Estrogen/androgen-mediated upregulation of progesterone receptor might lead to increased expression HSD17B11 which deactivates estrogens/androgens, providing a negative feedback loop: A data-driven hypothesis

The distruption of functionality or activity of sex steroid hormones such as estrogens and androgens contributes to pathogenesis of various human diseases. Since the hormone concentrations in blood do not always explain all processes observed in hormone-dependent tissues such as ovaries, the intra-tissue sex steroid concentrations which are determined by steroid metabolising enzymes might be relatively more important in certain contexts. Hydroxysteroid (17β) dehydrogenases (HSD17Bs), a family of enzymes that are frequently expressed in sex steroid target tissues, catalyse the conversion between the less active 17-keto steroids and the highly active 17β-hydroxy steroids. One of these enzymes, HSD17B11 (Hydroxysteroid 17-Beta Dehydrogenase 11; DHRS8; PAN1B), mediates the conversion of β-estradiol to estrone (less estrogenic derivative), and of testosterone to a-dione. Here, based on previous research and novel findings reported in the present study, I hypothesized that estrogen- and/or androgen-mediated increases in progesterone receptor (PR) levels might lead to increased levels of HSD17B11, which then deactivates androgens and estrogens (by converting them to less potent steroids), thus providing a negative feedback loop, in certain cell types. In other words, estrogens / androgens might increase cellular levels of HSD17B11 by upregulating the expression of progesterone receptor (PR) (which then upregulates HSD17B11 expression), resulting in increased HSD17B11-mediated metabolism and deactivation of these steroid hormones. This feedback mechanism might potentially limit the levels of active forms of these steroid hormones (since HSD17B11 catalyzes the inactivation of these hormones), providing protection against over-activity of these steroid hormones. I also discussed the potential implications of this hypothesis in endometriosis, for which deficient metabolism of E2 by several HSD17Bs including HSD17B11 might give rise to high local concentrations of E2, also considering progesterone resistance in this disease.