Ovarian estradiol (E) stimulates cellular proliferation in the human endometrium; during the secretory phase luteal progesterone (P) inhibits further E-induced proliferation of the luminal epithelium. The rodent has been used extensively as a model of hormonal control of uterine growth. In the ovariectomized (ovxd) rodent E stimulates DNA synthesis in uterine, cervical, and vaginal epithelia; P blocks E stimulation of uterine and cervical epithelia but not vaginal epithelium. Glucocorticoids also block the effect of E on uterine growth in rodents. In animals pretreated with P, E stimulates mitotic activity of the uterine stroma (subepithelial). High-dose progestin therapy is used to treat endometrial hyperplasia and endometrial carcinoma. It has been assumed that the mode of action in this therapy is to inhibit E-driven cellular events. However, recent evidence in rodents indicates that P inhibits uterine epithelial DNA synthesis that is ongoing in the absence of estrogen. In two models of estrogen-independent uterine epithelial growth, progestins and glucocorticoids inhibit DNA synthesis. The goal of the present proposal is to investigate the mechanisms of: 1) progestin and glucocorticoid inhibition of uterine epithelial proliferation; 2) E stimulation of uterine stromal DNA synthesis in P treated animals; 3) E stimulation of uterine and vaginal epithelial proliferation. Since both progestins and glucocorticoids inhibit uterine epithelium of rodents, two questions arise: 1) Do glucocorticoids inhibit human uterine epithelial proliferation? 2) Is P or glucocorticoid inhibition of the uterus mediated by the progesterone receptor (PR) or the glucocorticoid receptor? The first question will be answered by examining the response of human tissue to glucocorticoids in xenograft (athymic mouse). The second question will be answered by performing a number of studies comparing the modes of action of the two classes of steroids in the E-stimulated, and the E-independent models of uterine epithelial DNA synthesis in rodents. Proposed studies will: 1) examine the """"""""E-independent"""""""" models for signs of activated estrogenic mechanisms, i.e. the state of the estrogen receptor (cytosolic vs. nuclear fraction) and PR content; 2) determine the cell cycle specificities of the progestin and glucocorticoid responses; 3) compare relative binding affinities and dose response curves for several steroids with differing degrees of glucocorticoid and progestin activity; and 4) compare the effects of 3 antiprogestins with differing degrees of antigulcocorticoid activity. Possible interactions of the epithelia and stroma in determining the proliferative activity under hormonal influence will also be examined. Epithelial ablation in situ will determine whether that tissue is a necessary component of the stromal response to E in P-treated uterus. Heterotypic epithelial and stromal tissue recombinants will define the tissue source of the signal produced by hormones (E or E + P) administered. Expression of cellular homologs of viral oncogenes (c-onc) during E-stimulation and P-inhibition will be examined. Techniques of tissue separation to be used offer a defined system in which to examine the possible correlation of c-onc with hormonal stimulation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HD023244-05
Application #
3469622
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1988-01-01
Project End
1992-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Everett, L M; Li, A; Devaraju, G et al. (1997) A novel estrogen-enhanced transcript identified in the rat uterus by differential display. Endocrinology 138:3836-41
Everett, L M; Caperell-Grant, A; Bigsby, R M (1997) Mesenchymal-epithelial interactions in an in vitro model of neonatal mouse uterus. Proc Soc Exp Biol Med 214:49-53
Steinmetz, R; Young, P C; Caperell-Grant, A et al. (1996) Novel estrogenic action of the pesticide residue beta-hexachlorocyclohexane in human breast cancer cells. Cancer Res 56:5403-9
Bigsby, R M; Young, P C (1994) Estrogenic effects of the antiprogestin onapristone (ZK98.299) in the rodent uterus. Am J Obstet Gynecol 171:188-94
Bigsby, R M; Li, A (1994) Differentially regulated immediate early genes in the rat uterus. Endocrinology 134:1820-6
Bigsby, R M (1993) Progesterone and dexamethasone inhibition of estrogen-induced synthesis of DNA and complement in rat uterine epithelium: effects of antiprogesterone compounds. J Steroid Biochem Mol Biol 45:295-301
Bigsby, R M; Young, P C (1993) Progesterone and dexamethasone inhibition of uterine epithelial cell proliferation: studies with antiprogesterone compounds in the neonatal mouse. J Steroid Biochem Mol Biol 46:253-7
Bigsby, R M; Li, A X; Bomalaski, J et al. (1992) Immunohistochemical study of HER-2/neu, epidermal growth factor receptor, and steroid receptor expression in normal and malignant endometrium. Obstet Gynecol 79:95-100
Bigsby, R M; Everett, L M (1991) Effects of progestin antagonists, glucocorticoids and estrogen on progesterone-induced protein secreted by rabbit endometrial stromal cells in culture. J Steroid Biochem Mol Biol 39:27-32
Bigsby, R M; Li, A X; Luo, K et al. (1990) Strain differences in the ontogeny of estrogen receptors in murine uterine epithelium. Endocrinology 126:2592-6

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