Genetic Determinants of Hypothalamic Amenorrhea

下丘脑闭经的遗传决定因素

• 批准号: 10252596
• 负责人: Janet Hall
• 金额: $ 5.31万
• 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/10252596
• 关键词: Age; Amenorrhea; Androgens; Bioinformatics; Body Weight; Body Weight Changes; Characteristics; Clinical; Clinical Endocrinology; Clomiphene Citrate; Collaborations; Computer software; Constitutional; Control Groups; Data; Databases; 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; Physiological; 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; 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; programs; psychologic; 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功能减退症，在没有怀孕、雄激素过量、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史的情况下闭经3个月（这更符合多囊卵巢综合征），表明人群患病率为4.5%。血凝素表现为搏动性LH分泌不足，指示GnRH分泌功能障碍。血凝素的临床过程可能随着时间的推移而改变，黄体酮引起的停药性出血或枸橼酸克罗米芬引起的卵泡发育（两者都表明某种程度的雌激素暴露）在疾病过程中的某些时候发生，但在其他时候则不发生。脉动型黄体生成素分泌的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。