Ovarian aging is associated with enhanced ovarian fkbp51 expression: a molecular insight for age-related female fertility

Ovarian reserve is essential for fertility and inversely related to aging. The molecular mechanisms underlying ovarian aging remains unexplored although contributing factors such as mitochondrial dysfunction, genetic and epigenetic factors have been studied. An impaired ovarian microenvironment affects oocyte quality, and accelerates ovarian aging, leading to infertility. Excess extracellular matrix (ECM) accumulation contributes to ovarian fibrosis that increases with reproductive age. We previously showed that uterine fibroid tissue displays increased levels of FK506 binding protein 51 (FKBP51) which triggers ECM deposition and inhibits transcriptional activity of steroid receptors. Expression of FKBP51 is increased in stress conditions and advancing age, which contribute to the etiology of ovarian disorders. Despite the central role of FKBP51 in stress related disorders, the expression levels and impact of FKBP51 on ovarian biology are unknown. We hypothesized that FKBP51 contributes to ovarian fibrosis by dysregulation of ovarian microenvironment leading to ovarian aging or diminished ovarian reserve (DOR). Thus, we evaluate FKBP51 expression in human ovary to understand its role in ovarian aging and/or ovarian reserve. Immunohistochemistry for FKBP51 was performed in paraffin embedded ovarian tissues obtained from women of reproductive age (18-30 years; n=6) and post-menopausal women (50-65 years; n=6). Analysis by qPCR was used to measure FKBP5 levels in pooled cumulus cells (CCs) and granulosa cells (GCs) collected from women undergoing in vitro fertilization. Samples collected included those with young age with normal ovarian reserve (<35 years; n=12), advanced maternal age (>37 years; n=8) and DOR (anti-mullerian hormone (AMH) <1 ng/mL; n=10). Statistical analysis was performed using t-test and P<0.05 accepted as significant. Immunohistochemistry revealed that FKBP51 is highly expressed by ovarian stromal cells, GCs and CCs. FKBP51 levels were significantly enhanced in ovarian stroma of post-menopausal women versus reproductive age women (Mean ±SEM: 160.5± 17.7 vs. 120.6 ±14.3; P<0.01). Similarly, qPCR results showed that compared to young women with normal ovarian reserve: 1) CCs of women with advanced age display significantly higher FKBP5 levels (1.11± 0.5 vs. 1.84± 0.8; P<0.05), but not in DOR group; and 2) GCs of women display similar FKBP5 levels in advanced age women or . However, in a subgroup analysis of advanced age women with DOR versus advanced age women with normal ovarian reserve, the former displayed 4-fold increase in FKBP5 levels (P<0.05). We show, for the first time, the expression profile of FKBP51 in the human ovary. Our results indicate that with aging, FKBP51 levels increase in ovarian stroma and CCs, suggesting that enhanced ovarian FKBP51 levels could be an underlying mechanism for increased fibrosis leading to impaired oocyte release in ovarian aging. Moreover, increased FKBP51 levels in GCs of women with DOR may contribute to DOR pathogenesis.