The mechanism(s) by which estrogens control the growth of reproductive tissues such as the uterus, mammary gland and vaginal epithelium is not completely understood. Recent information in the scientific literature suggests that epidermal growth factor (EGF) may be a putative agent in mediating estrogen- stimulated uterine growth. A clearer picture of the relationship between EGF and estrogen in producing uterotrophic effects is important in further understanding the mechanism of action of estrogen at the cellular level and how the hormone may serve to temporally integrate disparate components of the growth process. This knowledge base might have useful clinical applications for endometriosis, estrogen responsive carcinomas and other reproductive tissue neoplasia, and certain aspects of infertility. The purpose of this study is to critically explore casual correlations among hormone estrogenicity (potency), uterine estrogen receptor availability, uterine EGF receptor content, uterine and serum EGF levels and the degree of the uterotrophic response. Specifically, ovariectomized rats will be administered estrogens of differing biological potency on long-term uterine growth (diethylstilbestrol, estradiol-17 beta, estriol or estradiol-17 alpha) or antiestrogens (nafoxidine, tamoxifen or CI-628) and the relationship between dose of hormone administered and extent of uterine growth ascertained with respect to tissue levels of EGF receptor and EGF peptide as measured by radioimmunoassay. The linkage between the estrogen receptor and the stimulation of uterine EGF receptor by exogenous steroid will also be assessed through altering estrogen receptor availability by prior antiestrogen treatment to differentially inhibit synthesis and turnover of the steroid receptor. Estrogen receptor-dependent and receptor-independent impairment of uterine growth can be induced by certain neonatal hormone treatments to provide models to further assess the relationship between estrogen receptor function, uterine growth and EGF receptor content. Finally, EGF secretion during the estrous cycle, the ability of EGF antibody to inhibit estrogen-induced uterine growth and a possible role for the submandibular salivary gland in the process of growth will also be studied.
