma et al.

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

KiSS-1 gene, are secreted from neurons in the arcuate which then inhibits pulsatile release of GnRH.5 Leptin nucleus. It binds with its receptor to form Kisspeptin/ regulates interaction between metabolic and hormonal GPR54 complex which stimulates GnRH release.2 signals.6 Raised cortisol also suppresses Hypothalamic- Neuropeptide Y (NPY) controls appetite center in pituitary-thyroid (HPT) axis in order to prevent further and inhibits GnRH secretion at low loss of energy.7 Genetic factors may also play a role in estrogen levels.3 Ghrelin also affects appetite center pathogenesis (Fig. 1). and inhibits GnRH secretion.4 Corticotropin-releasing- Suppression of HPO axis leads to hypoestrogenism hormone also increases Beta endorphin secretion which is responsible for long-term sequelae-

108 AIM Publications www.pajog.com Functional Hypothalamic Amenorrhea (FHA): Time to Think Beyond Polycystic Ovarian Syndrome compromised cardiovascular function, compromised Approach to Patient with bone and mental health. Estrogen stimulates bone Suspected FHA10,11 formation and remodeling while inhibiting bone Diagnosing FHA demands complete work up to rule resorption, thereby maintaining . Optimum out structural, endocrine, metabolic or systemic estrogen level to maintain bone health is > 50 pg/mL. causes. Prolonged irregular menstrual cycles can be Estrogen also stimulates synthesis of Insulin like growth physiological in the initial 1-2 years of menarche and factor (IGF-1) which exerts positive impact on bone so diagnosing FHA remains a challenge at puberty. mineral density (BMD). Eating disorders suppress bone However, all females with > 3 months of amenorrhea formation, and repair and hence peak or having persistent prolonged cycles of > 45 days need bone mass cannot be achieved. Young amenorrheic evaluation for FHA.11 females with eating disorders have 7 times increased A detailed history and thorough examination can risk of fracture. Due to this reason BMD should be exclude other causes. Particular focus should be laid measured by DEXA if female is amenorrheic for > 6 on personal history directed towards diet, exercise, months or earlier if energy deficit or skeletal fragility is weight fluctuations and mental status. Signs suggestive suspected. of systemic, endocrine or genetic anomalies should be looked for. Needless to say that exclusion of pregnancy Consequences remains the first step as in any other case of amenorrhea. Functional hypothalamic amenorrhea has short- This should be followed by other investigations relevant term and long-term effects on female reproduction with respect to history and examination findings— as well as bone, cardiovascular and mental health. baseline investigations, endocrine and radiological Suppression of HPO axis leads to in investigations in order to rule out the systemic, adolescents, secondary amenorrhea and rarely primary hormonal, structural or organic causes responsible for amenorrhea as well. Anovulation and hypoestrogenism primary and secondary amenorrhea (Fig. 2; Table 1). are responsible for . LH and FSH levels are low in hypothalamic Excessive exercise and altered diet leaves behind amenorrhea and levels may even be undetectable negative energy balance which reduce BMD. Also when the underlying cause is organic. If estradiol levels ideal energy requirement is 30 kcal/Kg and below this are also low, we can go for Gonadotropin stimulation Luteinizing hormone (LH) release is affected. Female test which results in positive response (2-3 times rise athletes should be screened for female athlete triad in gonadotropin levels) in hypothalamic amenorrhea (abnormal menstruation, reduced energy availability and not in others. Once organic and genetic causes with or without eating disorder and reduced BMD)8 and of hypothalamic amenorrhea are excluded, FHA is exercise should begin only when a certain threshold for diagnosed. Testosterone levels are raised in PCOS. energy availability is met.9 Chronic hypoestrogenism Adrenal pathology may be associated with raised further impairs bone health increasing , DHEA-S levels. Presence of raised testosterone and and risk of spontaneous fractures. DHEA-S along with virilizing signs is an indication Further estrogen is cardioprotective; hence for 17-hydroxyprogesterone assay at 8 AM and the hypoestrogenism is associated with hyperlipidemia, levels will be raised in non-classic congenital adrenal endothelial and vascular dysfunction. hyperplasia which can be confirmed with high dose Estrogen via various neuromodulators-serotonin, ACTH stimulation test. For raised cortisol levels, 24 dopamine and cortisol, is responsible for stabilizing hour urinary cortisol levels and 1mg dexamethasone mood. Hypoestrogenism has shown association with suppression test may be done to differentiate Cushing’s depression and anxiety; can lead to sexual dysfunction syndrome from FHA where circadian rhythm is as well. preserved. Abnormal TSH and raised levels Pregnancy in patients with FHA, due to associated suggest thyroid disorders and hyperprolactinemia energy deficit, is susceptible to increased incidence which require further evaluation. of abortion, intrauterine growth retardation, preterm In patients with normal uterus, positive progesterone labor and increased cesarean rate. 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 options. Initial step involves excluding pregnancy. and estrogen-deficient endometrium respectively. Further management should target the underlying Negative estrogen-progesterone challenge test suggests cause. investigating for outflow tract obstruction. Negative energy balance needs correction by life- style modifications—increasing the calorie intake, Management11,12 including balanced diet rich in nutrients (400-1000 Management of FHA needs multidisciplinary approach- IU of vitamin D and 1200-1500 mg of calcium) as per dietician or nutritionist, endocrinologist, gynecologist, individual requirement and reducing the exercise. psychiatrist and sports trainer. Counsel and educate This will help in normalizing weight and spontaneous the patient regarding FHA, its consequences if not resumption of menstruation and ovulation once weight intervened timely and the various management remains stabilized for > 6 months. It has been noted

