The overall objective of this project is to determine the mechanism(s) by which desensitization of uterine target cells to estrogen (E) and progesterone (P) is regulated. E and P action are believed to be mediated primarily by specific receptors present in uterine target cells which upon binding of the specific ligand (hormone) induce changes in gene expression. The interaction of these receptor systems and their mutual agonist and antagonistic properties within the physiological range of E and P will be a focus of this research proposal. Several systems of uterine desensitization to E or P in rodents (rats and hamsters) will be studied. Uterine desensitization to P will be studied: 1. during different sustained levels of serum P; 2. in the presence or absence of E priming; 3. during antiprogestin treatment. Desensitization of E action will be studied: 1. during P-dependent desensitization; 2. in P-independent desensitization (periods of the hamster estrous cycle); 3. during antiestrogen treatment. Because of the importance of differential uterine cell type responsiveness, desensitization mechanisms will be studied in specific uterine cell types i.e. epithelia, stroma, and myometrium. Receptor-related endpoints of E and P action will include: E- induced P receptor; E-induced retention of occupied nuclear E receptor; P-induced down-regulation of occupied nuclear E receptor; P-induced inactivation of its own receptor. Because in certain experimental or physiological models of desensitization these endpoints may be precluded, cell-free translation assays of mRNA isolated from these cell types will be used to examine the 'domains' of hormone-induced proteins. These approaches are intended to provide a more complete functional description of uterine desensitization. The desensitization of uterine target cells to E or P may constitute an important physiological mechanism by which reproductive function and cyclicity are regulated. The hormonal systems of uterine desensitization will be evaluated as models with which to understand physiological desensitization processes that occur during reproduction e.g. the estrous cycle, implantation, and pregnancy.
