Steroid transformations in pregnant mares: metabolism of exogenous progestins and unusual metabolic activity in vivo and in vitro.
The mare possesses unique steroid hormone metabolic activity during pregnancy in that peripheral 4-pregnene-3,20-dione (progesterone; P4) is undetectable by 220 days gestation. This study examines in vivo metabolism of progestins by the pregnant mare and in vitro metabolic activity of maternal and fetal tissues. Pregnant mares (n = 3) received intravenous infusions of 3 beta-hydroxy-5-pregnen-20-one (pregnenolone; P5), P4, 5 alpha-pregnane-3,20-dione (5 alpha-DHP), 3 beta-hydroxy-5 alpha-pregnan-20-one (3 beta-5 alpha), deuterium labeled (D4)-P5, D4-3 beta-5 alpha and vehicle. Anestrous mares (n = 2) were infused with P5, P4, and vehicle. Also, placenta, endometrium, fetal gonad, maternal and fetal liver, and adrenal from 4 animals were incubated in D4-P5, D4-5 alpha-DHP, or D4-3 beta-5 alpha. Pregnant mares (in vivo) converted infused P5 predominantly to 5-pregnene-3 beta,20 beta-diol (P5-beta beta), 5 alpha-DHP, 20 alpha-hydroxy-5 alpha-pregnan-3-one (20 alpha-5 alpha), and 3 beta-5 alpha while only minor concentrations of P4 were detected. Infused P4 was converted primarily to 5 alpha-DHP and 20 alpha-hydroxypregnanes and when 5 alpha-DHP served as a substrate, other 5 alpha-pregnanes were formed. Infused 3 beta-5 alpha was either reduced to beta alpha-diol or oxidized to 5 alpha-DHP. Regardless of treatment, anestrous mares were incapable of producing any 20 alpha-hydroxypregnanes but could convert P5 to P5-beta beta and P4 in quantities similar to that of pregnant mares. In vitro, placenta converted D4-P5 to D4-P4 while D4-3 beta-5 alpha was oxidized to D4-5 alpha-DHP. Endometrium converted substrate primarily to D4-20 alpha-hydroxypregnanes. Both maternal and fetal liver produced D4-20 beta-hydroxy compounds regardless of substrate. Maternal and fetal adrenal were capable of conversion of D4-P5 to D4-P4 while fetal gonad did not perform any significant metabolism of substrate, though it produced P5. These data explain the absence of P4 and presence of other progestin metabolites in maternal circulation during mid- and late pregnancy. Pregnenolone can be 5 alpha-reduced to 3 beta-5 alpha, and 3 beta-5 alpha could be 3-oxidized to 5 alpha-DHP. It is 5 alpha-DHP that may serve as substrate for other 5 alpha-pregnanes.
Schutzer
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Department of Animal Sciences, Oregon State University, Corvallis, USA.
Holtan
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D043582:5-alpha-Dihydroprogesterone; D000818:Animals; D001711:Biotransformation; D003903:Deuterium; D004717:Endometrium / Q000378:metabolism; D005260:Female; D006736:Horses / Q000378:metabolism*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008099:Liver / Q000196:embryology / Q000378:metabolism; D009928:Organ Specificity; D014677:Pharmaceutical Vehicles; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D011277:Pregnanediones / Q000493:pharmacokinetics; D011280:Pregnanolone / Q000493:pharmacokinetics; D011284:Pregnenolone / Q000493:pharmacokinetics; D011372:Progestins / Q000378:metabolism / Q000493:pharmacokinetics*
D014677:Pharmaceutical Vehicles; D011277:Pregnanediones; D011372:Progestins; D011284:Pregnenolone; D043582:5-alpha-Dihydroprogesterone; D003903:Deuterium; D011280:Pregnanolone