Genetics of Early and Normal Menopause

Menopause is defined as the permanent cessation of ovulation and hence menstruation due to ovarian failure. The median age of menopause is 51 years. However, early menopause might occur at 40 years of age while late menopause might happen as late as 62 years of age. Premature menopause is defined as the cessation of ovulation prior to the age of 40 years, a condition generally referred to as primary ovarian insufficiency (POI). Menopause is also a highly heritable condition. Genetic variants are known to contribute to ∼50% of the variation in age at menopause. Several genetic studies have tried to unravel this genetic background making use of different genetic techniques in population studies as well as in animal models. Genome-wide linkage studies have identified only a limited amount of genetic variants that seem to be associated with menopause. Population-based studies as well as animal research into the genetic background of POI have identified several genetic variants that seem to be associated with POI. However, a lot of these studies suffer from methodological flaws because results are generally not replicated in different independent samples and most of these studies are underpowered. Hence, results are conflicting. Recent genome-wide association studies (GWAS) have identified several genetic variants that are associated with menopause and POI. Genes seem to be involved in DNA repair and maintenance as well as in immune function. Biological as well as epidemiological data seem to indicate that reproductive performance, age at menopause, and longevity are interlinked through common genetic factors involved in DNA repair and maintenance. In case these systems fail, cell death and accelerated aging occur. Consequently, it seems that the aging of the soma, as a result of dysfunctional DNA repair, is responsible for failure to reproduce and the subsequent occurrence of menopause. Hence, reproductive performance constitutes a good predictor for general health in later life.