FUNCTIONAL HYPOTHALAMIC AMENORRHEA - DIAGNOSTIC OVERLAP WITH PCOS AND ITS RELEVANCE IN THE FEMALE ATHLETE TRIAD: CURRENT CHALLENGES AND THERAPEUTIC STRATEGIES

Joanna Kaczor; Zuzanna Wróbel; Maja Torbacka; Katarzyna Rozkosz; Katarzyna Torbacka; Aleksandra Sosin; Natalia Wróbel; Wojciech Bednarz; Patrycja Podlejska; Olga Jakubik

doi:10.31435/ijitss.4(48).2025.4433

Authors

Joanna Kaczor Independent Public Healthcare Institution in Myślenice, Szpitalna 2, 32-400 Myślenice, Poland https://orcid.org/0009-0002-1714-2630
Zuzanna Wróbel The West Hospital in Grodzisk Mazowiecki, Daleka 11, 05-825 Grodzisk Mazowiecki, Poland https://orcid.org/0009-0005-7529-0641
Maja Torbacka Jagiellonian University Collegium Medicum, Świętej Anny 12, 31-008 Kraków, Poland https://orcid.org/0009-0000-7139-2134
Katarzyna Rozkosz Independent Public Health Care Center of the Ministry of the Interior and Administration in Katowice named after sergeant Grzegorz Załoga, Wita Stwosza 39-41, 40-042 Katowice, Poland https://orcid.org/0009-0000-3610-1901
Katarzyna Torbacka 5 Military Clinical Hospital with Polyclinic SPZOZ, Wrocławska 1/3, 30-901 Kraków, Poland https://orcid.org/0009-0002-7208-3725
Aleksandra Sosin Jagiellonian University Collegium Medicum, Świętej Anny 12, 31-008 Kraków, Poland https://orcid.org/0009-0008-0440-5431
Natalia Wróbel 5 Military Clinical Hospital with Polyclinic SPZOZ, Wrocławska 1/3, 30-901 Kraków, Poland https://orcid.org/0009-0005-9236-9802
Wojciech Bednarz Independent Public Healthcare Institution of the Ministry of the Interior and Administration in Kraków, Kronikarza Galla 25, 30-053 Kraków, Poland https://orcid.org/0009-0003-9522-6298
Patrycja Podlejska Independent Public Health Care Center of the Ministry of the Interior and Administration in Katowice named after sergeant Grzegorz Załoga, Wita Stwosza 39-41, 40-042 Katowice, Poland https://orcid.org/0009-0002-0074-9778
Olga Jakubik Praski Hospital, Sp. z o.o., al. "Solidarności" 67, 03-401 Warszawa, Poland https://orcid.org/0009-0006-4378-7087

DOI:

https://doi.org/10.31435/ijitss.4(48).2025.4433

Keywords:

Functional Hypothalamic Amenorrhea, Polycystic Ovary Syndrome, Female Athlete Triade, Amenorrhea

Abstract

Introduction and Purpose: Functional hypothalamic amenorrhea (FHA) accounts for a significant proportion of secondary amenorrhea and remains frequently overlooked, particularly in active women. Its clinical overlap with polycystic ovary syndrome (PCOS) complicates accurate diagnosis. In athletes, FHA arises primarily from low energy availability, forming a key component of the Female Athlete Triad. This review aims to summarize current evidence on the pathophysiology, diagnostic challenges, and therapeutic strategies for FHA, with emphasis on implications for women engaged in high levels of physical activity.

Methods: A narrative literature review was conducted using the PubMed database, covering publications from 2012 to 2025. Search terms included amenorrhea, functional hypothalamic amenorrhea, polycystic ovary syndrome, and female athlete triad. Thirty-two relevant sources were included.

