Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment

Abstract

The mammalian ovarian reserve is comprised of a finite pool of primordial follicles, representing the lifetime reproductive capacity of females. In most mammals, the reserve is produced during embryonic and early postnatal development with oocyte numbers peaking during mid‐to‐late gestation, and then experiencing a dramatic decline continuing until shortly after birth. Oocytes remaining after the bulk of this attrition are subsequently surrounded by a layer of somatic pre‐granulosa cells with these units then referred to as “primordial follicles.” The complex and varied cell death mechanisms intrinsic to this process are not only characteristic of, but also essential for, the proper formation of this pool of follicles, and as a result must be immaculately balanced to ensure long‐term fertility and reproductive health. Too few follicles can lead to Primary Ovarian Insufficiency, resulting in fertility loss and other features of aging, such as an overall shorter lifespan. On the other hand, whereas an excess of follicles might extend reproductive lifespan, this might also be the underlying etiology of other ovarian pathologies. The last decade, in particular, has vastly expanded our understanding of oocyte attrition and determinants of ovarian reserve abundance. By continuing to decipher the intricacies underlying the cell death processes and development of the initial primordial follicle pool, we may be in a much better position to understand idiopathic cases of premature follicle depletion and improve ovarian health in reproductive‐age women.

Contextualizing Autophagy during Gametogenesis and Preimplantation Embryonic Development

“…The majority of follicle-enclosed oocytes (>99.9%) will never complete meiosis and most activated follicles undergo atresia while oocytes perish by apoptosis. Moreover, increasing evidence in mouse knockout models for core autophagy genes suggests that this process contributes to establishing and maintaining the oocyte pool in the ovary [59], as further described below.…”

“…The completion of oogenesis requires the interplay between oocytes and the follicle microenvironment [59]. Theca, granulosa, and cumulus cells are core cell types that make up ovarian follicles alongside oocytes contributing to the follicle microenvironment and oogenesis.…”

Meiotic Cohesin and Variants Associated With Human Reproductive Aging and Disease

“…In sexually mature females, follicle-stimulating hormone (FSH) promotes growth of a dominant follicle in the ovary. Proliferation of granulosa cells surrounding the follicle leads to estrogen production which ultimately triggers the pre-ovulatory luteinizing hormone (LH) surge ( McGee and Hsueh, 2000 ; Edson et al, 2009 ; Grive, 2020 ). The LH surge induces a decline in oocyte cAMP levels which then activates cyclin-dependent kinase 1 (CDK1) driving the transition of the oocyte out of prophase I arrest ( Mehlmann et al, 2002 ; Mehlmann, 2005 ; Norris et al, 2010 ; Li et al, 2019 ).…”

The Requirement of Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in Mouse Ovarian Development and Fertility

“…The remaining oocytes form the entire primordial follicle pool available during a female's reproductive lifetime and determine her reproductive capacity. This finite population of follicles remain quiescent until sexual maturation, when follicles are activated and recruited to undergo maturation and ovulation, or die due to follicular atresia [8,9]. In humans, the number of germ cells increases from approximately 600,000 to a peak of 6,800,000 during mid-gestation.…”