Reproductive ageing is linked to the depletion of ovarian primordial follicles, that causes an irreversible change to ovarian cellular function and ultimately reduces the capacity to reproduce. Our recent research has highlighted the role of bone morphogenetic protein (BMP) signalling in the regulation of the ovulation rate in sheep, and has led us to further investigate the molecular regulation of folliculogenesis by the BMPs (Regan et al. 2015). The current study aimed to profile the expression of bone morphogenetic protein receptor (BMPR1B), follicle stimulating hormone receptor (FSHR), luteinising hormone receptor (LHR), and growth hormone receptor (GHR) and also levels of apoptosis in IVF patients (101), in a range of ovarian primordial follicle depletion. An average of 8000 granulosa cells/follicle was analysed, and the follicles ranged in diameter from 4-27 mm. The granulosa cell, surface-expressed mature receptor protein density was measured by immunofluorescent labelling via flow cytometry. Ovarian reserve was measured indirectly by the antral follicle count (AFC). AFC is the number of follicles between 2-10 mm present on day 2-5 of a cycle.
A decline in granulosal BMPR1B and FSHR density occurred at the time of cyclic dominant follicle selection, and again during the terminal stage of folliculogenesis in the ‘good ovarian reserve’ IVF patients (23-30 years (y)). The older ‘poor ovarian reserve’ patients (40+ y) experienced a reversal of this pattern. The LHR density failed to be down-regulated during pre-ovulatory maturation in the 40+ y group, and GHR density was reduced with ovarian ageing. The level of apoptosis was reduced with ovarian reserve depletion.
The study’s results demonstrate the disrupting effect that age-induced depletion of the ovarian reserve has on receptor density at the two stage-specific, critical time points of dominant follicle selection and pre-ovulatory maturation. The dysregulation is potentially responsible for the reduction in oocyte quality in older patients.