Functional hypothalamic amenorrhea: etiology and pathogenesis, the role of genetic factors

DOI

https://dx.doi.org/10.18565/aig.2025.284

Ermakova D.M., Rakhmonova F.S., Dolgushina N.V.
Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia

Functional hypothalamic amenorrhea is a disease of reproductive-aged women, which is due to impaired activity of the hypothalamic-pituitary-ovarian axis. The main etiological factors leading to the manifestation of functional hypothalamic amenorrhea have been widely described but their elimination does not always result in the restoration of the menstrual cycle rhythmicity. Therefore, it is necessary to search for additional mechanisms that determine the duration of the disease and explain the lack of effectiveness of standard therapeutic strategies.
Increasing amounts of data suggest a significant role of genetic factors in the development and course of functional hypothalamic amenorrhea. It is believed that polymorphisms of genes involved in the regulation of energy metabolism, stress response, and hormonal homeostasis can influence the sensitivity of hypothalamic neurons to external stressors and modify individual responses to them.
During the preparation of this review, the studies on this subject available in the PubMed and eLibrary databases were analyzed. A search was conducted for articles published between 2014 and 2025 using the following keywords: functional hypothalamic amenorrhea, hypogonadotropic hypogonadism, stress, disordered eating, excessive exercise.
Conclusion: A detailed study of the genetic mechanisms underlying functional hypothalamic amenorrhea could help better understand its pathogenesis, confirm the multifactorial nature of the condition and open up opportunities for the development of personalized treatment strategies. This could also aid in predicting the course of the condition and facilitate early identification of high-risk individuals.

Authors’ contributions: Ermakova D.M. – developing the concept of the study; collection, analysis and systematization of literature data, preparing and editing the text of the article; Rakhmonova F.S. – collection and analysis of literature data, writing the text of the article; Dolgushina N.V. – developing the concept and design of the study, scientific supervision, critical revision of the manuscript text, approval of the final version of the article.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The study was conducted without sponsorship.
For citation: Ermakova D.M., Rakhmonova F.S., Dolgushina N.V. Functional hypothalamic amenorrhea:
etiology and pathogenesis, the role of genetic factors.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2025; (11): 53-61 (in Russian)
https://dx.doi.org/10.18565/aig.2025.284

functional hypothalamic amenorrhea

hypogonadotropic hypogonadism

stress

disordered eating

excessive exercise

Full text (in Russian)

