Deficient 17β-Hydroxysteroid Dehydrogenase Type 2 Expression in Endometriosis: Failure to Metabolize 17β-Estradiol¹

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.

Dienogest reduces HSD17β1 expression and activity in endometriosis

“…In contrast, the mRNA expression of HSD17b2, responsible for weakening estrogenic potency, was significantly lower in OESCs compared with EESCs and NESCs. This balance between the expressions of the two enzymes indicates that estradiol is more likely to be produced in OESCs compared with eutopic endometrium, which is concordant with results from previous studies (Zeitoun et al 1998, Matsuzaki et al 2006.…”

“…COX2 overexpression results in an excess of prostaglandin E 2 , which further stimulates aromatase expression via the orphan nuclear receptor steroidogenic factor 1. Furthermore, ERb activation downregulates PR, which leads to reduced induction of HSD17b2 via retinoic acid (Zeitoun et al 1998). The combination of upregulation of aromatase and downregulation of HSD17b2 contributes to the abnormally high levels of estradiol in endometriotic tissue.…”

“…In these tissues, estradiol, the most potent estrogen, is predominantly synthesized from less potent estrone by 17b-hydroxysteroid dehydrogenase 1 (HSD17b1), and the reverse reaction is catalyzed mainly by HSD17b2. In endometriotic tissues, the expression of HSD17b1 is higher than that of HSD17b2; thus, the reaction is tilted in favor of producing estradiol (Zeitoun et al 1998, Dassen et al 2007. The other major source of estrogens is estrone sulfate, an inactive conjugated form abundant in the circulation.…”

Disturbed estrogen and progesterone action in ovarian endometriosis

“…For oxidative 17β-HSDs, Zeitoun et al (1998) have reported an absence of 17β-HSD type 2 mRNA transcripts in extra-ovarian endometriotic tissue with Northern blotting; however, our more sensitive study saw this transcript in both the control and the endometriosis group, although we did not detect any significant changes in the expression levels between these groups (Šmuc et al, 2007a, Šmuc et al, 2007b) (p >0.05) (Fig. 1D).…”

Dislozierung basalen Endometriums

“…Die Expression der P450-Aromatase [32], des Progesteron-A-Isoform-Rezeptors (PRA) [2] sowie das Fehlen der Expression der 17β-Hydroxylase Typ 2 [41] in der späten Sekretionsphase des Zyklus wurde von einigen Autoren als Charakteristikum von Endometrioseherden beschrieben, wobei allerdings als Vergleich eutopes sekretorisches Endometrium diente, welches durch transzervikale Biopsie gewonnen wurde und vermutlich im Wesentlichen Funktionalis enthielt.…”