Disrupted, meiotic initiation in oocyte leads to Decreased, ovarian reserve

Although the entry into meiosis is required for oocyte development, the relationship between meiotic entry and final oocyte reserve remains unclear. However, there are strong correlations between disrupted meiosis and infertility (or aneuploidy) in females (Handel & Schimenti, 2010). For instance, in mice, ablation of Stra8 prevents oocytes from entering meiosis in the fetal ovaries and mature females are infertile (Baltus et al, 2006; Zhou et al, 2008). Mutation in Atm, a gene involved in recombination during meiosis, results in complete loss of primary oocytes in mice, and greatly reduced follicle pool in humans (Adelfalk et al, 2011; Agamanolis & Greenstein, 1979; Aguilar et al, 1968; Xu et al, 1996). Other examples include Fanca and Fancd2 genes that are involved in recombination. Mutations to these genes lead to oocyte degeneration and subfertility in mice (Cheng et al, 2000; Houghtaling et al, 2003; Wong et al, 2003).

Mice with Lhx8 ablation display total loss of oocytes. Lhx8-/- mice maintain oocytes during fetal development, but loose the oocytes shortly after birth by autophagy, likely because the oocytes have failed to enter meiosis in utero (Choi et al, 2008; D'Ignazio et al, 2018). Fzr1 is a regulator of mitotic cell division. When conditionally ablated from the germ cells, female mice display premature ovarian failure by 5 months of age and are subfertile; oocytes are lost in utero during early meiotic prophase I (Holt et al, 2014).

CYP51 (lanosterol 14 α-demethylase) is expressed by fetal oocytes and is involved in meiotic regulation (Mu et al, 2018).  Inhibition of CYP51 activity reduces the formation of primordial follicles (Zhang et al, 2009) by disrupting entry into diplotene stage (Mu et al, 2018).

The mechanisms and outcomes of meiosis I disruption may vary significantly across species, making it challenging to generalize findings from animal models to humans. Also, the extent of disruption that is required to significantly affect the ovarian reserve remains uncertain, as there may be potential threshold effects influenced by genetic, epigenetic, and environmental factors.

Timing of disruption to meiosis I initiation in oocytes may influence to what extent the ovary reserve is ultimately affected.

Methods to quantify the ovarian reserve (e.g. follicle count, AMH levels) may not directly reflect the impact of meiotic disruption, leading to inconsistencies in observed effects.

The ovarian follicle pool (ovarian reserve) refers to the final number of primordial follicles in the mature ovary and is established through a series of events. In most mammals, it is determined during gestation or just after birth and relies on i) how many germ cells were established during embryogenesis, ii) their proliferation during migration and early ovary development, iii) death rate during oogenesis and iv) formation of primordial follicles at nest breakdown (Findlay et al, 2015). The last two stages, which includes nest formation and breakdown, is largely influenced by the mitotic-meiotic transition, in that oocytes that have failed to enter meiosis may contribute to the cysts population, but only high quality oocytes in meiotic prophase are spared during cyst breakdown (Findlay et al, 2015). Thus, there is a response-response relationship between meiotic entry and final follicle pool, albeit the quantitative relationship is not that well understood.

The time-scale for oocyte mitotic-meiotic transition and subsequent nest breakdown varies between species, but generally takes place from mid gestation to around the time of birth. In mice, meiosis and nest formation is initiated from around E13, whereas in humans it initiates at around GW12-14 (Childs et al, 2012; Findlay et al, 2015; Grive & Freiman, 2015; Pepling, 2006; Tingen et al, 2009). Nest breakdown starts just before birth in mice and completes around postnatal day 5 (Grive & Freiman, 2015; Pepling, 2006). In humans, nest breakdown takes place during second trimester (Grive & Freiman, 2015; Tingen et al, 2009). 

No (known) relevant feedback loop.