Factors influencing establishment of the ovarian reserve and their effects on fertility

A reserve of primordial follicles is set up in the ovaries of fetuses or neonates, depending on the species, and serves as the source of developing follicles throughout the reproductive lifespan. This review focuses on the cellular and molecular mechanisms currently known to control the establishment of this reserve, and their regulation by environmental factors. Most mutations in genes controlling germ cell proliferation and survival, meiosis or follicle assembly lead to the absence of primordial follicles or a sharp reduction in their number, incompatible with fertility in adults. Inadequate maternal nutrition affects the cellular metabolism, increases the oxidative stress and delays follicle formation in fetal ovaries. Despite the existence of compensation mechanisms of some developmental processes, the early-life nutritional environment imprints the long-term ability of follicles to enter growth and develop in adult ovaries. However, maternal undernutrition, overfeeding or high-fat diet during the establishment of the ovarian reserve does not seem to affect the fertility of the female offspring, unless their metabolism or neuroendocrine status is altered. Exposure of fetal or neonatal ovaries to excess steroids inhibits or stimulates follicle formation in a complex manner depending on the nature of the steroid, the dose and the animal species. Estrogens can control follicle formation through intra-ovarian mechanisms involving members of the TGF-beta family such as activin and BMP2. Early-life exposure to synthetic estrogens or environmental pollutants with estrogen-like activity impairs meiotic progression and follicle assembly, and affects long-term primordial follicle activation in adult ovaries. The effects of compounds with estrogen-like activity on the ovarian reserve can be transmitted to several generations through the female germline. Further investigations are needed to establish the early-life effects of the environmental factors on the female reproductive lifespan and decipher the mechanisms of their epigenetic effects on the size and quality of the ovarian reserve.