Follicle stimulating hormone: ovarian reproductive function, health and aging

Abstract

Follicle stimulating hormone (FSH) is vital for ovarian function; however elevated circulating levels are associated with reproductive ageing and ovarian tumorigenesis in women. Transgenic FSH (TgFSH) mice developed in our laboratory exhibit progressively rising FSH levels with ageing, causing ovarian dysfunction and premature infertility but no ovarian tumours. We hypothesized that high FSH may decrease oocyte developmental competence and quality with age and may also promote ovarian tumorigenesis when combined with ovarian mutations (such as in Pten, Brca1 and Trp53) in mice. Our first study examined the effects of elevated FSH on oocyte developmental capacity and quality (Chapter 3). Follicle stimulating hormone is vital for ovarian function and serum FSH increases with age as ovarian function declines towards menopause. We hypothesize that elevated FSH may rescue follicles from a diminishing pool normally excluded from selection, thereby reducing oocyte function. TgFSH mice expressing progressively rising FSH levels with age displayed increased litter size initially but after 6 months of age exhibited decreased litter size and premature infertility due to increased embryo-foetal resorption; however, the specific mechanism was undefined. We hypothesized that premature infertility observed was due to increased circulating FSH exceeding a threshold thereby impairing oocyte development and functionality. We examined oocyte in vitro maturation and aneuploidy and cumulus cells (from cumulus-oocyte complexes) for gene expression analysis in TgFSH and non-TgFSH control mice aged 6, 12, 18 and 24 months. Oocytes of TgFSH mice exhibited an increased percentage of cells remaining at the germinal vesicle (GV) stage, accompanied by a reduction in oocytes at the meiosis II (MII) stage of maturation vs age-matched littermate controls. The reduced oocyte progression to the MII stage is attributable to stalling of the oocytes in the GV stage. The proportion of aneuploid oocytes increased with age but did not differ between genotypes. We also wanted to examine cumulus cells matched to aneuploidy analysed oocytes for potential biomarkers of oocyte quality. A panel of 12 different candidate genes (Has2, Inhba, Egfr, Grem1, Tnfaip6, Ptgs2, Cyp19, Serpine2, Pgk1, Rgs2, Ctnnd2, Cxcr4) were examined by gene expression analysis utilising aneuploidy analysed oocyte matched cumulus cells revealing three potential markers (Egfr, Inhba, Rgs2) of oocyte quality.