The Ovarian Reserve of Primordial Follicles and the Dynamic Reserve of Antral Growing Follicles: What Is the Link?1

Abstract

The growing follicles develop from a reserve of primordial follicles constituted early in life. From this pre-established reserve, a second ovarian reserve is formed, which consists of gonadotropin-responsive small antral growing follicles and is a dynamic reserve for ovulation. Its size, evaluated by direct antral follicular count or endocrine markers, determines the success of assisted reproductive technologies in humans and embryo production biotechnologies in animals. Strong evidence indicates that these two reserves are functionally related. The size of both reserves appears to be highly variable between individuals of similar age, but the equilibrium size of the dynamic reserve in adults seems to be specific to each individual. The dynamics of both follicular reserves appears to result from the fine tuning of regulations involving two main pathways, the phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDPK1)/v-akt murine thymoma viral oncogene homolog 1 (AKT1) and the bone morphogenetic protein (BMP)/anti-Müllerian hormone (AMH)/SMAD signaling pathways. Mutations in genes encoding the ligands, receptors, or signaling effectors of these pathways can accelerate or modulate the exhaustion rate of the ovarian reserves, causing premature ovarian insufficiency (POI) or increase in reproductive longevity, respectively. With female aging, the decline in primordial follicle numbers parallels the decrease in the size of the dynamic reserve of small antral follicles and the deterioration of oocyte quality. Recent progress in our knowledge of signaling pathways and their environmental and hormonal control during adult and fetal life opens new perspectives to improve the management of the ovarian reserves.

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

“…The mammalian ovary has a finite number of oocytes that are formed in foetal development (Monniaux et al 2014). During embryonic development, primordial germ cells migrate from the primitive streak through the endoderm to the genital ridge where they differentiate into oogonia while the foetal ovary forms (Richardson & Lehmann 2010).…”

“…Primordial follicles can become activated soon after their initial formation and it is not known why some follicles become activated early in life, whereas others are able to remain dormant for months, years or decades (Zhang & Liu 2015). The rate 233:1 of primordial follicle activation exceeds the rate at which mature oocytes are ovulated, with the excess developing follicles being removed via a process known as atresia (McGee & Hsueh 2000, Monniaux et al 2014.…”

Dehydroepiandrosterone improves the ovarian reserve of women with diminished ovarian reserve and is a potential regulator of the immune response in the ovaries

“…These changes are evident as women age. Some genetic mutations and disorders of the endocrine system can accelerate or modulate the rate at which the ovarian reserve is exhausted and cause premature ovarian insufficiency (POI) (1). Among the various causes of DOR, abnormal immune function may be a great contributor to this phenomenon (2).…”

The local regulation of folliculogenesis by members of the transforming growth factor superfamily and its relevance for advanced breeding programmes

“…The extracellular region of the BMPR2 is able to block the proliferative activity of GDF9 & BMP15 combined (Edwards et al, 2008). The extracellular region of the BMPR2 fused with an IgG domain can be produced in vitro (Myllymaa et al, 2010) and might provide a more controlled approach to mimic the neutralising effects of an active immunisation. However, both GDF9 and BMP15 regulate cumulus cell function and have been linked to improved oocyte development when used during in vitro oocyte maturation for in vitro production of embryos (reviewed in Russell et al, 2016; and thus reducing the bioactivity too far might decrease embryo quality.…”

“…In this review we will focus on members of the GDF, BMP and TGFB sub-groups of the TGFB superfamily. Readers are directed to additional reviews for information on other factors controlling ovarian follicular development (Young and McNeilly, 2010;Buratini and Price, 2011;Scaramuzzi et al, 2011;Knight et al, 2012;Campbell et al, 2014;Knight and Glister, 2014;Monniaux et al, 2014;Price, 2016;Shimizu, 2016;Silva et al, 2016;Pankhurst, 2017;Estienne and Price, 2018) DOI: 10.21451/1984 Figure 1. The stages of follicular development and initiation of expression of selected proteins in the healthy follicle.…”