Regulation of Steroidogenic Acute Regulatory Protein Expression and Progesterone Production in Endometriotic Stromal Cells

Abstract

The regulation of steroidogenic acute regulatory protein (StAR) gene expression and the synthesis of steroids from cholesterol in ectopic endometriosis tissues were investigated. Peritoneal fluid and endometrial tissues were collected from patients with endometriosis and otherwise healthy women. Peritoneal progesterone and 17 beta-E2 concentrations were highest in early stage endometriosis compared with those in advanced stage endometriosis and in normal women. In concordance with the profile of peritoneal steroids, StAR mRNA and protein were greatest in ectopic implants of early endometriosis. In the advanced stage, concentrations of StAR mRNA and protein were also greater compared with those in normal endometrium. In contrast, P450 side-chain cleavage enzyme and 3 beta-hydroxysteroid dehydrogenase transcripts were not different between normal endometrium and ectopic endometriotic implants. Expression of StAR mRNA was detected in purified stromal, but not epithelial, cells. Treatment with PGE(2), but not TNF alpha, or IL-1 beta significantly increased StAR expression and thus induced progesterone production in cultured endometriotic stromal cells. These results demonstrated that aberrant expression of StAR in ectopic endometriotic tissues leading to increased peritoneal progesterone is associated with the formation of endometriosis. Induction of StAR gene expression by peritoneal PGE(2) in endometriotic stromal cells may further contribute to the development of endometriosis.

Increased expression of CYP1A1 and CYP1B1 in ovarian/peritoneal endometriotic lesions

“…This may signify that even after several in vitro passages, the stromal cells are able to retain the expression pattern of the whole tissue, suggesting that epigenetic modifications might have occurred before isolating the cells, extending this phenotype through late in vitro passages. Interestingly, this 'retained memory' has been observed in other studies of isolated stromal endometrial cells (Tsai et al 2001, Aghajanova et al 2010. Paradoxically to the expression data, when we performed functional studies of estradiol metabolism with the same cells, a pronounced increase in estradiol half-life was observed in ovarian endometriotic stromal cells.…”

Estrogen and progesterone receptors in smooth muscle component of deep infiltrating endometriosis

“…In others words, general or locally produced steroid hormones bind to nuclear receptors and act either to increase or decrease production of specific growth factors or their receptors (18,19). To this point of view several recent studies have demonstrated that a series of namely StAR, P450 side-chain cleavage enzyme, 17-a-hydroxylase, 3 b-hydroxysteroid dehydrogenase, and aromatase may be biosynthesiedd locally by ectopic endometrial cells, leading to local production of both E 2 and progesterone (10,11), although the observation that local E 2 and progesterone takes place locally in endometriotic lesions suggests that these steroids could induce muscle hyperplasia via their receptors. To this point of view, for the first time, we have clearly demonstrated the presence of both ER and PR in the smooth muscle component of DIE, except colonic endometriosis, where ER were absent.…”

“…In endometriosis, recent studies have clearly showed an overexpression of both aromatase and steroidogenic acute regulatory protein (StAR), leading to a local estradiol (E 2 ) and progesterone biosynthesis, which could promote the growth of smooth muscle fibers via their related receptors (10,11).…”

Aromatase excess in cancers of breast, endometrium and ovary

“…In fact, work from our laboratory and other investigators over the past 10 years uncovered a molecular link between inflammation and estrogen production in endometriosis [86]. This is mediated by a positive feedback cycle that favors expression of aromatase and COX-2 and continuous local production of estradiol and PGE 2 in endometriotic tissue [107][108][109]. In this vicious cycle, PGE 2 induces aromatase, whereas the product of aromatase enzyme, i.e., estradiol, induces COX-2 and thus PGE 2 formation.…”