Genetic Determinants of Hypothalamic Amenorrhea

下丘脑闭经的遗传决定因素

• 批准号: 10929070
• 负责人: Janet Hall
• 金额: $ 23.88万
• 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/10929070
• 关键词: Age; Amenorrhea; Bioinformatics; Body Weight; Body Weight Changes; Characteristics; Clinical; Clinical Endocrinology; Clomiphene Citrate; Collaborations; Computer software; Constitution; 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; Heterozygote; Hyperprolactinemia; Hypogonadism; Hypothalamic structure; Individual; Journals; Manuscripts; Menstruation; Metabolic; Metabolic stress; Methodology; Modeling; Mutation; National Human Genome Research Institute; Nutritional; Oligonucleotides; Outcome; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Polycystic Ovary Syndrome; Population; Predisposition; Pregnancy; Prevalence; Progestins; Psychological Stress; Publications; Publishing; Quality Control; Questionnaires; Rare Diseases; Recontacts; 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; 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)是一种可逆性低促性腺激素减退症，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定义为在没有少闭经病史的情况下闭经3个月(这与多囊卵巢综合征更一致)，表明人群患病率为4.5%。HA表现为不同类型的搏动性黄体生成素分泌不足，提示促性腺激素释放激素分泌功能障碍。HA的临床病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，随着孕激素或卵泡发育对克罗米芬的反应(两者都表明有一定程度的雌激素暴露)而出现停血，但在另一些时候不会。黄体生成素的脉动分泌模式也可能随着时间的推移而改变。在选定人群中的研究表明，HA的患病率与运动、亚临床饮食障碍和较年轻的生殖年龄显著相关。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中起作用。 外周信号将有关摄食和整体营养状态的信息传递到下丘脑，这不仅影响饱腹感和代谢平衡，还影响生殖控制。同样，营养压力和心理压力都会影响生殖途径，而且有证据表明，至少有一些代谢信号是通过应激途径发挥作用的。 女性个体对明显相似的危险因素的反应具有显著的临床异质性，这一点具有临床和科学意义。例如，在Frisch对身高体重的研究中，在一名165厘米的继发性闭经女孩中，与恢复月经有关的95%可信区间为43-60公斤。同样，在对中长跑运动员的研究中，闭经百分比与每周跑步里程呈正相关，但即使是每周跑80英里，也只有50%的运动员闭经。在HA52良好控制的非人类灵长类动物模型中，代谢缺陷背景下对轻度应激反应的个体间差异也被注意到。因此，有重要证据表明，女性在生殖轴对运动、体重变化和压力的敏感度上存在差异。 对一组相对较小的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缺乏GnRH的完全患者扩展到较轻微的表型。这项研究在55名HA女性中的7名中发现了6个杂合子突变，总体患病率为13%。在422名健康对照女性中没有发现这些变异。这项研究表明，与先天性HH相关的基因杂合子罕见变异也可能出现在继发性闭经和功能性HA患者中。最近，与公开的数据库相比，在KS/nIHH中发现的基因中的稀有序列变体(RSV)在体质青春期延迟(CDP)患者中的表达过高，这提供了另一种背景，在KS/nIHH的罕见疾病中发现的这些基因可能与更常见的疾病有关。这些已发表的研究支持了我们的总体假设，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，以及在HA和GnRH基因的初始研究中使用的分析策略，按今天的标准是不能接受的，因此需要进一步的研究。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能会被更当前的分析方法所证实。这一发现可能会对有或没有HA危险因素的闭经妇女进行筛查，并可能允许改进对HA妇女生育结局的预测。 我们的手稿《下丘脑性闭经妇女GnRH相关基因稀有序列变异的负担增加》现已被《临床内分泌学和代谢杂志》接受发表。