Deficient 17 -Hydroxysteroid Dehydrogenase Type 2 Expression in Endometriosis: Failure to Metabolize 17 -Estradiol

Abstract

Aberrant aromatase expression in stromal cells of endometriosis gives rise to conversion of circulating androstenedione to estrone in this tissue, whereas aromatase expression is absent in the eutopic endometrium. In this study, we initially demonstrated by Northern blotting transcripts of the reductive 17beta-hydroxysteroid dehydrogenase (17betaHSD) type 1, which catalyzes the conversion of estrone to 17beta-estradiol, in both eutopic endometrium and endometriosis. Thus, it follows that the product of the aromatase reaction, namely estrone, that is weakly estrogenic can be converted to the potent estrogen, 17beta-estradiol, in endometriotic tissues. It was previously demonstrated that progesterone stimulates the inactivation of 17beta-estradiol through conversion to estrone in eutopic endometrial epithelial cells. Subsequently, 17betaHSD type 2 was shown to catalyze this reaction, and its transcripts were detected in the epithelial cell component of the eutopic endometrium in secretory phase. Because 17beta-estradiol plays a critical role in the development and growth of endometriosis, we studied 17betaHSD-2 expression in endometriotic tissues and eutopic endometrium. We demonstrated, by Northern blotting, 17betaHSD-2 messenger ribonucleic acid (RNA) in all RNA samples of secretory eutopic endometrium (n=12) but not in secretory samples of endometriotic lesions (n=10), including paired samples of endometrium and endometriosis obtained simultaneously from eight patients. This messenger RNA was not detectable in any samples of proliferative eutopic endometrium or endometriosis (n=4) as expected. Next, we confirmed these findings by demonstration of immunoreactive 17betaHSD-2 in epithelial cells of secretory eutopic endometrium in 11 of 13 samples employing a monoclonal antibody against 17betaHSD-2, whereas 17betaHSD-2 was absent in paired secretory endometriotic tissues (n=4). Proliferative eutopic endometrial (n=8) and endometriotic (n=4) tissues were both negative for immunoreactive 17betaHSD-2, except for barely detectable levels in 1 eutopic endometrial sample. Finally, we sought to determine whether deficient 17betaHSD-2 expression in endometriotic tissues is due to impaired progesterone action in endometriosis. We determined by immunohistochemistry the expression of progesterone and estrogen receptors in these paired samples of secretory (n=4) and proliferative (n=4) eutopic endometrium and endometriosis, and no differences could be demonstrated. In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone. The lack of 17betaHSD-2 expression in endometriosis is not due to alterations in the levels of immunoreactive progesterone or estrogen receptors in this tissue and may be related to an inhibitory aberration in the signaling pathway that regulates 17betaHSD-2 expression.

Differential expression of 17beta-hydroxysteroid dehydrogenases types 2 and 4 in human endometrial epithelial cell lines

“…The type 1 isozyme was the first 17 -HSD isozyme identified in endometrium (Mäentausta et al 1991). The importance of its function in this tissue is controversial, because it is expressed at very low levels compared with the other isozymes (Milewich et al 1989, Casey et al 1994, Zeitoun et al 1998. This was confirmed in our study, since the expression of both 17 -HSD types 2 and 4 is much higher in human endometrial tissue and in cell lines.…”

“…Oxidative 17 -HSD activity in the uterus has been assigned to two isozymes: 17 -HSD2 (in the human: Casey et al 1994, Mustonen et al 1998, Zeitoun et al 1998 or 17 -HSD4 (up to now shown only in porcine uterus: Adamski et al 1992, Husen et al 1994. Both belong to the gene family of short chain alcohol dehydrogenases, but they share only 16·4% amino acid identity (Labrie et al 1997).…”

Endometriosis-associated ovarian cancer

“…Также к факторам высокого риска ма-лигнизации можно отнести низкую чувствительность эндометриоидных гетеротопий к гормонотерапии, так называемый атипический эндометриоз [13]. Ряд ав-торов обращают внимание на влияние внешних фак-торов окружающей среды, а именно ее загрязнение, наличие полихлорированных бифенилов и диоксинов [14]. Таким образом, под действием многих факторов развивается атипический эндометриоз, для которого характерны выраженные адгезивные и миграционные свойства, изменения в метаболизме эстрогенов и гор-мональных рецепторах, ферментная недостаточность с накоплением агрессивных метаболитов стероидов.…”

Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

“…[1] E2 is known to play a crucial role in the development and progression of several estrogen dependent diseases (EDD). [2][3][4][5] Increased E2/E1 ratios as well as elevated 17β-HSD1 mRNA levels are indicators of the involvement of 17β-HSD1 in breast cancer [6,7], ovarian tumor [8], endometriosis [9], endometrial hyperplasia [10] and other EDD [11]. Consequently, the selective inhibition of this enzyme is considered as a valuable treatment option.…”