FUNCTIONAL HYPOTHALAMIC AMENORRHOEA IN FEMALE ATHLETES - PATHOPHYSIOLOGY, RISK FACTORS, CONSEQUENCES AND POSSIBLE TREATMENTS
Abstract
Introduction: Functional hypothalamic amenorrhoea is a prevalent endocrine disorder among female athletes, primarily caused by low energy availability (LEA). LEA induces a cascade of endocrine and neurohormonal changes, leading to disrupted GnRH pulsatility, anovulation, and hypoestrogenism. The health consequences of FHA are extensive, affecting bone density, cardiovascular function, fertility, and neuropsychiatric health.
Purpose: The aim of this paper was to review FHA in female athletes, focusing on its pathophysiology, clinical consequences, diagnosis, and treatment, while emphasising the need for early detection and multidisciplinary care.
Methodology: A narrative literature review was conducted using Google Scholar and PubMed. Relevant original research articles, systematic reviews, clinical guidelines, and authoritative textbooks were included to ensure comprehensive coverage of the topic.
Conclusions: Untreated FHA leads to serious health consequences. Early diagnosis and timely intervention are critical. Multidisciplinary approach should be implemented. Further studies are needed particularly in the areas of early identification, pathophysiological mechanisms, and effective, evidence-based treatment strategies.
References
Andrico, S., Gambera, A., Specchia, C., Pellegrini, C., Falsetti, L., & Sartori, E. (2002). Leptin in functional hypothalamic amenorrhoea. Human Reproduction, 17(8), 2043–2048. https://doi.org/10.1093/humrep/17.8.2043
Bairey Merz, C. N., Kelsey, S. F., Pepine, C. J., Reichek, N., Reis, S. E., Rogers, W. J., et al. (1999). The Women’s Ischemia Syndrome Evaluation (WISE) Study: Protocol design, methodology and feasibility report. Journal of the American College of Cardiology, 33(6), 1453–1461. https://doi.org/10.1016/S0735-1097(99)00082-0
Barrack, M. T., Ackerman, K. E., & Gibbs, J. C. (2013). Update on the female athlete triad. Current Reviews in Musculoskeletal Medicine, 6(2), 195–204. https://doi.org/10.1007/s12178-013-9168-9
Behary, P., & Comninos, A. N. (2022). Bone perspectives in functional hypothalamic amenorrhoea: An update and future avenues. Frontiers in Endocrinology, 13, 923791. https://doi.org/10.3389/fendo.2022.923791
Bomba, M., Gambera, A., Bonini, L., Peroni, M., Neri, F., Scagliola, P., & Nacinovich, R. (2007). Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents. Fertility and Sterility, 87(4), 876–885. https://doi.org/10.1016/j.fertnstert.2006.09.011
Bonazza, F., Politi, G., Leone, D., Vegni, E., & Borghi, L. (2023). Psychological factors in functional hypothalamic amenorrhea: A systematic review and meta-analysis. Frontiers in Endocrinology, 14, 981491. https://doi.org/10.3389/fendo.2023.981491
Brundu, B., Loucks, T. L., Adler, L. J., Cameron, J. L., & Berga, S. L. (2006). Increased cortisol in the cerebrospinal fluid of women with functional hypothalamic amenorrhea. Journal of Clinical Endocrinology & Metabolism, 91(4), 1561–1565. https://doi.org/10.1210/jc.2005-2422
Bumbuliene, Z., Klimasenko, J., Sragyte, D., & Zakareviciene, J. (2015). Uterine size and ovarian size in adolescents with functional hypothalamic amenorrhoea. Archives of Disease in Childhood, 100(10), 965–969. https://doi.org/10.1136/archdischild-2014-307504
Dundon, C. M., Rellini, A. H., Tonani, S., Santamaria, V., & Nappi, R. (2010). Mood disorders and sexual functioning in women with functional hypothalamic amenorrhea. Fertility and Sterility, 94(6), 2239–2243. https://doi.org/10.1016/j.fertnstert.2010.01.012
Falsetti, L., Gambera, A., Barbetti, L., & Specchia, C. (2002). Long-term follow-up of functional hypothalamic amenorrhea and prognostic factors. The Journal of Clinical Endocrinology & Metabolism, 87(2), 500–505. https://doi.org/10.1210/jcem.87.2.8195
Fang, J., Zhang, X., Chen, X., Wang, Z., Zheng, S., Cheng, Y., et al. (2023). The role of insulin-like growth factor-1 in bone remodeling: A review. International Journal of Biological Macromolecules, 238, 124125. https://doi.org/10.1016/j.ijbiomac.2023.124125
