Molecular & cellular response to gonadotropins in superovulation

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Hormone-induced ovarian stimulation, also termed superovulation, is an essential procedure for in vitro fertilization (IVF), embryo transfer, and other assisted reproductive technologies.  The methodology for ovarian stimulation in domestic animals has been available for many years.  However, the unpredictable ovarian response, in terms of viable eggs and embryo quality, are still the main factors limiting the success of assisted reproductive technology programs.  These problems have direct economic implications, since export of Canadian embryos, and pharmaceutical products for use in animal reproduction, amounts to several million dollars per year.  The current techniques for superovulation rely on the administration of an external source of gonadotropins including follicle stimulating hormone (FSH), and luteinizing hormone (LH).  Gonadotropins bind to cell-surface receptors of the developing follicle, and mediate biological activities through signal transduction pathways leading to cell proliferation and follicular growth.  A more recent approach to stimulate the ovaries involves the pharmacological inhibition of the phosphodiesterases (PDEs), the enzymes that inactivate the intracellular messenger that mediates the effects of the gonadotropins.  We propose that recombinant gonadotropins of very high potency (superagonists), combined with pharmacological inhibition of the PDEs, will represent a novel method to induce superovulation.  We aim to develop strategies to reduce the frequency of gonadotropin injection in order to lower the handling stress on the prospective donor and decrease the labour costs.  Reducing the amount of gonadotropins is advantageous because high levels are associated with a reduction in oocyte and embryo quality.  Therefore, we will synthesize recombinant agonists of the gonadotropins and characterize their responses in the ovary in combination with the PDE inhibitors.  By characterizing molecular and cellular responses to gonadotropins we will identify novel targets for pharmacological interventions in the ovary.  The emerging information will lead to the development of better methods of superovulation and improved rates of success in the application of assisted reproductive technologies to farmed game and domestic animals.