Genetics of Menopause and Primary Ovarian Insufficiency: Time for a Paradigm Shift?

Abstract

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!

Early menopause results from instead of causes premature general ageing

“…Reproductive senescence, which menopause actually is, is also dependent on multiple intrinsic genetic factors. Reproductive ageing is not isolated from the overall somatic ageing process, and several studies strongly support the link between an early age of menopause and morbidity and mortality (Laven, 2020).…”

“…Moreover, ageing oocytes seem to lose protective mechanisms against reactive oxygen species (ROS), giving rise to increased DNA damage (TABLE 1). Hence, accumulated ROS activity and increased vulnerability of oocytes to ROS lead to spindle instability, chromosomal abnormalities, telomere shortening and reduced developmental competence of aged oocytes (Laven, 2020). Last but not least there was an extensive overlap between the genetic variants associated with menopausal age and neurodegenerative and cardiovascular disease (CVD) as well as with diabetes mellitus (Ruth et al, 2021).…”

“…On the other hand, making the DDR pathways defective in genetically manipulated mice showed, apart from accelerated ageing, also an infertile phenotype in female mice characterized by an accelerated depletion of both ovaries within 4 weeks after birth. A phenotype very similar to the anti-Müllerian hormone (AMH) knockout mouse greatly resembles premature ovarian insufficiency (Laven, 2020). Hence, multiple lines of evidence support a causative role for DDR damage response defects in natural ageing and associated morbidities such as neurodegenerative diseases, diabetes mellitus and CVD.…”

“…It was also shown that relatively young women with type 1 diabetes mellitus (T1DM) had lower AMH concentrations compared with healthy controls without diabetes. There are also some scarce data indicating that women with T1DM enter menopause earlier in life (Laven, 2020).…”

Role of AMH in Prediction of Menopause

“…It remains to be determined whether the prediction of age at menopause, albeit with a range spanning several years, may ultimately be feasible in this group of women facing reproductive decisions at a relatively early age. Of note, AMH levels are reduced in girls with newly diagnosed cancer even before the cancer treatment has started and it is suggested that possibly in relation to this impaired DNA repair mechanisms are involved that also seem in part to be involved in determination of age at menopause (31)(32)(33).…”