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Table 1 Endocrine profile in FHA, PCOS and ovarian insufficiency FHA PCOS Ovarian insufficiency LH (IU/mL) Low/low normal (<10) < 15 >15 FSH (IU/mL) Low/low normal (<10) < 10 >15 (more than LH) LH/FSH ~1 >1 < 1 E2 (pg/mL) < 50 < 50 < 50 (usually < 20) P (ng/mL) < 1 < 1 < 1 TSH (µU/mL) Low normal Normal Normal/ raised Free T4 (µg/dL) Low normal Normal Normal/ raised Testosterone (ng/dL) Low normal High normal/ raised Low normal DHEA-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 that 5% increase in weight or an absolute weight gain of estradiol) is recommended.11,15,16 In patients with of 1-2 kg may spontaneously resume periods. Reassess FHA with grossly reduced BMD and delayed fracture the patient at 2-3 months intervals.11-13 healing short-term recombinant parathyroid hormone If stress is the underlying cause or if correcting may be prescribed.11 negative energy balance fails to treat amenorrhea, refer For infertility first line treatment targets the basic to psychiatrist. Aim should be to avoid the stressor and etiology of FHA-suppressed GnRH secretion; hence, reduce the stress. Cognitive behavioral therapy (CBT) the treatment includes pulsatile GnRH, which if improves hormonal profile (cortisol, TSH, leptin) and not available is to be followed by cautious use of may restore ovulation.11,14 gonadotropin (both LH & FSH) and ovulation induction Since oral contraceptive pill (OCP) trials in FHA with 10 days therapy of clomiphene provided estrogen patients revealed conflicting results, its use in FHA levels are normal. CBT acts as a good alternative/ for regularizing menstrual cycles and improving adjuvant therapy for infertility. Pregnancy should BMD is not recommended. If OCP are being used for be desired once the BMI reaches at least 18.5 kg/m2; contraception, the resultant chronic anovulation will otherwise one cannot reduce the associated adverse prevent return of spontaneous menstruation; hence obstetrical outcome.11,17,18 should be immediately stopped once FHA is diagnosed Though recombinant human Leptin decrease cortisol and alternative contraceptive method should be levels with resultant increase in estrogen levels, Leptin, offered.11 at present is neither recommended for improving If correcting negative energy balance and psycho­ BMD nor for treating infertility because of associated logical treatment fails to treat FHA within a period of weight loss and fat reduction. Biphosphonates have the 6-12 months, hormonal therapy should be introduced potential of getting deposited in the bones and being so as to prevent the long-term consequences on bone transferred to fetus and so are contraindicated for health and cardiovascular function. Since transdermal improving BMD in young females. Kisspeptin stimulates estradiol has positive effect on BMD as it does not down LH and FSH release but associated tachyphylaxis regulate IGF-1 (Insulin like growth factor 1); hence warrants further research.11,12 combination of transdermal estrogen (100 µg patch of To conclude FHA, one of the main contributors of 17 β estradiol twice weekly) with cyclic oral amenorrhea, is a diagnosis of exclusion with complex (micronized progesterone 200 mg daily for last 12 days underlying pathogenesis. Management is multimodal

