Perinatal hypoxia leads to primordial follicle activation and premature depletion of ovarian reserve

Abstract

Background The human ovary contains 6-million follicles during the 20th week of embryonic development and 1 million at birth. Girls born at small for gestational age weight demonstrate higher FSH levels during infancy, an earlier onset of puberty, and menarche. In light of these observations, we hypothesized that exposure to hypoxia at the early neonatal period might impact the primordial follicular pool and lead to premature depletion of ovarian reserve. Methods Ovarian development in the rat model at days 1–5 postpartum reflects its human counterpart in the late perinatal period. We exposed newborn rat pups (n = 5) to controlled hypoxia, (5% oxygen/95% nitrogen) for 10 min three times daily for days 1–5 postpartum. On day 5, ovaries were harvested, H&E, Ki-67, and TUNEL staining were performed. Results The percentage of primordial follicles out of total follicles in ovaries of pups exposed to hypoxia was lower compared to control (76 ± 8.2% and 90.33 ± 6.3% respectively, p < .05). Correspondingly the percentage of primary and secondary follicles was higher than in control. The mean stromal Ki67 staining score was significantly lower in the study group (1.67 ± 0.58 and 2.5 ± 0.55 respectively, p < .05). TUNEL staining demonstrated no difference in stromal apoptosis rates between both groups. Conclusions We provide evidence for the first time that perinatal hypoxia causes premature activation and growth initiation of dormant follicles. These changes were associated with decreased stromal cell proliferation, suggesting hypoxia-induced impairment of the support cell pool as a possible mechanism for accelerated follicular activation.