Abstract
Primordial follicles or non-growing follicles (NGFs) are the functional unit of reproduction, each comprising a single germ cell surrounded by supporting somatic cells. NGFs constitute the ovarian reserve (OR), prerequisite for germ cell ovulation and the continuation of the species. The dynamics of the reserve is determined by the number of NGFs formed and their complex subsequent fates. During the reproductive lifespan, the OR progressively diminishes due to follicle atresia as well as recruitment, maturation, and ovulation. The depletion of the OR is the major determining driver of menopause, which ensues when the number of primordial follicles falls below a threshold of ∼1,000. Therefore, genes and processes involved in follicle dynamics are particularly important to understand the process of menopause, both in the typical reproductive lifespan and in conditions like primary ovarian insufficiency, defined as menopause before age 40. Genes and their variants that affect the timing of menopause thereby provide candidates for diagnosis of and intervention in problems of reproductive lifespan. We review the current knowledge of processes and genes involved in the development of the OR and in the dynamics of ovarian follicles.
Highlights
The growing trend in all contemporary societies for childbearing later in women’s lives, accompanied by the increasing use of assisted reproduction technology, make the term ovarian reserve (OR) increasingly prominent in medical and scientific literature
Menopause ensues when regular recruitment decreases follicle numbers below a threshold. This process is at least partially genetically determined. It has much sharper timing in a population of women than other age-related declines, the dynamics of the reserve and the timing of menopause can be changed by mutations or environmental factors that alter the size of the initial reserve or slow the rate of recruitment/atresia
Double knock-out of Tsc1 and Pten enhanced the effect on follicle recruitment compared to single gene mutants (Adhikari et al, 2010). These results suggest an additive effect between Tsc1 and Pten, consistent with overlapping functions of the mTOR and AKT pathways in regulating the dynamics of the OR
Summary
The dynamics of the reserve is determined by the number of NGFs formed and their complex subsequent fates. The depletion of the OR is the major determining driver of menopause, which ensues when the number of primordial follicles falls below a threshold of ∼1,000. Genes and processes involved in follicle dynamics are important to understand the process of menopause, both in the typical reproductive lifespan and in conditions like primary ovarian insufficiency, defined as menopause before age 40. Genes and their variants that affect the timing of menopause thereby provide candidates for diagnosis of and intervention in problems of reproductive lifespan.
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