Roberts R.E., Farahani L., Webber L., Jayasena C. Current understanding of hypothalamic amenorrhoea. Ther. Adv. Endocrinol. Metab. 2020; 11: 2042018820945854. https://dx.doi.org/10.1177/2042018820945854
Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea: a committee opinion. Fertil. Steril. 2024; 122(1): 52-61. https://dx.doi.org/10.1016/j.fertnstert.2024.02.001
Morrison A.E., Fleming S., Levy M.J. A review of the pathophysiology of functional hypothalamic amenorrhoea in women subject to psychological stress, disordered eating, excessive exercise or a combination of these factors. Clin. Endocrinol. (Oxf). 2021; 95(2): 229-38. https://dx.doi.org/10.1111/cen.14399
Walsh B.T., Hagan K.E., Lockwood C. A systematic review comparing atypical anorexia nervosa and anorexia nervosa. Int. J. Eat. Disord. 2023; 56(4): 798-820. https://dx.doi.org/10.1002/eat.23856
Москвичева Ю.Б., Гусев Д.В., Табеева Г.И., Чернуха Г.Е. Оценка питания, состава тела и особенности диетологического консультирования пациенток с функциональной гипоталамической аменореей. Вопросы питания. 2018; 87(1): 85-91. [Moskvicheva Yu.B., Gusev D.V., Tabeeva G.I., Chernukha G.E. Evaluation of nutrition, body composition and features of dietetic counseling for patients with functional hypothalamic amenorrhea. Problems of Nutrition. 2018; 87(1): 85-91 (in Russian)]. https://dx.doi.org/10.24411/0042-8833-2018-10010
Бондаренко К.Р., Казанцева В.Д., Доброхотова Ю.Э. Функциональная гипоталамическая аменорея в практике клинициста: лечебно-диагностические особенности. Акушерство и гинекология. 2022; 5: 149-56. [Bondarenko K.R., Kazantseva V.D., Dobrokhotova Yu.E. Functional hypothalamic amenorrhea in the practice of a clinician: therapeutic and diagnostic features. Obstetrics and Gynecology. 2022; (5): 149-156 (in Russian)]. https://dx.doi.org/10.18565/aig.2022.5.149-156
Чернуха Г.Е., Бобров А.Е., Гусев Д.В., Табеева Г.И., Никитина Т.Е., Агамамедова И.Н. Психопатологические особенности и эндокринно-метаболический профиль пациенток с функциональной гипоталамической аменореей. Акушерство и гинекология. 2019; 2: 105-12. [Chernukha G.E., Bobrov A.E., Gusev D.V., Tabeeva G.I., Nikitina T.E., Agamamedova I.N. Psychopathological features and endocrine-metabolic profile of patients with functional hypothalamic amenorrhea. Obstetrics and Gynecology. 2019; (2): 105-12 (in Russian)]. https://dx.doi.org/10.18565/aig.2019.2.105-112
Шпаков А.О., Деркач К.В. Гонадолиберин – синтез, секреция, молекулярные механизмы и мишени действия. Acta Biomed. Sci. 2019; 4(2): 9-17. [Shpakov A.O., Derkach K.V. Gonadoliberin – synthesis, secretion, molecular mechanisms and targets of action. Acta Biomed. Sci. 2019; 4(2): 9-17 (in Russian)]. https://dx.doi.org/10.29413/ABS.2019-4.2.1
Ryterska K., Kordek A., Załęska P. Has menstruation disappeared? Functional hypothalamic amenorrhea-What is this story about? Nutrients. 2021; 13(8): 2827. https://dx.doi.org/10.3390/nu13082827
Moore A.M., Coolen L.M., Lehman M.N. Kisspeptin/Neurokinin B/Dynorphin (KNDy) cells as integrators of diverse internal and external cues: evidence from viral-based monosynaptic tract-tracing in mice. Sci. Rep. 2019; 9(1): 14768. https://dx.doi.org/10.1038/s41598-019-51201-0
Stamatiades G.A., Kaiser U.B. Gonadotropin regulation by pulsatile GnRH: Signaling and gene expression. Mol. Cell. Endocrinol. 2018; 463: 131-41. https://dx.doi.org/10.1016/j.mce.2017.10.015
Męczekalski B., Niwczyk O., Battipaglia C., Troia L., Kostrzak A., Bala G. et al. Neuroendocrine disturbances in women with functional hypothalamic amenorrhea: an update and future directions. Endocrine. 2024; 84(3): 769-85. https://dx.doi.org/10.1007/s12020-023-03619-w
