Project: Research project

Project Details


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.
Effective start/end date8/1/877/31/93


  • National Institutes of Health: $88,680.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)

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