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requiring multidisciplinary approach. Main aim is repeated stress. Neuroendocrinology 2005;81:183–92. resumption of menses and prevention of long-term 8. Committee on Adolescent Health Care. ACOG Committee Opinion No.702: Female Athlete Triad. negative impact on bone health by targeting the basic Obstet Gynecol 2017;129:160-7. underlying cause. 9. Mountjoy M, Sundgot-Borgen J, Burke L, et al. The IOC consensus statement: beyond the female athlete triad—relative energy deficiency in sport (RED-S). Br J Source of Support Sports Med. 2014; 48(7):491–7. 10. Sharma R, Monga JK. Approach to a women presenting Nil with amenorrhea.In: Manju Puri, editor.Clinical methods in Obstetrics & . 2nd edition. New Delhi: Jaypee brothers Medical publishers; 2021. Conflict of Interest p. 414-26. None to declare. 11. Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab Financial Disclosure 2017;102:1413-39. 12. Gibson MES, Fleming N, Zuijdwijk C, et al. Where have Nil the periods gone? The evaluation and management of functional hypothalamic amenorrhea. J Clin Res Pediatr Endocrinol 2020;12(Suppl 1):18-27. Acknowledgment 13. Kopp-Woodroffe SA, Manore MM, Dueck CA, et al. Nil Energy and nutrient status of amenorrheic athletes participating in a diet and exercise training intervention program. Int J Sport Nutr 1999;9:70-88. 14. Michopoulos V, Mancini F, Loucks TL, Berga SL. References Neuroendocrine recovery initiated by cognitive 1. Roa J, Tena-Sempere M. KiSS-1 system and reproduction: behavioral therapy in women with functional comparative aspects and roles in the control of female hypothalamic amenorrhea: a randomized, controlled gonadotropic axis in mammals. Gen Comp Endocrinol trial. Fertil Steril. 2013;99(7):2084–2091.e1. 2007; 153:132–140. 15. Kam GY, Leung KC, Baxter RC, Ho KK. 2. Practice Committee of the American Society for exert route- and dose-dependent effects on insulin- Reproductive Medicine: Current evaluation of like growth factor (IGF)-binding protein-3 and the amenorrhea. Fertil Steril 2006;86:S148. acid-labile subunit of the IGF ternary complex. J Clin 3. Kalra SP, Crowley WR. Neuropeptide Y: a novel Endocrinol Metab. 2000;85(5):1918–22. neuroendocrine peptide in the control of pituitary 16. Ackerman KE, Singhal V, Baskaran C, et al. Oestrogen hormone secretion, and its relation to luteinizing replacement improves bone mineral density in oligo- hormone. Front Neuroendocrinol 1992;13:1–46. amenorrhoeic athletes: a randomised clinical trial. Br 4. Schneider LF, Warren MP. Functional hypothalamic J Sports Med 2019;53:229-36. amenorrhea is associated with elevated ghrelin and 17. Christou F, Pitteloud N, Gomez F. The induction of disordered eating. Fertil Steril 2006;86:1744–9. ovulation by pulsatile administration of GnRH: an 5. Katz N, Mazer NA. The impact of opioids on the appropriate method in hypothalamic amenorrhea. endocrine system. Clin J Pain 2009;25: 170–5. Gynecol Endocrinol 2017; 33:598-601. 6. Andrico S, Gambera A, Specchia C, et al. Leptin in 18. Dumont A, Dewailly D, Plouvier P, et al. Comparison functional hypothalamic amenorrhoea. Hum Reprod. between pulsatile GnRH therapy and 2002;17:2043–48. for ovulation induction in women with both functional 7. Helmreich DL, Parfitt DB, Lu XY, et al. Relation between hypothalamic amenorrhea and polycystic ovarian the hypothalamic- pituitary-thyroid (HPT) axis and morphology. Gynecol Endocrinol 2016;32:999-1004. the hypothalamic–pituitary–adrenal (HPA) axis during

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