Boegl M., Dewailly D., Marculescu R., Steininger J., Ott J., Hager M. The LH:FSH ratio in functional hypothalamic amenorrhea: an observational study. J. Clin. Med. 2024; 13(5): 1201. https://dx.doi.org/10.3390/jcm13051201
Pape J., Herbison A.E., Leeners B. Recovery of menses after functional hypothalamic amenorrhoea: if, when and why. Hum. Reprod. Update. 2021; 27(1): 130-53. https://dx.doi.org/10.1093/humupd/dmaa032
Behary P., Comninos A.N. Bone perspectives in functional hypothalamic amenorrhoea: an update and future avenues. Front. Endocrinol. (Lausanne). 2022; 13: 923791. https://dx.doi.org/10.3389/fendo.2022.923791
Абсатарова Ю.С., Евсеева Ю.С., Андреева Е.Н., Шереметьева Е.В., Григорян О.Р., Михеев Р.К. Трудности дифференциальной диагностики функциональной гипоталамической аменореи и синдрома поликистозных яичников: систематический обзор. Проблемы эндокринологии. 2025; 71(1): 83-91. [Absatarova Yu.S., Evseeva Yu.S., Andreeva E.N., Sheremetyeva E.V., Grigoryan O.R., Mikheev R.K. Difficulties of differential diagnosis of functional hypothalamic amenorrhea and polycystic ovary syndrome: a systematic review. Problems of Endocrinology. 2025; 71(1): 83-91 (in Russian)]. https://dx.doi.org/10.14341/probl13529
Workman C., Blalock D.V., Mehler P.S. Bone density status in a large population of patients with anorexia nervosa. Bone. 2020; 131: 115161. https://dx.doi.org/10.1016/j.bone.2019.115161
Meczekalski B., Katulski K., Czyzyk A., Podfigurna-Stopa A., Maciejewska-Jeske M. Functional hypothalamic amenorrhea and its influence on women’s health. J. Endocrinol. Invest. 2014; 37(11): 1049-56. https://dx.doi.org/10.1007/s40618-014-0169-3
Pruneti C., Guidotti S. Cognition, behavior, sexuality, and autonomic responses of women with hypothalamic amenorrhea. Brain Sci. 2022; 12(11): 1448. https://dx.doi.org/10.3390/brainsci12111448
Бобров А.Е., Ильина Н.А. Психические расстройства у женщин, страдающих частыми формами вторичной аменореи: нозографическая структура и психологические маркеры. Российский психиатрический журнал. 2022; 5: 74-83. [Bobrov A.E., Ilyina N.A. Mental disorders in women suffering from frequent forms of secondary amenorrhea: nosographic structure and psychological markers. Russian Psychiatric Journal. 2022; 5: 74-83 (in Russian)]. https://dx.doi.org/10.47877/1560-957Х-2022-10507
Bonazza F., Politi G., Leone D., Vegni E., Borghi L. Psychological factors in functional hypothalamic amenorrhea: a systematic review and meta-analysis. Front. Endocrinol. (Lausanne). 2023; 14: 981491. https://dx.doi.org/10.3389/fendo.2023.981491
Podfigurna A., Maciejewska-Jeske M., Meczekalski B., Genazzani A.D. Kisspeptin and LH pulsatility in patients with functional hypothalamic amenorrhea. Endocrine. 2020; 70(3): 635-43. https://dx.doi.org/10.1007/s12020-020-02481-4
Hofmann T., Elbelt U., Haas V., Ahnis A., Klapp B.F., Rose F. Sa1999 kisspeptin is inversely associated with exercise in patients with anorexia nervosa. Gastroenterology. 2016; 150(4): S428. https://dx.doi.org/10.1016/S0016-5085(16)31487-1
Hu X., Wang Z., Wang W., Cui P., Kong C., Chen X. et al. Irisin as an agent for protecting against osteoporosis: a review of the current mechanisms and pathways. J. Adv. Res. 2024; 62: 175-86. https://dx.doi.org/10.1016/j.jare.2023.09.001
Patel A.H., Koysombat K., Pierret A., Young M., Comninos A.N., Dhillo W.S. et al. Kisspeptin in functional hypothalamic amenorrhea: pathophysiology and therapeutic potential. Ann. N. Y. Acad. Sci. 2024; 1540(1): 21-46. https://dx.doi.org/10.1111/nyas.15220
