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Advances in Human Primordial Follicle Activation and Premature Ovarian Insufficiency

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Advances in Human Primordial Follicle Activation and Premature Ovarian Insufficiency 159 1 REPRODUCTIONREVIEW Advances in human primordial follicle activation and premature ovarian insufficiency Emmalee A Ford1,2, Emma L Beckett2,3, Shaun D Roman1,2,4, Eileen A McLaughlin1,5,6 and Jessie M Sutherland1,2 1Priority Research Centre for Reproductive Science, Schools of Biomedical Science & Pharmacy and Environmental & Life Sciences, University of Newcastle, Callaghan, New South Wales, Australia, 2Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia, 3School of Environmental & Life Sciences, Faculty of Science, University of Newcastle, Callaghan, New South Wales, Australia, 4Priority Research Centre for Drug Development, University of Newcastle, Callaghan, New South Wales, Australia, 5School of Science, Faculty of Science & Technology, University of Canberra, Bruce, Australian Capital Territory, Australia and 6School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand Correspondence should be addressed to J M Sutherland; Email: [email protected] Abstract In women, the non-growing population of follicles that comprise the ovarian reserve is determined at birth and serves as the reservoir for future fertility. This reserve of dormant, primordial follicles and the mechanisms controlling their selective activation which constitute the committing step into folliculogenesis are essential for determining fertility outcomes in women. Much of the available data on the mechanisms responsible for primordial follicle activation focuses on a selection of key molecular pathways, studied primarily in animal models, with findings often not synonymous in humans. The excessive induction of primordial follicle activation may cause the development of premature ovarian insufficiency (POI), a condition characterised by menopause before age 40 years. POI affects 1–2% of all women and is accompanied by additional health risks. Therefore, it is critical to further our understanding of primordial follicle activation in order to diagnose, treat and prevent premature infertility. Research in primordial follicle activation has focused on connecting new molecules to already established key signalling pathways, such as phosphatidylinositol 3-Kinase (PI3K) and mammalian target of rapamycin (mTOR). Additionally, other aspects of the ovarian environment, such as the function of the extracellular matrix, in contributing to primordial follicle activation have gained traction. Clinical applications are examining replication of this extracellular environment through the construction of biological matrices mimicking the 3D ovary, to support follicular growth through to ovulation. This review outlines the importance of the events leading to the establishment of the ovarian reserve and highlights the fundamental factors known to influence primordial follicle activation in humans presenting new horizons for female infertility treatment. Reproduction (2020) 159 R15–R29 Introduction Primordial follicle activation involves the recruitment of primordial follicles into folliculogenesis for the The total number of immature primordial follicles that eventual selection of one oocyte for ovulation. As reside in a woman’s ovaries are established in utero women age, the pool of primordial follicles, from from germ cell nests and is termed the ovarian reserve. which to source candidates for activation, plummets. Moreover, an estimation of a woman’s ovarian reserve is When there are ~1000 primordial follicles remaining, considered a fundamental indicator of fertility. Of equal this results in the cessation of fertility and the onset of importance to fertility is the rate at which these immature menopause (Faddy et al. 1992, Hansen et al. 2008). primordial follicles are recruited for growth through a A key aspect of our understanding of the depletion of process known as ‘activation’. Of these original primordial the ovarian reserve is that primordial follicles cannot follicles, numbering between 500,000 and 1,000,000 in be regenerated or replaced. This concept has been total at birth, only approximately 400 will fully mature into contested by the identification of oogonial stem cells able primary oocytes capable of being ovulated and fertilised to produce new oocytes within the mouse ovary, with during a woman’s reproductive years (Hansen et al. emerging evidence for their presence in human ovaries 2008, Findlay et al. 2015). The overwhelming majority (Clarkson et al. 2018), but there is still conjecture over are fated to undergo atresia (ovarian-mediated cell death) a physiological role for these cells based on definitive (Baker 1963, Tilly 2001, Marcozzi et al. 2018). evidence (reviewed in Horan & Williams 2017). © 2020 Society for Reproduction and Fertility https://doi.org/10.1530/REP -19-0201 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via https://rep.bioscientifica.com Downloaded from Bioscientifica.com at 09/29/2021 03:56:24PM via free access -19-0201 R16 E A Ford and others Thus, the challenge for research is to elucidate the Early events within the ovary establish the ovarian mechanisms controlling the depletion of the ovarian reserve that sustains fertility reserve via primordial follicle activation, so that we may provide solutions for those faced with the threat of early During human embryo sex determination, the primitive fertility loss, such as in the case of premature ovarian gonads are endowed with the primordial germ cells (Tam insufficiency (POI). & Snow 1981) (Fig. 1). The germ cells migrate to the genital POI may also be referred to as premature ovarian ridge of the primitive gonad, then rapidly proliferate until failure, but for the purpose of this review, either term they number 5–6 million (Motta et al. 1997, Mamsen applies interchangeably. POI is an infertility condition et al. 2011, Myers et al. 2014). This proliferation occurs diagnosed when menopause occurs prior to the age rapidly and as cytokinesis is not wholly completed, of 40, due to a significant reduction in, or absence of, clusters of germ cells (termed germ cell nests) connected a woman’s pool of primordial follicles. This condition via cytoplasmic bridges remain (reviewed by Pepling occurs globally in 1–2% of all women (Coulam et al. 2006). Germ cell nest breakdown directly precedes 1986). POI is defined as the premature cessation or primordial follicle formation and is a major factor absence of ovarian function and is characterised by influencing the initial size of the ovarian reserve. During amenorrhea, hypoestrogenism and an increase in this process, pre-granulosa cells (flattened, squamous gonadotrophin levels (Bachelot et al. 2009, Shelling granulosa cells prior to differentiation into cuboidal 2010). A common cause of POI is an acceleration in the granulosa cells) are primed to encapsulate the oocytes rate of primordial follicle activation, thereby resulting via signalling originating from oocytes and intracellular in a depletion of the ovarian reserve (Nelson 2009). communication between other pre-granulosa cells (De However, the ovarian reserve may also be depleted Felici et al. 2005, Grive & Freiman 2015, Suzuki et al. via primordial follicle loss (Depalo et al. 2003) or 2015a). Only a small fraction of the original population from iatrogenic causes such as chemotherapeutics of germ cells go on to form primordial follicles, while (Ben-Aharon & Shalgi 2012). Women often receive a the remaining oocytes, estimated between one and diagnosis of POI when they are already in significant two thirds, are targeted for coordinated degradation via reproductive decline, and as a consequence of their classical apoptotic mechanisms (Albamonte et al. 2008). diagnosis may face psychological impacts in addition The role of autophagy in protecting germ cells from to the physiological symptoms and infertility of this apoptosis has been established in mice (Rodrigues et al. condition (Van Der Stege et al. 2008, Welt 2008). Long- 2009), with preliminary evidence this occurs in humans term physical consequences of POI may be severe, too (Sun et al. 2017, Zhou et al. 2019). The cause for even with traditional hormone replacement therapies such a substantial loss of oocytes is still unknown, but to ameliorate the negative effects of a loss of ovarian it is possible that a quality control mechanism exists hormonal support. Women with POI have an increased through which faulty nuclei are lost, and healthy oocytes risk of cardiovascular disease, osteoporosis, urogenital are preferentially encapsulated into primordial follicles atrophy and neurodegenerative disorders (reviewed in (Tilly 2001, Sun et al. 2017). Additionally, a self-sacrifice Podfigurna-Stopa et al. 2016). Thus, it is critical that mechanism previously established in Drosophila (de we continue towards understanding the process of Cuevas et al. 1997), and later observed in mice may also primordial follicle activation as a means of intervention be responsible for mammalian germ cell nest breakdown to preserve the ovarian reserve. (Grive & Freiman 2015, Pepling 2016). In this mechanism, Both the establishment of the ovarian reserve and the essential cellular factors are transported via cytoplasmic initial wave of primordial follicle activation occur in bridges from neighbouring germ cells within a cluster utero, prior to sexual maturity and gonadotrophic input, to the germ cells that will survive and become oocytes thus relying largely upon regulation by intraovarian in primordial follicles, but this mechanism has not been factors (Lew
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