Description of the State of Knowledge: FHA develops due to reduced pulsatile secretion of gonadotropin-releasing hormone (GnRH), resulting in suppressed LH and FSH release and impaired ovulation. Key contributing factors-energy deficit, excessive training, and psychological stress-disrupt neuroendocrine regulation and activate the hypothalamic-pituitary-adrenal axis. Recent studies highlight altered cortisol rhythms and changes in neurokinin B and nesfatin-1 as potential mechanisms. Differentiating FHA from PCOS remains a diagnostic challenge, particularly given the high prevalence of polycystic ovarian morphology in both conditions. Hormonal parameters such as SHBG, testosterone, and the LH:FSH ratio provide useful discrimination. Treatment focuses on restoring energy availability through nutritional rehabilitation and activity modification, supported by psychological interventions when indicated. For fertility restoration, pulsatile GnRH therapy offers a physiological approach, while IVF remains an effective alternative. Emerging options-including kisspeptin and L-carnitine-show promise in modulating neuroendocrine pathways.

Conclusion: FHA is a prevalent yet underrecognized condition with substantial reproductive and skeletal consequences. Early identification and multidisciplinary management are essential to improving long-term health outcomes, particularly among physically active women.

References

Beitl, K., Dewailly, D., Seemann, R., Hager, M., Bünker, J., Mayrhofer, D., Holzer, I., & Ott, J. (2022). Polycystic Ovary Syndrome Phenotype D Versus Functional Hypothalamic Amenorrhea With Polycystic Ovarian Morphology: A Retrospective Study About a Frequent Differential Diagnosis. Frontiers in Endocrinology, 13. https://doi.org/10.3389/fendo.2022.904706

Berz, K., & McCambridge, T. (2016). Amenorrhea in the Female Athlete: What to Do and When to Worry. Pediatric Annals, 45(3), e97–e102. https://doi.org/10.3928/00904481-20160210-03

Boegl, M., Dewailly, D., Marculescu, R., Steininger, J., Ott, J., & Hager, M. (2024). The LH:FSH Ratio in Functional Hypothalamic Amenorrhea: An Observational Study. Journal of Clinical Medicine, 13(5). https://doi.org/10.3390/jcm13051201

Carmina, E., Fruzzetti, F., & Lobo, R. A. (2016). Increased anti-Mullerian hormone levels and ovarian size in a subgroup of women with functional hypothalamic amenorrhea: Further identification of the link between polycystic ovary syndrome and functional hypothalamic amenorrhea. American Journal of Obstetrics and Gynecology, 214(6), 714.e1-714.e6. https://doi.org/10.1016/j.ajog.2015.12.055

Christou, F., Pitteloud, N., & Gomez, F. (2017). The induction of ovulation by pulsatile administration of GnRH: an appropriate method in hypothalamic amenorrhea. Gynecological Endocrinology, 33(8), 598–601. https://doi.org/10.1080/09513590.2017.1296948

De Souza, M. J., Nattiv, A., Joy, E., Misra, M., Williams, N. I., Mallinson, R. J., Gibbs, J. C., Olmsted, M., Goolsby, M., & Matheson, G. (2014). 2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International conference held in San Francisco, California, May 2012 and 2nd International conference held in Indianapolis, Indiana, May 2013. British Journal of Sports Medicine, 48(4), 289. https://doi.org/10.1136/bjsports-2013-093218

Dumont, A., Dewailly, D., Plouvier, P., Catteau-Jonard, S., & Robin, G. (2016). Does polycystic ovarian morphology influence the response to treatment with pulsatile GnRH in functional hypothalamic amenorrhea? Reproductive Biology and Endocrinology, 14(1). https://doi.org/10.1186/s12958-016-0159-8

Genazzani, A. D., Despini, G., Czyzyk, A., Podfigurna, A., Simoncini, T., & Meczekalski, B. (2017). Modulatory effects of l-carnitine plus l-acetyl-carnitine on neuroendocrine control of hypothalamic functions in functional hypothalamic amenorrhea (FHA). Gynecological Endocrinology, 33(12), 963–967. https://doi.org/10.1080/09513590.2017.1332587

Genazzani, A. D., Podfigurna-Stopa, A., Czyzyk, A., Katulski, K., Prati, A., Despini, G., Angioni, S., Simoncini, T., & Meczekalski, B. (2016). Short-term estriol administration modulates hypothalamo-pituitary function in patients with functional hypothalamic amenorrhea (FHA). Gynecological Endocrinology, 32(3), 253–257. https://doi.org/10.3109/09513590.2015.1118452

