Genetic Determinants of Hypothalamic Amenorrhea

下丘脑闭经的遗传决定因素

• 批准号: 10696796
• 负责人: Janet Hall
• 金额: $ 4.9万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696796
• 关键词: Age; Amenorrhea; Bioinformatics; Body Weight; Body Weight Changes; Characteristics; Clinical; Clinical Endocrinology; Clomiphene Citrate; Collaborations; Computer software; Constitutional; Control Groups; Data; Delayed Puberty; Development; Discrimination; Disease; Eating Disorders; Endocrine; Endocrinology; Environmental Risk Factor; Equilibrium; Estrogens; Exercise; Female; Fertility; Functional disorder; GNRH1 gene; Genes; Genetic Determinism; Genetic Diseases; Genetic Predisposition to Disease; Height; Hemorrhage; Hyperprolactinemia; Hypogonadism; Hypothalamic structure; Individual; Journals; Manuscripts; Menstruation; Metabolic; Metabolic stress; Methodology; Modeling; Mutation; National Human Genome Research Institute; Nutritional; Outcome; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Play; Polycystic Ovary Syndrome; Population; Predisposition; Pregnancy; Prevalence; Progestins; Psychological Stress; Publications; Publishing; Quality Control; Questionnaires; Rare Diseases; Recording of previous events; Reproductive system; Research; Research Personnel; Risk; Risk Factors; Role; Running; Sample Size; Satiation; Signal Transduction; Signs and Symptoms; Statistical Methods; Stress; Testing; Thyroid Gland; Time; Update; Variant; Weight; Withdrawal; Woman; androgen excess; case control; clinical heterogeneity; epidemiology study; exome sequencing; feeding; functional hypothalamic amenorrhea; girls; hypothalamic-pituitary-adrenal axis; improved; individual response; insight; inter-individual variation; nonhuman primate; phenotypic data; physiologic stressor; programs; psychologic; public database; rare variant; reproductive; reproductive axis; response; screening

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.

功能性下丘脑闭经 (HA) 是一种可逆性促性腺激素性性腺功能减退症，定义为在没有妊娠、雄激素过多、高催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 定义为没有少闭经病史（与多囊卵巢综合征更一致）的情况下闭经 3 个月，表明人群患病率为 4.5%。 HA 表现为不同模式的脉动 LH 分泌不足，表明 GnRH 分泌功能障碍。 HA 的临床病程可能会随着时间的推移而发生变化，在疾病过程中的某些时候会出现因孕激素引起的撤退性出血或因克罗米芬柠檬酸盐引起的卵泡发育（两者都表明一定程度的雌激素暴露）而发生变化，但在其他情况下则不然。脉动 LH 分泌模式也可能随时间而改变。对特定人群的研究表明，HA 的患病率明显较高，与运动、亚临床饮食失调和较年轻的生育年龄有关。 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。 外周信号将有关进食和整体营养状态的信息传递给下丘脑，这不仅影响饱腹感和代谢平衡，还影响生殖控制。同样，营养和心理压力都会影响生殖途径，并且有证据表明至少有一些代谢信号通过压力途径发挥作用。 个体女性对明显相似的危险因素的反应存在显着的临床异质性，这具有临床和科学重要性。例如，在 Frisch 的体重与身高研究中，对于患有继发性闭经的身高 165 厘米的女孩，与月经恢复相关的 95% 置信区间为 43-60 公斤。同样，在中长跑运动员的研究中，闭经百分比与每周跑步的英里数呈正相关，但即使每周跑 80 英里，也只有 50% 的运动员出现闭经。在 HA 52 的良好控制的非人类灵长类动物模型中，还注意到代谢缺陷情况下对轻度应激的反应存在个体间差异。因此，有重要证据表明，女性生殖轴对运动的敏感性存在差异。 、体重变化和压力。 对一小部分 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 GnRH 缺乏的患者延伸到较温和的表型。这项研究在 55 名 HA 女性中的 7 名中发现了 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，与先天性 HH 相关的基因中的罕见杂合变异也可能出现在继发性闭经和功能性 HA 患者中。最近，与公开数据库相比，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) 患者中表现过高，这提供了在罕见疾病中鉴定这些基因的另一种环境KS/nIHH 可能导致更常见的疾病。 这些发表的研究支持了我们的总体假设，即遗传易感性可能导致生殖系统对生理应激反应的变异性，从而导致 HA。 然而，由于HA和GnRH基因最初研究中的样本量较小以及所使用的分析策略以今天的标准来看是不可接受的，因此还需要进一步的研究。上述涉及 CDP 受试者的研究提供了一些信心，即我们之前在 HA 患者中的发现实际上可以通过更当前的分析方法得到证实。这一发现可能对筛查患有或不患有HA危险因素的闭经女性有影响，并可能有助于改进对患有HA的女性的生育结果的预测。 我们的手稿“下丘脑闭经女性 GnRH 相关基因中稀有序列变异的负担增加”现已被《临床内分泌与代谢杂志》接受发表。