Women with polycystic ovary syndrome characterized by oligomenorrhea, hyperinsulinemia, and hyperandrogenism experience significantly higher rates of pregnancy loss. It is not clear what abnormality is responsible for this increased incidence. As a result of the high insulin levels, however, serum levels of bioactive IGF-1 are elevated and it is known that high IGF-1 levels impair blastocyst development. The objective of this proposal is to discover to what extent high IGF-1 levels are responsible for the increased miscarriage rate in these patients. From preliminary studies we have learned that that high concentrations of IGF-1 or insulin induce extensive DNA fragmentation in nuclei of embryos cultured from a two-cell to blastocyst stage This appears to be an apoptotic process since caspase inhibitors prevent this phenomenon. High levels of IGF-1 also decrease insulin-stimulated glucose transport in these embryos and this event is downstream of IGF-1/IGF-IR binding. Finally we have also determined that IGF-1 protein expression is decreased upon exposure to IGF-1 suggesting a downregulation of the receptor, providing a possible explanation for the decreased downstream glucose transport. The three aims to be pursued by this proposal are: 1. To what extent does exposure in vitro to high concentrations of IGF-1 adversely affect preimplantation embryo expression of the IGF-1 receptor and decrease signaling via this receptor? 2. How do high in vitro concentrations of IGF- 1 trigger apoptosis and which cell death associated pathways are involved? 3. Do the same changes in insulin-stimulated glucose transport, alterations in IGF-1/IGF-1R signaling, and increased apoptosis seen in vitro occur in vivo using models of excess IGF- 1 and does this manifest as a pregnancy loss? The rationale of this project is if the increase in pregnancy loss among these patients is due to increased IGF-1 levels, then attempts should be made to lower insulin and thus IGF-1 levels in order to decrease embryo exposure. Results of this work are expected to have a significant impact on reproductive endocrinology by providing scientific evidence to support new clinical interventions in patients with polycystic ovary syndrome.