Gordon, C. M., Ackerman, K. E., Berga, S. L., Kaplan, J. R., Mastorakos, G., Misra, M., Murad, M. H., Santoro, N. F., & Warren, M. P. (2017). Functional hypothalamic amenorrhea: An endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism, 102(5), 1413–1439. https://doi.org/10.1210/jc.2017-00131

Hager, M., Dewailly, D., Marculescu, R., Ghobrial, S., Parry, J. P., & Ott, J. (2023). Stress and polycystic ovarian morphology in functional hypothalamic amenorrhea: a retrospective cohort study. Reproductive Biology and Endocrinology, 21(1). https://doi.org/10.1186/s12958-023-01095-5

Hager, M., Ott, J., Marschalek, J., Marschalek, M. L., Kinsky, C., Marculescu, R., & Dewailly, D. (2022). Basal and dynamic relationships between serum anti-Müllerian hormone and gonadotropins in patients with functional hypothalamic amenorrhea, with or without polycystic ovarian morphology. Reproductive Biology and Endocrinology, 20(1). https://doi.org/10.1186/s12958-022-00961-y

Holzer, I., Marculescu, R., Begemann, V., Haaser, S., Dewailly, D., & Ott, J. (2024). Prevalence of functional hypothalamic amenorrhea in a cohort of women referred because of polycystic ovary syndrome. Reproductive Medicine and Biology, 23(1). https://doi.org/10.1002/rmb2.12591

Jayasena, C. N., Abbara, A., Veldhuis, J. D., Comninos, A. N., Ratnasabapathy, R., De Silva, A., Nijher, G. M. K., Ganiyu-Dada, Z., Mehta, A., Todd, C., Ghatei, M. A., Bloom, S. R., & Dhillo, W. S. (2014). Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of kisspeptin-54. Journal of Clinical Endocrinology and Metabolism, 99(6). https://doi.org/10.1210/jc.2013-1569

Koltun, K. J., de Souza, M. J., Scheid, J. L., & Williams, N. I. (2020). Energy availability is associated with luteinizing hormone pulse frequency and induction of luteal phase defects. Journal of Clinical Endocrinology and Metabolism, 105(1), 185–193. https://doi.org/10.1210/clinem/dgz030

Koukoubanis, K., Stefanaki, K., Karagiannakis, D. S., Kalampalikis, A., & Michala, L. (2023). Comparison of salivary cortisol levels between women with functional hypothalamic amenorrhea and healthy women: a pilot study. Endocrine, 82(2), 399–405. https://doi.org/10.1007/s12020-023-03448-x

Łagowska, K., Strock, N. C. A., Koltun, K. J., Williams, N. I., & De Souza, M. J. (2022). Association of diet quality and hormonal status in exercising women with menstrual disturbances. Applied Physiology, Nutrition, and Metabolism, 47(11), 1085–1095. https://doi.org/10.1139/apnm-2021-0789

Lawson, E. A., Ackerman, K. E., Estella, N. M., Guereca, G., Pierce, L., Sluss, P. M., Bouxsein, M. L., Klibanski, A., & Misra, M. (2013). Nocturnal oxytocin secretion is lower in amenorrheic athletes than nonathletes and associated with bone microarchitecture and finite element analysis parameters. European Journal of Endocrinology / European Federation of Endocrine Societies, 168(3), 457–464. https://doi.org/10.1530/EJE-12-0869

Lawson, E. A., Ackerman, K. E., Slattery, M., Marengi, D. A., Clarke, H., & Misra, M. (2014). Oxytocin secretion is related to measures of energy homeostasis in young amenorrheic athletes. Journal of Clinical Endocrinology and Metabolism, 99(5). https://doi.org/10.1210/jc.2013-4136

Lord, M., Jenkins, S. M., & Sahni, M. (2025). Secondary Amenorrhea.

