Effects of progestins on local estradiol biosynthesis and action in the Z-12 endometriotic epithelial cell line

• Published in: The Journal of steroid biochemistry and molecular biology 2012-11, Vol.132 (3-5), p.303-310
• Main Authors: Beranič, Nataša, Rižner, Tea Lanišnik
• Format: Article
• Language: English
• Subjects: Aromatase - genetics; Aromatase - metabolism; Aromatase pathway; Cell Line; Cell Membrane - metabolism; Cell Nucleus - metabolism; Dienogest; Dydrogesterone; Dydrogesterone - pharmacology; Endometriosis - genetics; Endometriosis - metabolism; Endometriosis - pathology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Estradiol - biosynthesis; Estradiol Dehydrogenases - genetics; Estrogen Receptor alpha - genetics; Female; Gene Expression Regulation, Enzymologic - drug effects; Humans; Intracrine estradiol biosynthesis; Medroxyprogesterone Acetate - pharmacology; Medroxyprogestrone acetate; Nandrolone - analogs & derivatives; Nandrolone - pharmacology; Progestins - metabolism; Progestins - pharmacology; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Receptors, G-Protein-Coupled - genetics
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2012.07.004

► Progestins decrease HSD17B1 and CYP19A and increase HSD17B2 expression. ► Dydrogesterone and dienogest suppress ESR1 and ESR2 transcription. ► MPA and dydrogesterone reduce mRNA levels of GPER. ► Progestins thus prevent local E2 biosynthesis through the aromatase pathway. ► Progestins also minimize E2 mediated proliferation through ESR1 and GPER. Endometriosis is a common estrogen-dependent gynecological disease. In patients with endometriosis estradiol can be synthesized locally in the endometriotic lesions from inactive precursors of adrenal or ovarian origin, via the aromatase pathway. These increased estradiol levels stimulate proliferation of endometriotic tissue. The progestins have been used in the therapy of endometriosis for more than 40 years but their pharmacological action is still not understood in detail. In the present study we therefore aimed to evaluate the effects of three progestins most commonly used in the therapy of endometriosis; medroxyprogesterone acetate, dydrogesterone and dienogest on expression of all genes encoding enzymes of the aromatase pathway and estrogen receptors in the Z-12 model epithelial cell line of peritoneal endometriosis, by qPCR and Western blotting. Our results show that application of medroxyprogestrone acetate, dydrogesterone and dienogest significantly decreases HSD17B1 and CYP19A1 expression and significantly increases HSD17B2 expression. Dydrogesterone and dienogest also significantly suppress ESR1 and ESR2 transcription, whereas medroxyprogestrone acetate and dydrogesterone significantly reduce mRNA levels of GPER. Our results thus suggest that in peritoneal endometriosis the beneficial effects of these progestins can be explained by lower HSD17B1 and higher HSD17B2 mRNA and protein levels, which lead to reduced local E2 biosynthesis. Although progestins significantly decrease CYP19A1 mRNA levels, the protein itself was not detectable by Western blotting. As progestins down-regulate expression of ESR1, ESR2 and GPER, they might also prevent E2-mediated proliferation.