Fontana, L., Garzia, E., Marfia, G., Galiano, V., & Miozzo, M. (2022). Epigenetics of functional hypothalamic amenorrhea. Frontiers in Endocrinology, 13, 953431. https://doi.org/10.3389/fendo.2022.953431
Gibson, M. E. S., Fleming, N., Zuijdwijk, C., & Dumont, T. (2020). Where have the periods gone? The evaluation and management of functional hypothalamic amenorrhea. Journal of Clinical Research in Pediatric Endocrinology, 12(Suppl 1), 18–27. https://doi.org/10.4274/jcrpe.galenos.2019.2019.S0178
Gimunová, M., Paulínyová, A., Bernaciková, M., & Paludo, A. C. (2022). The prevalence of menstrual cycle disorders in female athletes from different sports disciplines: A rapid review. International Journal of Environmental Research and Public Health, 19(21), 14243. https://doi.org/10.3390/ijerph192114243
Hwang, W. J., Lee, T. Y., Kim, N. S., & Kwon, J. S. (2020). The role of estrogen receptors and their signaling across psychiatric disorders. International Journal of Molecular Sciences, 22(1), 373. https://doi.org/10.3390/ijms22010373
Indirli, R., Lanzi, V., Mantovani, G., Arosio, M., & Ferrante, E. (2022). Bone health in functional hypothalamic amenorrhea: What the endocrinologist needs to know. Frontiers in Endocrinology, 13, 946695. https://doi.org/10.3389/fendo.2022.946695
Javed, A., Tebben, P. J., Fischer, P. R., & Lteif, A. N. (2013). Female athlete triad and its components: Toward improved screening and management. Mayo Clinic Proceedings, 88(9), 996–1009. https://doi.org/10.1016/j.mayocp.2013.07.001
Kamel-ElSayed, S. A., Fahmy, M. W., & Schwartz, J. (2023). Physiology, pituitary gland. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459247/
Khan, K. M., Liu-Ambrose, T., Sran, M. M., Ashe, M. C., Donaldson, M. G., Wark, J. D., & Nattiv, A. (2002). New criteria for female athlete triad syndrome? British Journal of Sports Medicine, 36(1), 10–13. https://doi.org/10.1136/bjsm.36.1.10
Kyriakidis, M., Caetano, L., Anastasiadou, N., Karasu, T., & Lashen, H. (2016). Functional hypothalamic amenorrhoea: Leptin treatment, dietary intervention and counselling as alternatives to traditional practice – systematic review. European Journal of Obstetrics & Gynecology and Reproductive Biology, 198, 131–137. https://doi.org/10.1016/j.ejogrb.2016.01.018
Li, Y., Zhao, P., Jiang, B., Zhao, W., Wang, T., Zhao, Y., et al. (2023). Modulation of the vitamin D/vitamin D receptor system in osteoporosis pathogenesis: Insights and therapeutic approaches. Journal of Orthopaedic Surgery and Research, 18, 860. https://doi.org/10.1186/s13018-023-04320-4
Liu, S. L., & Lebrun, C. M. (2006). Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: A systematic review. British Journal of Sports Medicine, 40(1), 11–24. https://doi.org/10.1136/bjsm.2005.020065
Meczekalski, B., Katulski, K., Czyzyk, A., et al. (2014). Functional hypothalamic amenorrhea and its influence on women’s health. Journal of Endocrinological Investigation, 37(11), 1049–1056. https://doi.org/10.1007/s40618-014-0169-3
Męczekalski, B., Niwczyk, O., Battipaglia, C., Troia, L., Kostrzak, A., Bala, G., et al. (2023). Neuroendocrine disturbances in women with functional hypothalamic amenorrhea: An update and future directions. Endocrine, 84(3), 769–785. https://doi.org/10.1007/s12020-023-03619-w
Mountjoy, M., Sundgot-Borgen, J., Burke, L., Carter, S., Constantini, N., Lebrun, C., et al. (2014). The IOC consensus statement: Beyond the Female Athlete Triad—Relative Energy Deficiency in Sport (RED-S). British Journal of Sports Medicine, 48(7), 491–497. https://doi.org/10.1136/bjsports-2014-093502
Mudd, L. M., Fornetti, W., & Pivarnik, J. M. (2007). Bone mineral density in collegiate female athletes: Comparisons among sports. Journal of Athletic Training, 42(3), 403–408. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978462/
Nawaz, G., Rogol, A. D., & Jenkins, S. M. (2024). Amenorrhea. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482168/
Nazem, T. G., & Ackerman, K. E. (2012). The female athlete triad. Sports Health, 4(4), 302–311. https://doi.org/10.1177/1941738112439685
Orlowski, M., & Sarao, M. S. (2023). Physiology, follicle stimulating hormone. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK535442/
