Pape Janna, Herbison A E, Leeners B
Department of Reproductive Endocrinology, University Hospital Zurich, 8091 Zurich, Switzerland.
Department of Physiology, Development and Neuroscience, University of Cambridge CB2 3EG, UK.
Hum Reprod Update. 2021 Jan 4;27(1):130-153. doi: 10.1093/humupd/dmaa032.
Prolonged amenorrhoea occurs as a consequence of functional hypothalamic amenorrhoea (FHA) which is most often induced by weight loss, vigorous exercise or emotional stress. Unfortunately, removal of these triggers does not always result in the return of menses. The prevalence and conditions underlying the timing of return of menses vary strongly and some women report amenorrhoea several years after having achieved and maintained normal weight and/or energy balance. A better understanding of these factors would also allow improved counselling in the context of infertility. Although BMI, percentage body fat and hormonal parameters are known to be involved in the initiation of the menstrual cycle, their role in the physiology of return of menses is currently poorly understood. We summarise here the current knowledge on the epidemiology and physiology of return of menses.
The aim of this review was to provide an overview of (i) factors determining the recovery of menses and its timing, (ii) how such factors may exert their physiological effects and (iii) whether there are useful therapeutic options to induce recovery.
We searched articles published in English, French or German language containing keywords related to return of menses after FHA published in PubMed between 1966 and February 2020. Manuscripts reporting data on either the epidemiology or the physiology of recovery of menses were included and bibliographies were reviewed for further relevant literature. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria served to assess quality of observational studies.
Few studies investigate return of menses and most of them have serious qualitative and methodological limitations. These include (i) the lack of precise definitions for FHA or resumption of menses, (ii) the use of short observation periods with unsatisfactory descriptions and (iii) the inclusion of poorly characterised small study groups. The comparison of studies is further hampered by very inhomogeneous study designs. Consequently, the exact prevalence of resumption of menses after FHA is unknown. Also, the timepoint of return of menses varies strongly and reliable prediction models are lacking. While weight, body fat and energy availability are associated with the return of menses, psychological factors also have a strong impact on the menstrual cycle and on behaviour known to increase the risk of FHA. Drug therapies with metreleptin or naltrexone might represent further opportunities to increase the chances of return of menses, but these require further evaluation.
Although knowledge on the physiology of return of menses is presently rudimentary, the available data indicate the importance of BMI/weight (gain), energy balance and mental health. The physiological processes and genetics underlying the impact of these factors on the return of menses require further research. Larger prospective studies are necessary to identify clinical parameters for accurate prediction of return of menses as well as reliable therapeutic options.
功能性下丘脑性闭经（FHA）可导致长期闭经，FHA最常见的诱因是体重减轻、剧烈运动或情绪压力。遗憾的是，去除这些诱因并不总能使月经恢复。月经恢复的患病率及相关情况差异很大，一些女性在体重和/或能量平衡恢复正常并维持数年之后仍有闭经现象。更好地了解这些因素有助于在不孕症咨询中提供更优质的建议。虽然已知体重指数（BMI）、体脂百分比和激素参数与月经周期的启动有关，但它们在月经恢复生理过程中的作用目前尚不清楚。在此，我们总结当前关于月经恢复的流行病学和生理学的知识。
本综述旨在概述：（i）决定月经恢复及其时间的因素；（ii）这些因素如何发挥生理作用；（iii）是否存在有效的诱导月经恢复的治疗方法。
我们检索了1966年至2020年2月期间发表在PubMed上的英文、法文或德文文章，这些文章包含与FHA后月经恢复相关的关键词。纳入报告月经恢复流行病学或生理学数据的手稿，并查阅参考文献以获取更多相关文献。采用加强流行病学观察性研究报告（STROBE）标准评估观察性研究的质量。
很少有研究调查月经恢复情况，且大多数研究存在严重的定性和方法学局限性。这些局限性包括：（i）对FHA或月经恢复缺乏精确的定义；（ii）观察期较短且描述不充分；（iii）纳入的研究小组特征不明确且规模较小。研究设计的极不均匀性进一步阻碍了研究间的比较。因此，FHA后月经恢复的确切患病率尚不清楚。此外，月经恢复的时间点差异很大，且缺乏可靠的预测模型。虽然体重、体脂和能量供应与月经恢复有关，但心理因素对月经周期以及已知会增加FHA风险的行为也有很大影响。使用米替普明或纳曲酮进行药物治疗可能为增加月经恢复的机会提供更多选择，但这些都需要进一步评估。
虽然目前关于月经恢复生理学的知识尚不完善，但现有数据表明BMI/体重（增加）、能量平衡和心理健康的重要性。这些因素对月经恢复产生影响的生理过程和遗传学需要进一步研究。需要开展更大规模的前瞻性研究，以确定准确预测月经恢复的临床参数以及可靠的治疗方法。
