Abstract
Egg quality dictates fertility outcomes, and although there is a well-documented decline with advanced reproductive age, how it changes during puberty is less understood. Such knowledge is critical, since advances in Assisted Reproductive Technologies are enabling pre- and peri-pubertal patients to preserve fertility in the medical setting. Therefore, we investigated egg quality parameters in a mouse model of the pubertal transition or juvenescence (postnatal day; PND 11–40). Animal weight, vaginal opening, serum inhibin B levels, oocyte yield, oocyte diameter, and zona pellucida thickness increased with age. After PND 15, there was an age-associated ability of oocytes to resume meiosis and reach metaphase of meiosis II (MII) following in vitro maturation (IVM). However, eggs from the younger cohort (PND 16–20) had significantly more chromosome configuration abnormalities relative to the older cohorts and many were at telophase I instead of MII, indicative of a cell cycle delay. Oocytes from the youngest mouse cohorts originated from the smallest antral follicles with the fewest cumulus layers per oocyte, suggesting a more developmentally immature state. RNA Seq analysis of oocytes from mice at distinct ages revealed that the genes involved in cellular growth signaling pathways (PI3K, mTOR, and Hippo) were consistently repressed with meiotic competence, whereas genes involved in cellular communication were upregulated in oocytes with age. Taken together, these data demonstrate that gametes harvested during the pubertal transition have low meiotic maturation potential and derive from immature follicular origins.
Highlights
Female reproductive aging is associated with a striking reduction in gamete quantity and quality beginning when women reach their mid-thirties, and this contributes to both loss of fertility and endocrine function (Hassold and Chiu, 1985; Speroff, 1994; Armstrong, 2001; Franasiak et al, 2014)
We used a mouse model of the pubertal transition and an experimental paradigm that mimics how gametes are obtained clinically in the fertility preservation setting for young females, whereby oocytes from antral follicles are isolated from unstimulated ovaries and matured in vitro to obtain eggs arrested at metaphase stage of meiosis II (MII) (Revel et al, 2009; Abir et al, 2016)
gonadotropin-releasing hormone (GnRH) is secreted in a pulsatile fashion beginning at postnatal day (PND) 5, and the highest GnRH pulse frequencies are observed between PND 40–45 (Prevot et al, 2003)
Summary
Female reproductive aging is associated with a striking reduction in gamete quantity and quality beginning when women reach their mid-thirties, and this contributes to both loss of fertility and endocrine function (Hassold and Chiu, 1985; Speroff, 1994; Armstrong, 2001; Franasiak et al, 2014). Due to clinical advances in diagnostics and therapeutics, more than 80% of children with a malignancy will achieve a 5-year survival, making approximately 1 in 750 a childhood cancer survivor in the United States (Ward et al, 2014) Despite these life-saving improvements, childhood cancer survivors show accelerated aging phenotypes relative to their cancer-free siblings (Green et al, 2009). With regards to reproductive function, survivors are more likely than their siblings to experience infertility (Green et al, 2009; Nielsen et al, 2013) This has fueled the field of Oncofertility—the merging of oncology and fertility—to explore and expand fertility preservation options for men, women, and children (Gracia and Woodruff, 2012; Woodruff, 2015)
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