Pelosi Emanuele, Simonsick Eleanor, Forabosco Antonino, Garcia-Ortiz Jose Elias, Schlessinger David
Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
Biol Reprod. 2015 May;92(5):130. doi: 10.1095/biolreprod.114.127381. Epub 2015 Apr 22.
The narrow standard age range of menopause, ∼50 yr, belies the complex balance of forces that govern the underlying formation and progressive loss of ovarian follicles (the "ovarian reserve" whose size determines the age of menopause). We show here the first quantitative graph of follicle numbers, distinguished from oocyte counts, across the reproductive lifespan, and review the current state of information about genetic and epidemiological risk factors in relation to possible preservation of reproductive capacity. In addition to structural X-chromosome changes, several genes involved in the process of follicle formation and/or maintenance are implicated in Mendelian inherited primary ovarian insufficiency (POI), with menopause before age 40. Furthermore, variants in a largely distinct cohort of reported genes-notably involved in pathways relevant to atresia, including DNA repair and cell death-have shown smaller but additive effects on the variation in timing of menopause in the normal range, early menopause (age <45), and POI. Epidemiological factors show effect sizes comparable to those of genetic factors, with smoking accounting for about 5% of the risk of early menopause, equivalent to the summed effect of the top 17 genetic variants. The identified genetic and epidemiological factors underline the importance of early detection of reproductive problems to enhance possible interventions.
绝经的标准年龄范围较窄，约为50岁，这掩盖了控制卵巢卵泡（“卵巢储备”，其大小决定绝经年龄）潜在形成和逐渐丧失的各种力量之间的复杂平衡。我们在此展示了整个生殖寿命期内卵泡数量（与卵母细胞计数不同）的首张定量图表，并回顾了与生殖能力可能保存相关的遗传和流行病学风险因素的当前信息状态。除了结构性X染色体变化外，参与卵泡形成和/或维持过程的几个基因与孟德尔遗传性原发性卵巢功能不全（POI）有关，即40岁之前绝经。此外，一大批报道基因中的变异——特别是涉及与闭锁相关途径的基因，包括DNA修复和细胞死亡——对正常范围、早期绝经（年龄<45岁）和POI中绝经时间的变异显示出较小但累加的影响。流行病学因素显示出与遗传因素相当的效应大小，吸烟约占早期绝经风险的5%，相当于前17个遗传变异的累加效应。已确定的遗传和流行病学因素突显了早期发现生殖问题以加强可能干预措施的重要性。
