Despite contraceptive availability and refinement, unplanned pregnancy remains a troubling global reproductive health issue. Global estimates suggest that of the 208 million pregnancies per year, roughly half (41%) are unplanned, leading to millions of unsafe abortions and maternal deaths1. A major reason for this is the serious side-effects of hormone contraceptives, including cardiovascular and breast cancer risks and increased depression, which lead to their non-use or discontinued use. There is an acute need for new safer contraceptives that can overcome the systemic side-effects of hormone therapy and offer wider contraceptive choice to women.
We developed a high-throughput approach for screening broad classes of drugs for potential ovulation blocking capacity using automated assessment of cumulus oocyte complex (COC) adhesion to ECM in-vitro. One “hit” compound from the drug library screen that potently and dose dependently inhibited COC adhesion in vitro caused significantly reduced ovulation (11 vs. 26 oocytes/ovary; p-5.8*10^-6) compared to controls in mice in-vivo. There was no difference in the growing follicular count but ovulated follicle structures were significantly reduced in drug treated group. This was not due to LH-pathway downregulation as Lhcgr and downstream signalling remained intact. Both ovarian histology and immunofluorescence revealed structural dysgenesis of COCs with an apparent loss of contact between oocyte and cumulus cells. Importantly, no difference in proliferative (Ki-67) or apoptotic (cleaved caspase-3) cell counts was detected between groups, suggesting minimal drug toxicity. Treatment of COCs with this drug during in vitro maturation severely inhibited COC expansion and oocyte meiotic resumption. Overall, this study is the first to 1) develop a unique high-throughput model for screening drugs for contraceptive potential; 2) identify, evaluate and validate a new class of drugs with potent in vitro and in vivo potential; and 3) demonstrate a critical role of oocyte-cumulus signalling by this target during folliculogenesis and ovulation.