Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Semin Reprod Med. 2020 Sep;38(4-05):256-262. doi: 10.1055/s-0040-1721796. Epub 2021 Mar 1.
This review summarizes the existing information concerning the genetic background of menopause and primary ovarian insufficiency (POI). There is overwhelming evidence that majority of genes are involved in double-strand break repair, mismatch repair, and base excision repair. The remaining loci were involved in cell energy metabolism and immune response. Gradual (or in case of rapid POI) accumulation of unrepaired DNA damage causes (premature) cell death and cellular senescence. This in turn leads to exhaustion of cell renewal capacity and cellular dysfunction in affected organs and eventually to aging of the entire soma. Similar erosion of the genome occurs within the germ cell line and the ovaries. Subsequently, the systemic "survival" response intentionally suppresses the sex-steroid hormonal output, which in turn may contribute to the onset of menopause. The latter occurs in particular when age-dependent DNA damage accumulation does not cease. Both effects are expected to synergize to promote (premature) ovarian silencing and install (early) menopause. Consequently, aging of the soma seems to be a primary driver for the loss of ovarian function in women. This challenges the current dogma which implies that loss of ovarian function initiates aging of the soma. It is time for a paradigm shift!
这篇综述总结了有关绝经和原发性卵巢功能不全（POI）的遗传背景的现有信息。有大量证据表明，大多数基因参与双链断裂修复、错配修复和碱基切除修复。其余的基因座参与细胞能量代谢和免疫反应。未修复的 DNA 损伤逐渐（或在快速 POI 的情况下）积累会导致（过早）细胞死亡和细胞衰老。这反过来又导致受影响器官的细胞更新能力耗尽和细胞功能障碍，并最终导致整个体细胞的衰老。在生殖细胞系和卵巢中也会发生类似的基因组侵蚀。随后，系统的“生存”反应会有意抑制性激素的分泌，这反过来又可能导致绝经的发生。当年龄相关的 DNA 损伤积累不停时，尤其会发生这种情况。这两种效应预计会协同作用，促进（过早）卵巢沉默并引发（早期）绝经。因此，体细胞的衰老似乎是女性卵巢功能丧失的主要驱动因素。这对目前的主流观点提出了挑战，即卵巢功能的丧失引发了体细胞的衰老。现在是转变观念的时候了！