Mahdavi K., Zendehdel M., Zarei H. Decoding the role of ghrelin and its interactions with central signaling pathways in avian appetite regulation. Vet. Res. Commun. 2025; 49(2): 73. http://dx.doi.org/10.1007/s11259-025-10644-9
Saadedine M., Berga S.L., Faubion S.S., Shufelt C.L. The silent pandemic of stress: impact on menstrual cycle and ovulation. Stress. 2025; 28(1): 2457767. https://dx.doi.org/10.1080/10253890.2025.2457767
Perakakis N., Upadhyay J., Ghaly W., Chen J., Chrysafi P., Anastasilakis A.D. et al. Regulation of the activins-follistatins-inhibins axis by energy status: impact on reproductive function. Metabolism. 2018; 85: 240-9. https://dx.doi.org/10.1016/j.metabol.2018.05.003
Gifford R.M., O'Leary T.J., Wardle S.L., Double R.L., Homer N.Z.M., Howie A.F. et al. Reproductive and metabolic adaptation to multistressor training in women. Am. J. Physiol. Endocrinol. Metab. 2021; 321(2): E281-91. https://dx.doi.org/10.1152/ajpendo.00019.2021
Абдулкадырова З.К., Абашова Е.И. Значение ингибина как маркера состояния репродуктивной системы. Часть 1. Журнал акушерства и женских болезней. 2019; 68(3): 61-70. [Abdulkadyrova Z.K., Abashova E.I. Inhibin as a reproductive biomarker. Part 1. Journal of Obstetrics and Women’s Diseases. 2019; 68(3): 61-70 (in Russian)]. https://dx.doi.org/10.17816/ JOWD68361-70
Young J. Does genetic susceptibility of the gonadotropic axis explain the variable impact of stressors causing functional hypothalamic amenorrhea? J. Clin. Endocrinol. Metab. 2021; 106(3): e1473-5. https://dx.doi.org/10.1210/clinem/dgaa677
Caronia L.M., Martin C., Welt C.K., Sykiotis G.P., Quinton R., Thambundit A. et al. A Genetic basis for functional hypothalamic amenorrhea. N. Engl. J. Med. 2011; 364(3): 215-25. https://dx.doi.org/10.1056/NEJMoa0911064
Klein D.A., Emerick J.E., Sylvester J.E., Vogt K.S. Disorders of puberty: an approach to diagnosis and management. Am. Fam. Physician. 2017; 96(9): 590-9.
Кокорева К.Д., Чугунов И.С., Безлепкина О.Б. Врожденный изолированный гипогонадотропный гипогонадизм: клинический и молекулярно-генетический полиморфизм. Проблемы эндокринологии. 2021; 67(4): 46-56. [Kokoreva K.D., Chugunov I.S., Bezlepkina O.B. Molecular genetics and phenotypic features of congenital isolated hypogonadotropic hypogonadism. Problems of Endocrinology. 2021; 67(4): 46-56 (in Russian)]. https://dx.doi.org/10.14341/probl12787
Delaney A., Burkholder A.B., Lavender C.A., Plummer L., Mericq V., Merino P.M. et al. Increased burden of rare sequence variants in GnRH-associated genes in women with hypothalamic amenorrhea. J. Clin. Endocrinol. Metab. 2021; 106(3): e1441-52. https://dx.doi.org/10.1210/clinem/dgaa609
Lippincott M.F., Schafer E.C., Hindman A.A., He W., Brauner R., Delaney A. et al. Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 2024; 110(1): e61-7. https://dx.doi.org/10.1210/clinem/dgae166
Cangiano B., Swee D.S., Quinton R., Bonomi M. Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease. Hum. Genet. 2021; 140(1): 77-111. https://dx.doi.org/10.1007/s00439-020-02147-1
Amato L.G.L., Montenegro L.R., Lerario A.M., Jorge A.A.L., Guerra Junior G., Schnoll C. et al. New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism. Eur. J. Endocrinol. 2019; 181(2): 103-19. https://dx.doi.org/10.1530/EJE-18-0764
Kałużna M., Budny B., Rabijewski M., Dubiel A., Trofimiuk-Müldner M., Szutkowski K. et al. Variety of genetic defects in GnRH and hypothalamic-pituitary signaling and development in normosmic patients with IHH. Front. Endocrinol. (Lausanne). 2024; 15: 1396805. https://dx.doi.org/10.3389/fendo.2024.1396805
