The oral contraceptive pill has had enormous social and economic benefit by preventing unwanted pregnancies. Yet, unplanned pregnancy remains one of the most troubling global reproductive health issues. Global yearly estimates suggest that roughly 85 million pregnancies are unplanned, leading to millions of unsafe abortions and over 500,000 maternal deaths worldwide [1]. A major reason for this are the serious side-effects of hormone contraceptives, including cardiovascular and breast cancer risks, 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 choices to women.
We have recently developed an in vitro, high-throughput screening model of ovulation, using a well-established cumulus-oocyte-complex (COC) adhesion assay. Using this approach to screen drug libraries, we identified a new class of drugs that potently and dose-dependently inhibit COC adhesion. In vivo testing in a mouse ovulation assay demonstrated highly significantly reduced ovulation with one candidate compound (11 vs. 26 oocytes/ovary;p5.8*10^-6) compared to controls. Notably, while there was no difference in the growing follicle counts, there was a clear increase in large pre-ovulatory follicles that failed to ovulate in the drug treated group. Gene expression analysis revealed that LH-Receptor expression and downstream signalling remained intact. Importantly, immunohistochemical analysis showed no difference in proliferative or apoptotic follicle counts between groups, suggesting minimal drug toxicity. Further, mechanistic investigations showed that drug treatment severely inhibited COC expansion and oocyte meiotic maturation when treated during in vitro maturation. Overall, this study is the first to 1) develop a unique high-throughput model for screening drugs for contraceptive indication; 2) identify and validate a new class of drugs with potent in vitro and in vivo potential; and 3) demonstrate a critical role for this target in oocyte-cumulus signalling during folliculogenesis and ovulation.