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.

功能下丘脑闭经（HA）是一种可逆性的催眠型性肌功能减退症，在没有怀孕，雄激素过量，过度胃痛素或甲状腺高或其他内分泌功能障碍的情况下，由3-6个月的闭经3-6个月定义。在没有少甘露明病史的情况下，将HA定义为3个月的闭经（与多囊卵巢综合征更一致）的流行病学研究表明人口流行率为4.5％。 HA通过不足的脉动LH分泌的可变模式表现出来，这表明GNRH分泌功能障碍。在疾病的某些时候，随着孕激素或卵泡发育的响应，HA的临床过程可能会随着时间的流逝而变化，响应于孕激素或卵泡发育，以响应酸性柠檬酸克罗米芬（两者都表示雌激素暴露程度），但在这种疾病过程中却没有。脉动LH分泌的模式也可能随着时间而变化。在某些人群中的研究表明，与运动，亚临床饮食失调和年轻生殖年龄相关的HA患病率显着更高。 其他研究表明，下丘脑 - 垂体 - 肾上腺（HPA）轴的心理特征，压力和/或激活也可能在HA中发挥作用。 外围信号将有关喂养和整体营养状态的信息传达给下丘脑，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，至少某些代谢信号通过应力途径运行。 临床和科学意义既具有临床和科学的重要性，即单个女性对显然类似危险因素的反应有明显的临床异质性。例如，在弗里奇（Frisch）的身高重量研究中，在一个165厘米的女孩中，含有闭经症，与月经的恢复相关的95％置信度限制为43-60 kg。同样，在对中距离跑步者的研究中，闭经百分比与每周的里程呈正相关，但即使以每周80英里的速度，只有50％的运动员是Amenorrheic。在良好控制的非人类灵长类动物模型中，HA 52的非代谢缺乏症的反应反应中的个体间差异也被发现。因此，有很大的证据表明，妇女在生殖轴易感性方面有所不同，体重改变和压力。 对相对较小的HA患者进行了7种与GNRH相关的基因的测序，以确定这些基因中的突变是否可能从完全GNRH缺乏症的完整患者延伸到温和表型。这项研究确定了55公顷女性中7个杂合突变，总体患病率为13％。在422名健康对照妇女中未发现这些变体。这项研究表明，在继发性闭经和功能性HA的患者中，也可以看到与先天性形式HH相关的基因的杂合稀有变异。与公开可用的数据库相比，最近在KS/NIHH中鉴定出的基因的罕见序列变体（RSV）在青春期延迟（CDP）的患者中被证明过多代表，从而提供了另一种在稀有疾病中鉴定出的基因的设置KS/NIHH可能会导致更多常见的疾病。 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的生理胁迫的反应变异性。 但是，由于样本量较小，以及在当今标准标准不可接受的HA和GNRH基因中使用的分析策略，因此需要进一步的研究。上述涉及患有CDP的受试者的研究表明，我们以前在HA患者中的发现实际上可能通过当前的分析方法来证实。这样的发现可能对筛查患有或没有危险因素的HA的妇女筛查妇女有影响，并且可以改善HA患者的生育能力预测。 我们的手稿“下丘脑闭经的女性GNRH相关基因中罕见序列变异的负担增加”已被接受在《临床内分泌学和代谢杂志》上发表。