低能量可用性与功能性下丘脑性闭经的相关性进展

doi:10.12280/gjszjk.20260145

摘要/Abstract

摘要：

功能性下丘脑性闭经（functional hypothalamic amenorrhea，FHA）是一种中枢性、非器质性、可逆性闭经，由体内外各种因素，如能量摄入不足、过度运动、心理应激及遗传易感性，诱发下丘脑-垂体-卵巢（hypothalamic-pituitary-ovarian，HPO）轴功能抑制所致。近年来，低能量可用性（low energy availability，LEA）为理解FHA的发生提供了理论框架。机体LEA时会启动适应性反应机制，优先维持生命必需功能，同时抑制高能耗的生殖活动，表现为外周代谢信号水平改变及下丘脑Kisspeptin/神经激肽B/强啡肽（Kisspeptin/neurokinin B/dynorphin，KNDy）神经元功能受损，最终导致促性腺激素释放激素脉冲分泌障碍及HPO轴功能减退。基于改善LEA治疗FHA的策略，恢复能量可用性是核心，基础治疗以生活方式干预为主，包括营养支持、合理运动和心理干预；此外，基于Kisspeptin及其受体的靶向治疗也展现出潜在应用前景。

关键词: 低能量可用性, 闭经, 功能性下丘脑性闭经, Kisspeptin/神经激肽B/强啡肽神经元, 促性腺素释放激素, 下丘脑-垂体系统

Abstract:

Functional hypothalamic amenorrhea (FHA) is a central, non-organic, and reversible form of amenorrhea, resulting from the suppression of hypothalamic-pituitary-ovarian (HPO) axis induced by various intrinsic and extrinsic factors, such as insufficient energy intake, excessive physical activity, psychological stress, and genetic susceptibility. In recent years, low energy availability (LEA) has provided a unifying theoretical framework for understanding the pathophysiology of FHA. Under LEA, the body initiates adaptive responses that prioritize vital physiological functions while suppressing energy-demanding reproductive processes. These adaptations are characterized by the alterations in peripheral metabolic signals and impaired function of hypothalamic Kisspeptin/neurokinin B/dynorphin (KNDy) neurons, ultimately leading to the disrupted gonadotropin-releasing hormone (GnRH) pulsatility and the attenuation of HPO axis function. Based on improving LEA, strategies for treating the FHA primarily focus on restoring energy availability. First-line management mainly involves lifestyle interventions, including nutritional support, appropriate exercise modification, and psychological intervention. In addition, the targeted therapies involving Kisspeptin and its receptor have also shown a potential therapeutic prospect.

Key words: Low energy availability, Amenorrhea, Functional hypothalamic amenorrhea, Kisspeptin/neurokinin B/dynorphin neurons, Gonadotropin-releasing hormone, Hypothalamo-hypophyseal system

张宇, 丁雪松, 郭瀛瀛, 薛薇, 王阳, 孙爱军. 低能量可用性与功能性下丘脑性闭经的相关性进展[J]. 国际生殖健康/计划生育杂志, 2026, 45(4): 336-341.

ZHANG Yu, DING Xue-song, GUO Ying-ying, XUE Wei, WANG Yang, SUN Ai-jun. Advances in the Relationship between Low Energy Availability and Functional Hypothalamic Amenorrhea[J]. Journal of International Reproductive Health/Family Planning, 2026, 45(4): 336-341.

