title: The effect of progesterone analogues, naturally occurring steroids, and contraceptive progestins on hypothalamic and anterior pituitary delta4-steroid (progesterone) 5alpha-reductase.
abstract: The effects of a number of steroids on the conversion of progesterone to 5alpha-dihydroprogesterone by hypothalamic and pituitary progesterone 5alpha-reductase have been investigated. Using enzyme preparations from female rats and 3H-progesterone as substrate, 5alpha-reduced products (5alpha-dihydroprogesterone and 3alpha-hydroxy-5alpha-pregnan-20-one) were analyzed by reverse isotopic dilution analysis. The amount of total 5alpha-reduced products formed was compared in the presence and absence of the test steroid. Derivatives lacking the delta4 and/or the 3-keto moiety were without effect. Corticosterone had no effect. 16beta-Methylprogesterone inhibited progesterone 5alpha-reduction in both tissues by at least 65%, while the 2alpha-, 6alpha-, and 7alpha-methylated derivatives had lesser effects. 3-Oxo-4-pregnene-20beta-carboxaldehyde and 21-fluoroprogesterone were potent inhibitors. 17-Hydroxyprogesterone was a competitive inhibitor (substrate) with Ki's of 0.27 micrometer (pituitary) and 0.29 micrometer (hypothalamus). Medroxyprogesterone exerted little inhibitory effect. Of the 19-nor-steroids examined, only norethindrone appreciably inhibited the 5alpha-reduction. These results suggest that some natural delta4-3-ketosteroids can modify enzymatic activity. Also, inhibitory analogues may be useful for studies on the role of this 5alpha-reduction of progesterone.
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000818:Animals; D003345:Corticosterone / Q000494:pharmacology; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology*; D066298:In Vitro Techniques; D007700:Kinetics; D008745:Methylation; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000201:enzymology*; D011374:Progesterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology*; D011375:Progesterone Reductase / Q000378:metabolism*; D051381:Rats; D013256:Steroids / Q000494:pharmacology*; D013739:Testosterone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D045167:Progesterone Congeners; D013256:Steroids; D013739:Testosterone; D011374:Progesterone; D015096:3-Hydroxysteroid Dehydrogenases; D011375:Progesterone Reductase; D003345:Corticosterone