title: Rosiglitazone and pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase.
abstract: The effects of rosiglitazone or pioglitazone (thiazolidinediones, TZDs) on estrogen production and aromatase activity in human ovarian cells were examined. Human granulosa cells were incubated in the tissue culture medium supplemented with androstenedione or testosterone, with or without insulin, TZDs, or type 1 17β-hydroxysteroid-dehydrogenase (17β-HSD) inhibitor. Estrogen concentrations in the conditioned medium, aromatase mRNA and protein expression in the cells and androgen substrate binding to aromatase were measured. With androstenedione as substrate, rosiglitazone or pioglitazone inhibited estrone production by up to 22% (p<0.012) while type 1 17β-HSD inhibitor enhanced this effect of rosiglitazone or pioglitazone by 37% (p<0.001) and by 67% (p<0.001), respectively. With testosterone as substrate, rosiglitazone or pioglitazone inhibited estradiol production by 32% (p<0.001). With (3)H-testosterone as substrate, rosiglitazone or pioglitazone inhibited the (3)H-tritiated water release by the cultured cells by 45% and 35%, respectively, thus directly demonstrating inhibition of aromatase. Rosiglitazone or pioglitazone, however, had no significant effect on aromatase mRNA or protein expression. Rosiglitazone or pioglitazone inhibited (125)I-androstenedione and (125)I-testosterone binding to aromatase by 38% (p<0.001). It was concluded that rosiglitazone or pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase.
authors.affiliation: G J Friedman Diabetes Institute and Division of Endocrinology, Department of Medicine, Beth Israel Medical Center and Albert Einstein College of Medicine, New York, USA. dyoung@chpnet.org
authors.forename: D
authors.initials: D
authors.lastname: Seto-Young
authors.forename: D
authors.initials: D
authors.lastname: Avtanski
authors.forename: G
authors.initials: G
authors.lastname: Parikh
authors.forename: P
authors.initials: P
authors.lastname: Suwandhi
authors.forename: M
authors.initials: M
authors.lastname: Strizhevsky
authors.forename: T
authors.initials: T
authors.lastname: Araki
authors.forename: Z
authors.initials: Z
authors.lastname: Rosenwaks
authors.forename: L
authors.initials: L
authors.lastname: Poretsky
mesh_terms: D000728:Androgens / Q000378:metabolism*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D004967:Estrogens / Q000096:biosynthesis*; D004970:Estrone / Q000096:biosynthesis; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D000077205:Pioglitazone; D011485:Protein Binding / Q000187:drug effects; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000728:Androgens; D004967:Estrogens; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004970:Estrone; D001141:Aromatase; D000077205:Pioglitazone