Age-related changes in Folliculogenesis and potential modifiers to improve fertility outcomes - A narrative review

Abstract

Reproductive aging is characterized by a decline in oocyte quantity and quality, which is directly associated with a decline in reproductive potential, as well as poorer reproductive success and obstetrical outcomes. As women delay childbearing, understanding the mechanisms of ovarian aging and follicular depletion have become increasingly more relevant. Age-related meiotic errors in oocytes are well established. In addition, it is also important to understand how intraovarian regulators change with aging and how certain treatments can mitigate the impact of aging. Individual studies have demonstrated that reproductive pathways involving antimullerian hormone (AMH), vascular endothelial growth factor (VEGF), neurotropins, insulin-like growth factor 1 (IGF1), and mitochondrial function are pivotal for healthy oocyte and cumulus cell development and are altered with increasing age. We provide a comprehensive review of these individual studies and explain how these factors change in oocytes, cumulus cells, and follicular fluid. We also summarize how modifiers of folliculogenesis, such as vitamin D, coenzyme Q, and dehydroepiandrosterone (DHEA) may be used to potentially overcome age-related changes and enhance fertility outcomes of aged follicles, as evidenced by human and rodent studies.

Keywords: Antimullerian hormone; Coenzyme Q; Dehydroepiandrosterone; Folliculogenesis; Insulin-like growth factor; Neurotropins; Ovarian aging; Vascular endothelial growth factor; Vitamin D.

Fig. 1

Folliculogenesis: Primordial follicles are surrounded with a single layer of squamous granulosa cells. With primordial activation, primordial follicles are recruited into folliculogenesis, initially becoming primary follicles with a single layer of cuboidal granulosa cells. With replication, granulosa cells form layers surrounding the oocyte, thus forming the secondary follicle. The early/small antral follicle is comprised of multiple layers of granulosa cells, which are differentiated into cumulus cells that immediately surround the oocyte as well as small pockets of antrum. The antral follicle is characterized by a large antrum containing follicular fluid, and is ready to be ovulated out of the ovarian cortex. Follicles can undergo atresia at any stage of folliculogenesis. AMH is secreted by preantral follicles and control primordial follicle recruitment as well as follicular atresia. In comparison, VEGF stimulates recruitment of primordial follicles to become primary

Fig. 2

Age related changes of intraovarian small molecules and mitochondrial function within the follicle: Aging is related to decreased IGF1, decreased AMH, decreased BDNF, increased VEGF levels as well as mitochondrial dysfunction. Altered mitochondrial dynamics, disrupted mitochondrial homeostasis and increased mtDNA mutations are age related changes that occur within mitochondria and lead to impaired oxygenation-phosphorylation. Impaired oxygenation-phosphorylation leads to increased ROS accumulation which leads to follicular atresia