Hormones action in endometriosis

University Of Illinois At Chicago, Chicago IL

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Abstract

The long-term objective of this application is to characterize the common cellular and molecular mechanisms responsible for resistance to progesterone action and impaired estradiol metabolism in endometriotic tissue in contrast to the eutopic endometrium. Progesterone induces the expression of 17beta-hydroxysteroid dehydrogenase (HSD) type 2, which catalyzes the conversion of the potent estrogen, estradiol to a less estrogenic steroid, estrone in endometrial epithelial cells. Our recent data are suggestive that stromal progesterone receptors (PR) mediate the stimulatory effect of progesterone on 17beta-HSD type 2 expression in epithelial cells. Our recent data are suggestive that stromal progesterone receptors (PR) mediate the stimulatory effect of progesterone on 17beta-hSD type 2 expression in epithelial cells. Interestingly,, we also demonstrated in vivo the absence of 17beta-HSD type 2 expression in epithelial cells of endometriotic tissue in response to progesterone stimulation and interpreted this find as evidence for resistance to progesterone action. We further showed the that PR isoform B, which mediates the transactivating effects of progesterone in general is absent in endometriotic tissue, whereas only the transrepressor type isoform PR- A is present in this tissue. In contrast, both PR-B and PR-A are expressed and regulated by ovarian steroids in the eutopic endometrium. We hypothesize that the lack of PR-B causes resistance to progesterone action and disruption of the paracrine signaling, which mediates 17beta-HSD type 2 induction in epithelial cells. This results in elevated levels of estradiol, a mitogen for endometriotic tissue. Additionally, the absence of PR-B and the unopposed functions of PR- A may inhibit differentiation and apoptosis and enhance proliferation in endometriotic cells. We propose the following specific aims. (1) The cellular and molecular mechanisms responsible for the lack of PR-B expression in endometriotic tissue will be determined. We will determine, in particular, whether aberrations in steroid receptor expression in endometriotic tissue modulate the differential effects of estradiol on PR-A and PR-B expression. (2) Aberrations in epithelial- stromal interactions, which disrupt the progesterone induction of 17beta-HSD type 2 expression in endometriotic tissue will be characterized. (3) We will determine whether the lack of PR-B and the unopposed functions of PR-A in endometriotic tissue are responsible for altered differentiation, apoptosis and proliferation in endometriotic tissue. Identification of the molecular mechanisms responsible for progesterone resistance and their functional consequences in endometriotic tissue may lead to novel strategies for treatment of endometriosis such as the development and use of selective progesterone receptor modulators.