Lu, Y., Lu, P., Lin, L., Chen, H., Zhang, F., & Li, X. (2024). Characteristics of bone mineral density in patients with functional hypothalamic amenorrhoea and its association with reproductive hormones and body composition. Clinical Endocrinology, 100(4), 358–365. https://doi.org/10.1111/cen.15016

Michopoulos, V., Mancini, F., Loucks, T. L., & Berga, S. L. (2013). Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: A randomized, controlled trial. Fertility and Sterility, 99(7). https://doi.org/10.1016/j.fertnstert.2013.02.036

Mountjoy, M., Sundgot-Borgen, J. K., Burke, L. M., Ackerman, K. E., Blauwet, C., Constantini, N., Lebrun, C., Lundy, B., Melin, A. K., Meyer, N. L., Sherman, R. T., Tenforde, A. S., Torstveit, M. K., & Budgett, R. (2018). IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. British Journal of Sports Medicine, 52(11), 687–697. https://doi.org/10.1136/bjsports-2018-099193

Munro, M. G., Balen, A. H., Cho, S. H., Critchley, H. O. D., Díaz, I., Ferriani, R., Henry, L., Mocanu, E., & van der Spuy, Z. M. (2022). The FIGO ovulatory disorders classification system. International Journal of Gynecology and Obstetrics, 159(1), 1–20. https://doi.org/10.1002/ijgo.14331

Notaristefano, G., Merola, A., Scarinci, E., Ubaldi, N., Ranalli, M., Tropea, A., Diterlizzi, A., Fabozzi, S. M., Alesiani, O., Silvestrini, A., Mordente, A., Capristo, E., Lanzone, A., & Apa, R. (2022). Circulating irisin levels in functional hypothalamic amenorrhea: a new bone damage index? A pilot study. Endocrine, 77(1), 168–176. https://doi.org/10.1007/s12020-022-03050-7

Notaristefano, G., Ponziani, F. R., Ranalli, M., Diterlizzi, A., Policriti, M. A., Stella, L., Del Zompo, F., Fianchi, F., Picca, A., Petito, V., Del Chierico, F., Scanu, M., Toto, F., Putignani, L., Marzetti, E., Ferrarese, D., Mele, M. C., Merola, A., Tropea, A., … Apa, R. (2024). Functional hypothalamic amenorrhea: gut microbiota composition and the effects of exogenous estrogen administration. American Journal of Physiology-Endocrinology and Metabolism, 326(2), E166–E177. https://doi.org/10.1152/ajpendo.00281.2023

Quaas, P., Quaas, A. M., Fischer, M., & De Geyter, C. (2022). 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, 39(12), 2729–2736. https://doi.org/10.1007/s10815-022-02656-0

Robin, G., Gallo, C., Catteau-Jonard, S., Lefebvre-Maunoury, C., Pigny, P., Duhamel, A., & Dewailly, D. (2012). Polycystic Ovary-Like Abnormalities (PCO-L) in Women with Functional Hypothalamic Amenorrhea. The Journal of Clinical Endocrinology & Metabolism, 97(11), 4236–4243. https://doi.org/10.1210/jc.2012-1836

Selzer, C., Ott, J., Dewailly, D., Marculescu, R., Steininger, J., & Hager, M. (2024). Prolactin levels in functional hypothalamic amenorrhea: a retrospective case–control study. Archives of Gynecology and Obstetrics, 309(2), 651–658. https://doi.org/10.1007/s00404-023-07277-1

Szeliga, A., Podfigurna, A., Bala, G., & Meczekalski, B. (2023). Decreased neurokinin B as a risk factor of functional hypothalamic amenorrhea. Gynecological Endocrinology, 39(1). https://doi.org/10.1080/09513590.2023.2216313

Szeliga, A., Podfigurna, A., & Meczekalski, B. (2022). Nesfatin-1 as a potential marker for functional hypothalamic amenorrhea. Gynecological Endocrinology, 38(11), 992–996. https://doi.org/10.1080/09513590.2022.2126455

Zhang, C. M., Zhang, H., Yang, R., Chen, L. X., Liu, P., Li, R., Qiao, J., & Wang, Y. (2022). The Reproductive Outcome of Women with Hypogonadotropic Hypogonadism in IVF. Frontiers in Endocrinology, 13. https://doi.org/10.3389/fendo.2022.850126