INDUCTION OF APOPTOSIS BY GONADOTROPIN RELEASING HORMONE DURING PREGNANCY

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The findings from this laboratory suggest that administration of a gonadotropin-releasing hormone agonist (GnRH-Ag; WY-40972) inhibits luteal progesterone (P) synthesis and release in pregnant rats. We have demonstrated that in vivo or in vitro administration of a GnRH-Ag suppresses luteal synthesis within 12 hours after the treatment during early pregnancy when the ovarian P secretion is under the control of pituitary. The recent data from our laboratory support the hypothesis that GnRH-Ag induces apoptosis in the rat corpus luteum (CL) during pregnancy. Therefore, the purpose of the current proposal is to investigate how GnRH- Ag induces apoptotic cell death in the CL during early pregnancy in rats. The animal model developed in our laboratory will be used to answer the questions raised in this proposal. The specific aims of this proposal are: (1) To confirm our preliminary observations that continuous administration of GnRH-Ag induces apoptosis in the rat CL during early pregnancy and to further determine whether the effect is mediated by PGF/2alpha. Does functional apoptosis procedure structural apoptosis or vice versa? (2) To determine if nitric oxide (NO) mediates the induction of apoptosis in the rat CL by the GnRH-Ag treatment. (3) To assess whether the effect of GnRH- Ag is a direct effect on the L which is a GnRH receptor mediated effect; and (4) To determine whether the decline in P secretion after the GnRH-Ag treatment with time is proportional to viable cells that have not undergone apoptosis. The long-term goal of this investigation is to understand the mechanisms involved in inducing the demise of the CL by administering a GnRH-AG. The results of the proposed study could lead to an application of a new approach to contraception in the human by inducing the lysis of the CL during the first 2 weeks of pregnancy.