Patel, A. H., Koysombat, K., Pierret, A., Young, M., Comninos, A. N., Dhillo, W. S., & Abbara, A. (2024). Kisspeptin in functional hypothalamic amenorrhea: Pathophysiology and therapeutic potential. Annals of the New York Academy of Sciences, 1512(1), 24–36. https://doi.org/10.1111/nyas.15220
Pedreira, C. C., Maya, J., & Misra, M. (2022). Functional hypothalamic amenorrhea: Impact on bone and neuropsychiatric outcomes. Frontiers in Endocrinology, 13, 953180. https://doi.org/10.3389/fendo.2022.953180
Podfigurna, A., & Meczekalski, B. (2021). Functional hypothalamic amenorrhea: A stress-based disease. Endocrines, 2(3), 203–211. https://doi.org/10.3390/endocrines2030020
Quaas, P., Quaas, A. M., Fischer, M., & De Geyter, C. (2023). Use of pulsatile gonadotropin-releasing hormone (GnRH) in patients with functional hypothalamic amenorrhea (FHA) results in monofollicular ovulation and high cumulative live birth rates: A 25-year cohort. Journal of Assisted Reproduction and Genetics, 40(1), 149–157. https://doi.org/10.1007/s10815-022-02656-0
Raj, M. A., Creech, J. A., & Rogol, A. D. (2023). Female athlete triad. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534833/
Roberts, R. E., Farahani, L., Webber, L., & Jayasena, C. (2020). Current understanding of hypothalamic amenorrhoea. Therapeutic Advances in Endocrinology and Metabolism, 11, 2042018820945854. https://doi.org/10.1177/2042018820945854
Rosen Vollmar, A. K., Mahalingaiah, S., & Jukic, A. M. (2025). The menstrual cycle as a vital sign: A comprehensive review. Current Opinion in Clinical Nutrition and Metabolic Care, 6(1), 100081. https://doi.org/10.1016/j.xfnr.2024.100081
Saadedine, M., Kapoor, E., & Shufelt, C. (2023). Functional hypothalamic amenorrhea: Recognition and management of a challenging diagnosis. Cleveland Clinic Journal of Medicine, 98(9), 1376–1385. https://doi.org/10.3949/ccjm.98a.ccc081
Sanders, K. M., Kawwass, J. F., Loucks, T., & Berga, S. L. (2018). Heightened cortisol response to exercise challenge in women with functional hypothalamic amenorrhea. American Journal of Obstetrics and Gynecology, 218(2), 230.e1–230.e6. https://doi.org/10.1016/j.ajog.2017.11.579
Shufelt, C. L., Torbati, T., & Dutra, E. (2017). Hypothalamic amenorrhea and the long-term health consequences. Seminars in Reproductive Medicine, 35(3), 256–262. https://doi.org/10.1055/s-0037-1603581
Simoncini, T., Giannini, A., & Genazzani, A. R. (2017). The long-term cardiovascular risks associated with amenorrhea. In C. Sultan & A. R. Genazzani (Eds.), Frontiers in gynecological endocrinology (pp. 111–121). Springer. https://doi.org/10.1007/978-3-319-41433-1_10
Sowińska-Przepiera, E., Andrysiak-Mamos, E., Jarząbek-Bielecka, G., & others. (2015). Functional hypothalamic amenorrhoea — diagnostic challenges, monitoring, and treatment. Endokrynologia Polska, 66(5), 386–397. https://doi.org/10.5603/EP.2015.0033
Streicher, C., Heyny, A., Andrukhova, O., Haigl, B., Slavic, S., Schüler, C., et al. (2017). Estrogen regulates bone turnover by targeting RANKL expression in bone lining cells. Scientific Reports, 7, 6460. https://doi.org/10.1038/s41598-017-06614-0
Tegg, N. L., Myburgh, C., O'Donnell, E., Kennedy, M., & Norris, C. M. (2024). Impact of secondary amenorrhea on cardiovascular disease risk in physically active women: A systematic review and meta‐analysis. Journal of the American Heart Association, 13(6), e033154. https://doi.org/10.1161/JAHA.123.033154
Vukicevic, S., & Grgurevic, L. (2009). BMP-6 and mesenchymal stem cell differentiation. Cytokine & Growth Factor Reviews, 20(5–6), 441–448. https://doi.org/10.1016/j.cytogfr.2009.10.020
World Health Organization. (2020). WHO guidelines on physical activity and sedentary behaviour. World Health Organization. https://www.ncbi.nlm.nih.gov/books/NBK566046/
Young, E. R., & Jialal, I. (2023). Biochemistry, ghrelin. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK547692/
Zanker, C. L. (2006). Regulation of reproductive function in athletic women: An investigation of the roles of energy availability and body composition. British Journal of Sports Medicine, 40(6), 489–490. https://doi.org/10.1136/bjsm.2004.016758
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