Topaloglu A.K., Turan I. Genetic etiology of idiopathic hypogonadotropic hypogonadism. Endocrines. 2022; 3(1): 1-15. https://dx.doi.org/10.3390/endocrines3010001
Lippincott M.F., Xu W., Smith A.A., Miao X., Lafont A., Shennib O. et al. The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay. Genet. Med. 2022; 24(12): 2501-15. https://dx.doi.org/10.1016/j.gim.2022.08.025
Sun B., Stockman S., Stamou M., Plummer L., Salnikov K., Kotan D. et al. 9242 SOX11 mutations cause hypogonadotropic hypogonadism through both hypothalamic and pituitary level deficits. J. Endocr. Soc. 2024; 8(Suppl. 1): bvae163.1756. https://dx.doi.org/10.1210/jendso/bvae163.1756
Al Sayed Y., Howard S.R. Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism – a clinical perspective. Eur. J. Hum. Genet. 2023; 31(4): 387-94. https://dx.doi.org/10.1038/s41431-022-01261-0
Gonçalves C., Bastos M., Pignatelli D., Borges T., Aragüés J.M., Fonseca F. et al. Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform. Fertil. Steril. 2015; 104(5): 1261-7.e1. https://dx.doi.org/10.1016/j.fertnstert.2015.07.1142
Barbagallo F., Bosoni D., Perone V., Cucinella L., Dealberti D., Cannarella R. et al. Gene-environment interaction in functional hypothalamic amenorrhea. Front. Endocrinol. (Lausanne). 2024; 15: 1423898. https://dx.doi.org/10.3389/fendo.2024.1423898
Zannas A.S., Wiechmann T., Gassen N.C., Binder E.B. Gene-stress-epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology. 2016; 41(1): 261-74. https://dx.doi.org/10.1038/npp.2015.235
Lind M.J., Marraccini M.E., Sheerin C.M., Bountress K., Bacanu S.A., Amstadter A.B. et al. Association of posttraumatic stress disorder with rs2267735 in the ADCYAP1R1 gene: a meta-analysis. J. Trauma Stress. 2017; 30(4):389-98. https://dx.doi.org/10.1002/jts.22211
Donato K., Ceccarini M.R., Dhuli K., Bonetti G., Medori M.C., Marceddu G. et al. Gene variants in eating disorders. Focus on anorexia nervosa, bulimia nervosa, and binge-eating disorder. J. Prev. Med. Hyg. 2022; 63(2 Suppl. 3): E297-305. https://dx.doi.org/10.15167/2421-4248/jpmh2022.63.2S3.2772
Kang Q., Chen J., Yu Sh., Yuan A., Zhang Y., Zhang R. et al. Association of the 5-HT(2A) receptor gene promoter polymorphism-1438G/A with anorexia nervosa and psychopathological traits in the Chinese Han population: a preliminary study. Asia-Pacific Psych. 2017; 9(3): 12284. https://dx.doi.org/10.1111/appy.12284
Yan P., Gao B., Wang S., Wang S., Li J., Song M. Association of 5-HTR2A -1438A/G polymorphism with anorexia nervosa and bulimia nervosa: a meta-analysis. Neurosci. Lett. 2021; 755: 135918. https://dx.doi.org/10.1016/j.neulet.2021.135918

Received 09.10.2025

Accepted 01.11.2025

Daria M. Ermakova, PhD, Researcher, obstetrician-gynecologist, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, d_ermakova@oparina4.ru, https://orcid.org/0000-0002-8558-4687
Farzona S. Rakhmonova, PhD student, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Moscow, Russia, Ac. Oparin str., 4, f_rakhmonova@oparina4.ru, https://orcid.org/0009-0000-6615-9426
Nataliya V. Dolgushina, Dr. Med. Sci., Professor, Deputy Director for Scientific Work, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Moscow, Russia, Ac. Oparin str., 4, n_dolgushina@oparina4.ru, https://orcid.org/0000-0003-1116-138X
Corresponding author: Daria M. Ermakova, d_ermakova@oparina4.ru

Functional hypothalamic amenorrhea: etiology and pathogenesis, the role of genetic factors

Ermakova D.M., Rakhmonova F.S., Dolgushina N.V.

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