In this invited review article P.I. presented current theories on pathogenesis of endometriosis, followed by an overview on estrogen biosynthesis and action in normal and diseased endometrium. The potential role of aberrant expression of individual estrogen-metabolizing enzymes was discussed, and a model mechanism for increased formation of estradiol was presented separately for three different types of endometriosis: ovarian, peritoneal and deep infiltrating endometriosis. Finally, the interplay between estrogen action, inflamation and proliferation was described.
COBISS.SI-ID: 25555929
We examined the expression of estrogen and progesterone metabolizing enzymes and their corresponding receptors in ovarian endometriosis. Our data indicate that several enzymes of estrogen and progesterone metabolism are aberrantly expressed in endometriosis, which can lead to increased local levels of mitogenic estradiol and decreased levels of protective progesterone. Changes in estrogen receptor expression suggest that estradiol may act via estrogen receptor alfa (ERalfa) or via non-ER mediated pathways.
COBISS.SI-ID: 24638937
We examined expression of pre-receptor regulatory enzymes: aromatase, 17beta-hydroxysteroid dehydrogenases, 20alfa-hydroxysteroid dehydrogenases (AKR1C1, AKR1C3), sulfatase and sulfotransferase, and estrogen (ERs) and progesterone (PRs) receptors in samples of endometrial cancer and adjacent control endometrium. Our results show that up-regulation of aromatase in concert with AKR1C3 can lead to increased levels of estradiol, which acts via ERalfa. Upregulation of AKR1C1 and AKR1C3 can result in lower levels of protective progesterone, which acts mainly via PR-B.
COBISS.SI-ID: 24859609
We examined inhibitory action of flavonoids, cinnamic acids and their derivatives against 17beta-HSD type 1. As flavonoids are structural analogues of estrogens, we examined their proliferative action in ER positive breast cancer cell line T-47D. Among 10 flavonoids 6 showed more than 70% inhibition of 17beta-HSD type 1 at 6 microM concentration. In a series of 18 derivatives of cinnamic acid, the best inhibitor was 4-cyanophenyl 3,4-methylenedioxycinnamate, with more than 70% inhibition of 17beta-HSD type 1. None of flavonoids affected the proliferation of T-47D breast cancer cells.
COBISS.SI-ID: 24720601
Gene expression analysis at the mRNA and protein levels showed disturbed phase I and II estrogen metabolism in endometrial cancer. Real-time PCR analysis revealed downregulation of CYP1B1 in CYP3A7, higher levels of SULT2B1, UGT2B7 and GSTP1, and no statistical difference in COMT, CYP1A1, CYP3A5, SULT1E1 and SULT2A1. Expression of CYP1B1 and COMT was examined also at the protein and cellular levels by Western blot and immunohistochemistry. We were the first to show higher levels of soluble protein COMT in cancerous endometrium and higher levels of mebrane bound COMT in control endometrium.
COBISS.SI-ID: 27490009