参考文献 42

[1]	马世月, 朱梅. 功能性下丘脑性闭经研究进展[J]. 国际生殖健康/计划生育杂志, 2020, 39(1):67-70. doi: 10.3969/j.issn. 1674-1889.2020.01.015.
[2]	Shufelt CL, Torbati T, Dutra E. Hypothalamic Amenorrhea and the Long-Term Health Consequences[J]. Semin Reprod Med, 2017, 35(3):256-262. doi: 10.1055/s-0037-1603581. pmid: 28658709
[3]	Saadedine M, Kapoor E, Shufelt C. Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis[J]. Mayo Clin Proc, 2023, 98(9):1376-1385. doi: 10.1016/j.mayocp.2023.05.027. pmid: 37661145
[4]	De Souza MJ, Williams NI, Misra M, et al. 2025 Update to the Female Athlete Triad Coalition Consensus Statement Part 1: State of the Science and Introduction of a New Adolescent Model[J]. Sports Med, 2026, 56(2):327-373. doi: 10.1007/s40279-025-02333-z.
[5]	Jeppesen JS, Hellsten Y, Melin AK, et al. Short-Term Severe Low Energy Availability in Athletes: Molecular Mechanisms, Endocrine Responses, and Performance Outcomes-A Narrative Review[J]. Scand J Med Sci Sports, 2025, 35(6):e70089. doi: 10.1111/sms.70089.
[6]	Patel AH, Koysombat K, Pierret A, et al. Kisspeptin in functional hypothalamic amenorrhea: Pathophysiology and therapeutic potential[J]. Ann N Y Acad Sci, 2024, 1540(1):21-46. doi: 10.1111/nyas.15220.
[7]	Moore AM, Coolen LM, Lehman MN. Kisspeptin/Neurokinin B/Dynorphin (KNDy) cells as integrators of diverse internal and external cues: evidence from viral-based monosynaptic tract-tracing in mice[J]. Sci Rep, 2019, 9(1):14768. doi: 10.1038/s41598-019-51201-0. pmid: 31611573
[8]	Funcke JB, Scherer PE. Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication[J]. J Lipid Res, 2019, 60(10):1648-1684. doi: 10.1194/jlr.R094060.
[9]	Hofmann T, Elbelt U, Haas V, et al. Plasma kisspeptin and ghrelin levels are independently correlated with physical activity in patients with anorexia nervosa[J]. Appetite, 2017, 108:141-150. doi: 10.1016/j.appet.2016.09.032. pmid: 27693487
[10]	Konvička J, Káňová M, Borzenko N, et al. Low Energy Availability and Its Impact on Bone Health and Metabolism in Athletes: A Narrative Review[J]. Physiol Res, 2025, 74(Suppl 1):S19-S35. doi: 10.33549/physiolres.935749.
[11]	Fields JB, Jones MT, Kitts SE, et al. Relationships Between Disordered Eating, Body Dissatisfaction, and Low Energy Availability in Women Collegiate Athletes[J]. J Strength Cond Res, 2026, 40(2):e164-e171. doi: 10.1519/JSC.0000000000005281.
[12]	Logue DM, Madigan SM, Melin A, et al. Low Energy Availability in Athletes 2020: An Updated Narrative Review of Prevalence, Risk, Within-Day Energy Balance, Knowledge, and Impact on Sports Performance[J]. Nutrients, 2020, 12(3):835. doi: 10.3390/nu12030835.
[13]	Torres Dos Ramos A, Bellver M, Esquius L, et al. Prevalence of physically active females at risk for the female athlete triad in Spain[J]. J Int Soc Sports Nutr, 2025, 22(1):2590641. doi: 10.1080/15502783.2025.2590641.
[14]	Miles M, Pritchett K, Pritchett R, et al. Risk of low energy availability, disordered eating, and menstrual dysfunction in female recreational runners[J]. Women Sport Phys Act J, 2024, 32(1): wspaj.2023-0100. doi: 10.1123/wspaj.2023-0100.
[15]	Puscheck LJ, Kennel J, Saenz C. Evaluating the prevalence of eating disorder risk and low energy availability risk in collegiate athletes[J]. J Eat Disord, 2025, 13(1):53. doi: 10.1186/s40337-025-01218-w. pmid: 40119446
[16]	Dobranowska K, Plińska S, Dobosz A. Dietary and Lifestyle Management of Functional Hypothalamic Amenorrhea: A Comprehensive Review[J]. Nutrients, 2024, 16(17):2967. doi: 10.3390/nu16172967.
[17]	Reed JL, De Souza MJ, Mallinson RJ, et al. Energy availability discriminates clinical menstrual status in exercising women[J]. J Int Soc Sports Nutr, 2015, 12:11. doi: 10.1186/s12970-015-0072-0.
[18]	Koltun KJ, De Souza MJ, Scheid JL, et al. Energy Availability Is Associated With Luteinizing Hormone Pulse Frequency and Induction of Luteal Phase Defects[J]. J Clin Endocrinol Metab, 2020, 105(1):185-193. doi: 10.1210/clinem/dgz030.
[19]	徐仰英, 郝翠芳, 张玉, 等. KNDy神经元在女性生殖内分泌中的研究与应用[J]. 国际妇产科学杂志, 2021, 48(3):300-304. doi: 10.12280/gjfckx.20200671.
[20]	孙凌宇, 严翊, 陈静. 下丘脑Kiss1神经元在能量代谢调节中的作用[J]. 生物化学与生物物理进展, 2023, 50(11):2559-2569. doi: 10.16476/j.pibb.2022.0468.
[21]	Szeliga A, Podfigurna A, Bala G, et al. The influence of estro-progestin therapy on neurohormonal activity in functional hypothalamic amenorrhea[J]. Gynecol Endocrinol, 2022, 38(11):997-1002. doi: 10.1080/09513590.2022.2128103.
[22]	Tsuchida H, Mostari P, Yamada K, et al. Paraventricular Dynorphin A Neurons Mediate LH Pulse Suppression Induced by Hindbrain Glucoprivation in Female Rats[J]. Endocrinology, 2020, 161(11):bqaa161. doi: 10.1210/endocr/bqaa161.
