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Aldo-keto reductases AKR1C1, AKR1C2 and AKR1C3 may enhance progesterone metabolism in ovarian endometriosis
Hevir-Kene, Neli ...
Endometriosis is a very common disease that is characterized by increased formation of estradiol and disturbed progesterone action. This latter is usually explained by a lack of progesterone receptor ...B (PR-B) expression, while the role of pre-receptor metabolism of progesterone is not yet fully understood. In normal endometrium, progesterone is metabolized by reductive 20alpha-hydroxysteroid dehydrogenases (20alpha-HSDs), 3alpha/beta-HSDs and 5alpha/beta-reductases. The aldo-keto reductases 1C1 and 1C3 (AKR1C1 and AKR1C3) are the major reductive 20alpha-HSDs, while the oxidative reaction is catalyzed by 17beta-HSD type 2 (HSD17B2). Also, 3alpha-HSD and 3beta-HSD activities have been associated with the AKR1C isozymes. Additionally, 5alpha-reductase types 1 and 2 (SRD5A1, SRD5A2) and 5beta-reductase (AKR1D1) are responsible for the formation of 5alpha- and 5beta-reduced pregnanes. In this study, we examined the expression of PR-AB and the progesterone metabolizing enzymes in 31 specimens of ovarian endometriosis and 28 specimensof normal endometrium. Real-time PCR analysis revealed significantly decreased mRNA levels of PR-AB, HSD17B2 and SRD5A2, significantly increased mRNA levels of AKR1C1, AKR1C2, AKR1C3 and SRD5A1, and negligible mRNA levels of AKR1D1. Immunohistochemistry staining of endometriotic tissue compared to control endometrium showed significantly lower PR-B levels in epithelial cellsand no significant differences in stromal cells, there were no significant differences in the expression of AKR1C3 and significantly higher AKR1C2 levels were seen only in stromal cells. Our expression analysis data atthe mRNA level and partially at the cellular level thus suggest enhanced metabolism of progesterone by SRD5A1 and the 20alpha-HSD and 3alpha/beta-HSD activities of AKR1C1, AKR1C2 and AKR1C3.
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