Genetic Determinants of Hypothalamic Amenorrhea

功能性下丘脑性闭经（HA）是一种可逆的低促性腺激素性腺功能减退症，定义为在没有妊娠、雄激素过多、高泌乳素血症或甲状腺或其他内分泌功能障碍的情况下闭经3-6个月。流行病学研究将HA定义为闭经3个月且无少经病史（与多囊卵巢综合征更一致），表明人群患病率为4.5%。HA表现为不同模式的LH脉冲分泌不足，提示GnRH分泌功能障碍。HA的临床过程可能会随着时间的推移而改变，在疾病过程中的某些时候，由于对阿托伐他汀的反应而发生撤退性出血，或者由于对克罗米芬的反应而发生卵泡发育（两者都表明一定程度的雌激素暴露），但在其他时候则不会。LH脉冲分泌的模式也可能随时间而改变。在选定人群中的研究表明，HA的患病率显着较高，与运动，亚临床饮食失调和年轻的生育年龄。 其他研究表明，心理特征，压力和/或下丘脑-垂体-肾上腺（HPA）轴的激活也可能在HA中发挥作用。 外周信号将进食和整体营养状态的信息传递到下丘脑，不仅影响饱腹感和代谢平衡，而且影响生殖控制。同样，营养和心理压力都会影响生殖途径，有证据表明至少有一些代谢信号通过压力途径发挥作用。 这是临床和科学的重要性，有显着的临床异质性的反应，个别妇女显然相似的危险因素。例如，在Frisch关于身高体重的研究中，在一个165 cm的继发性闭经女孩中，与月经恢复相关的95%置信限范围为43-60 kg。同样，在对中距离跑步者的研究中，闭经的百分比与每周跑步的英里数呈正相关，但即使每周跑步80英里，也只有50%的运动员患有闭经。在HA 52的良好对照非人灵长类动物模型中，也观察到代谢缺陷背景下对轻度应激反应的个体间差异。因此，有重要的证据表明，女性的生殖轴对运动、体重变化和压力的敏感性各不相同。 一个相对较小的组与HA患者进行了7个GnRH相关基因的测序，以确定这些基因的突变是否可能从完全的GnRH缺乏症患者的轻度表型。本研究在55例HA女性中的7例中发现了6种杂合突变，总体患病率为13%。在422名健康对照女性中未发现这些变异。这项研究表明，在继发性闭经和功能性HA患者中，也可观察到与先天性HH相关的基因中的杂合罕见变异。最近，与公开数据库相比，在KS/nIHH中鉴定的基因中的罕见序列变异（RSV）在体质性青春期延迟（CDP）患者中的比例过高，这提供了另一种情况，即在KS/nIHH罕见疾病中鉴定的这些基因可能导致更常见的疾病。 这些已发表的研究支持我们的总体假设，即遗传易感性可能有助于生殖系统对导致HA的生理应激反应的变异性。 然而，由于样本量小以及HA和GnRH基因初步研究中使用的分析策略，需要进行进一步的研究，这在今天的标准下是不可接受的。上述涉及CDP受试者的研究提供了一些信心，即我们先前在HA患者中的发现实际上可以通过更先进的分析方法得到证实。这一发现可能对筛查有或无HA危险因素的闭经妇女有意义，并可能改善HA妇女生育结局的预测。 我们的手稿“下丘脑闭经妇女GnRH相关基因中罕见序列变异的负担增加”现已被临床内分泌学和代谢杂志接受出版。

Functional hypothalamic amenorrhea (HA) is a reversible form of hypgonadotropic hypogonadism that is defined by 3-6 months of amenorrhea in the absence of pregnancy, androgen excess, hyperprolactinemia or thyroid or other endocrine dysfunction. Epidemiologic studies that define HA as 3 months of amenorrhea in the absence of a history of oligoamenorrhea (which is more consistent with polycystic ovarian syndrome), suggest a population prevalence of 4.5%. HA is manifest by variable patterns of deficient pulsatile LH secretion, indicative of GnRH secretory dysfunction. The clinical course of HA may change over time with withdrawal bleeding in response to a progestin or follicle development in response to clomiphene citrate (both indicative of some degree of estrogen exposure) at some times over the course of the disorder, but not at others. The pattern of pulsatile LH secretion may also change over time. Studies in select populations indicate that the prevalence of HA is significantly higher in association with exercise, subclinical eating disorders and younger reproductive age. Other studies suggest that psychological characteristics, stress and/or activation of the hypothalamic-pituitary-adrenal (HPA) axis may also play a role in HA. Peripheral signals convey information about feeding and overall nutritional state to the hypothalamus that influence not only satiety and metabolic balance, but also reproductive control. Similarly, both nutritional and psychological stress impact reproductive pathways and there is evidence that at least some metabolic signaling operates through stress pathways. It is of both clinical and scientific importance that there is significant clinical heterogeneity in the response of individual women to apparently similar risk factors. For example, in the Frisch studies of weight for height, in a girl of 165 cm with secondary amenorrhea, the 95% confidence limits associated with resumption of menses ranged from 43-60 kg. Likewise, in studies of middle distance runners, percent amenorrhea was positively associated with miles run per week, but even at 80 miles per week, only 50% of athletes were amenorrheic. Inter-individual variability in the response to mild stress in the setting of metabolic deficiency was also noted in the well-controlled non-human primate model of HA 52. Thus there is significant evidence that women vary in the susceptibility of the reproductive axis to exercise, weight changes, and stress. A relatively small group of patients with HA were sequenced for 7 GnRH-related genes to determine whether mutations in these genes might extend from complete patients with complete GnRH deficiency to milder phenotypes. This study identified six heterozygous mutations in 7 of the 55 HA women for an overall prevalence of 13%. These variants were not identified in 422 healthy control women. This study indicated that heterozygous rare variants in genes associated with congenital forms of HH may also be seen in patients with secondary amenorrhea and functional HA. More recently rare sequence variants (RSVs) in genes identified in KS/nIHH were shown to be overrepresented in patients with constitutional delay of puberty (CDP) when compared with the publicly available databases, providing another setting in which these genes identified in the rare disorders of KS/nIHH may contribute to more common disorders. These published studies support our overall hypothesis that genetic susceptibility may contribute to the variability in the reproductive system response to physiologic stresses that results in HA. However, further studies are needed due to both the small sample size and the analysis strategy used in the initial study of HA and GnRH genes that would not be acceptable by todays standards. The above study involving subjects with CDP provides some confidence that our previous findings in patients with HA may in fact be confirmed with more current analytic methodologies. Such a finding could have implications for screening women with amenorrhea with or without risk factors for HA and may allow for improved prediction of fertility outcomes for women with HA. Our manuscript "Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women with Hypothalamic Amenorrhea" has now been accepted for publication in the Journal of Clinical Endocrinology and Metabolism.