Phorbol ester inhibition of ovarian and testicular steroidogenesis in vitro.
Possible influences of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) upon gonadal steroidogenesis were investigated in vitro. Granulosa cells from hypophysectomized, estrogen-treated rats were cultured for 2 days in medium containing 0.1 microM androstenedione. Follicle-stimulating hormone (FSH) treatment increased estrogen, progesterone, and 20 alpha-hydroxypregn-4-en-3-one production. Concomitant TPA treatment inhibited FSH-stimulated estrogen production by up to 95% [concentration that induced 50% inhibition of steroid production (ED50), 1.1 ng/ml]. TPA also inhibited FSH-stimulated progesterone (ED50, approximately 0.6 ng/ml) and 20 alpha-hydroxypregn-4-en-3-one (ED50, approximately 1.1 ng/ml) production. N6O2'-dibutyryl cyclic adenosine 3':5'-monophosphate increased steroidogenesis; however, cotreatment with TPA blocked progestin but not estrogen production. The TPA inhibition of progestin biosynthesis was accompanied by decreases in FSH-stimulated pregnenolone biosynthesis and 3 beta-hydroxysteroid dehydrogenase activity without decreasing the activity of 20 alpha-hydroxysteroid dehydrogenase. In primary cultures of rat testicular cells, human chorionic gonadotropin treatment increased testosterone production 44-fold, whereas concomitant treatment with TPA inhibited testosterone production by up to 86% (ED50, 10 ng/ml). Cholera toxin and N6O2'-dibutyryl cyclic adenosine 3':5'-monophosphate also increased testosterone production, while the actions of these agents were decreased by TPA. The TPA suppression of testosterone production was associated with a decrease in accumulation of 17 alpha-hydroxyprogesterone and androstenedione and an increase in progesterone production, suggesting a specific inhibition of 17 alpha-hydroxylase and 17,20-lyase activities. These results demonstrate the inhibitory effects of a tumor promoter upon gonadotropin-stimulated steroidogenesis by cultured rat granulosa and Leydig cells through specific regulation of steroidogenic enzymes. Additional studies may assist in further elucidation of cellular mechanisms associated with carcinogenesis and steroidogenesis.
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D004967:Estrogens / Q000096:biosynthesis; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis*; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010704:Phorbols / Q000633:toxicity*; D011374:Progesterone / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013256:Steroids / Q000096:biosynthesis*; D013737:Testis / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D004967:Estrogens; D012739:Gonadal Steroid Hormones; D010704:Phorbols; D013256:Steroids; D011374:Progesterone; D003994:Bucladesine; D005640:Follicle Stimulating Hormone; D013755:Tetradecanoylphorbol Acetate