PDE3 Inhibitors: Selective Blockers of Oocyte Maturation

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DESCRIPTION (provided by applicant): The need for contraception has never been greater, as evidenced by a world population of over 6 billion, and greater than one billion young people currently in the prime reproductive years. Overpopulation is a pernicious public health affliction that ravages infrastructure and limits the achievement of hard fought gains in overall health status by threatening the basic infrastructure of humanity. Contraception also provides significant preventative health benefits by reducing unintended pregnancy, abortions, and unwanted births. As side effects, access, and cultural or moral objections limit the universal acceptance of current methods, research into novel contraceptives is warranted. The purpose of this grant is to explore the hypotheses that selective expression of phosphodiesterase (POE) isoforms exists in the primate ovary, that selective blockade of PDE3 can be exploited to prevent spontaneous and gonadotropin induced oocyte maturation, and that chronic treatment with a PDE3 inhibitor can prevent pregnancy in primates without affecting menstrual cyclicity or luteal function. The Specific Aims are to: (1) Describe the basic biology of PDE expression in the primate ovary. The goal of this aim is to characterize the PDE isoenzymes expressed in the macaque ovary. An additional goal will be to test novel PDE3 inhibitors for their ability to prevent spontaneous resumption of meiosis in vitro to learn if greater selectivity or potency can be achieved. (2) Determine if PDE3 inhibitors prevent oocyte maturation, but not ovulation and function of the corpus luteum in rhesus monkeys undergoing controlled ovarian stimulation (COS) protocols or during natural cycles in vivo. The goals of this aim will be to document that oocyte inhibition can be effectively and selectively achieved in vivo, and to investigate the systemic toxicity of PDE3 inhibitors at pharmacologically active dosages in vivo. 3) Determine whether PDE3 inhibitors function as contraceptive agents in regularly cycling rhesus monkeys in paired mating situations. The goal of this aim is to document the efficacy and practicality of systemic administration of a PDE3 inhibitor as a potential contraceptive through longer-term observation. Experimental designs will include: characterization of PDE gene products (mRNA and protein) in somatic and germ cells from ovarian tissue (Aim 1), in vitro incubation of immature oocytes and granulosa cells with PDE3 inhibitors (Aim 1), in vivo administration of a PDE3 inhibitor to monkeys during COS and spontaneous menstrual cycles, followed by follicular aspiration to assess oocyte maturation and fertilizability in vitro, plus endocrine and toxicity measurements (Aim 2), and chronic administration of a PDE 3 inhibitor to fertile females caged with fertile males to assess contraceptive efficacy and long term toxicity (Aim 3). This approach is expected to provide a foundation for future Phase 1 trials of PDE3 inhibitors in humans.