[23]	Podfigurna A, Szeliga A, Meczekalski B. Serum kisspeptin and corticotropin-releasing hormone levels in patients with functional hypothalamic amenorrhea[J]. GREM, 2020, 1(1):37-42. doi:10.53260/grem.201017.
[24]	Fontana A, Vieira JG, Vianna JM, et al. Reduction of leptin levels during acute exercise is dependent on fasting but not on caloric restriction during chronic exercise: A systematic review and meta-analysis[J]. PLoS One, 2023, 18(11):e0288730. doi: 10.1371/journal.pone.0288730.
[25]	Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa[J]. Lancet, 2005, 366(9479):74-85. doi:10.1016/S0140-6736(05)66830-4. pmid: 15993236
[26]	Holtkamp K, Mika C, Grzella I, et al. Reproductive function during weight gain in anorexia nervosa: leptin represents a metabolic gate to gonadotropin secretion[J]. J Neural Transm(Vienna), 2003, 110(4):427-435. doi:10.1007/s00702-002-0800-x.
[27]	Mallinson RJ, Williams NI, Olmsted MP, et al. A case report of recovery of menstrual function following a nutritional intervention in two exercising women with amenorrhea of varying duration[J]. J Int Soc Sports Nutr, 2013, 10:34. doi: 10.1186/1550-2783-10-34.
[28]	Schneider LF, Warren MP. Functional hypothalamic amenorrhea is associated with elevated ghrelin and disordered eating[J]. Fertil Steril, 2006, 86(6):1744-1749. doi: 10.1016/j.fertnstert.2006. 05.051. pmid: 17074331
[29]	Kluge M, Schüssler P, Schmidt D, et al. Ghrelin suppresses secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in women[J]. J Clin Endocrinol Metab, 2012, 97(3):E448-E451. doi: 10.1210/jc.2011-2607.
[30]	Frazao R, Dungan Lemko HM, da Silva RP, et al. Estradiol modulates Kiss1 neuronal response to ghrelin[J]. Am J Physiol Endocrinol Metab, 2014, 306(6):E606-E614. doi: 10.1152/ajpendo.00211.2013.
[31]	Kluess HA, Neidert LE, Sandage MJ, et al. Neuropeptide Y and dipeptidyl peptidase IV in normally cycling and postmenopausal women: A prospective pilot study[J]. Medicine(Baltimore), 2019, 98(13):e14982. doi: 10.1097/MD.0000000000014982.
[32]	Chen X, Xiao Z, Cai Y, et al. Hypothalamic mechanisms of obesity-associated disturbance of hypothalamic-pituitary-ovarian axis[J]. Trends Endocrinol Metab, 2022, 33(3):206-217. doi: 10.1016/j.tem.2021.12.004.
[33]	Szeliga A, Podfigurna A, Meczekalski B. Nesfatin-1 as a potential marker for functional hypothalamic amenorrhea[J]. Gynecol Endocrinol, 2022, 38(11):992-996. doi: 10.1080/09513590. 2022.2126455.
[34]	Delaney A, Burkholder AB, Lavender CA, et al. Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea[J]. J Clin Endocrinol Metab, 2021, 106(3):e1441-e1452. doi: 10.1210/clinem/dgaa609.
[35]	Neyazi A, Buchholz V, Burkert A, et al. Association of leptin gene DNA methylation with diagnosis and treatment outcome of anorexia nervosa[J]. Front Psychiatry, 2019, 10:197. doi:10.3389/fpsyt.2019.00197. pmid: 31031654
[36]	Gordon CM, Ackerman KE, Berga SL, et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline[J]. J Clin Endocrinol Metab, 2017, 102(5):1413-1439. doi: 10.1210/jc.2017-00131. pmid: 28368518
[37]	El Ghoch M, Calugi S, Chignola E, et al. Body fat and menstrual resumption in adult females with anorexia nervosa: a 1-year longitudinal study[J]. J Hum Nutr Diet, 2016, 29(5):662-666. doi: 10.1111/jhn.12373. pmid: 27230963
[38]	Amoroso AP, Fiorini S, Lopes Neri LC, et al. Functional hypothalamic amenorrhea and dietary intervention: A systematic review to guide further research in amenorrheic women without overt eating disorder[J]. Nutr Res, 2025, 140:102-115. doi: 10.1016/j.nutres.2025.06.008. pmid: 40682949
[39]	De Souza MJ, Mallinson RJ, Strock NCA, et al. Randomised controlled trial of the effects of increased energy intake on menstrual recovery in exercising women with menstrual disturbances: the 'REFUEL' study[J]. Hum Reprod, 2021, 36(8):2285-2297. doi: 10.1093/humrep/deab149.
[40]	Hakimi O, Cameron LC. Effect of Exercise on Ovulation: A Systematic Review[J]. Sports Med, 2017, 47(8):1555-1567. doi: 10.1007/s40279-016-0669-8. pmid: 28035585
[41]	Tranoulis A, Soldatou A, Georgiou D, et al. Adolescents and young women with functional hypothalamic amenorrhoea: is it time to move beyond the hormonal profile?[J]. Arch Gynecol Obstet, 2020, 301(4):1095-1101. doi: 10.1007/s00404-020-05499-1. pmid: 32179966
[42]	Kotanidou S, Nikolettos N, Kritsotaki N, et al. Kisspeptins Regulating Fertility: Potential Future Therapeutic Approach in Infertility Treatment[J]. J Clin Med, 2025, 14(10):3284. doi: 10.3390/jcm14103284.