DIFFERENTIAL EFFECT OF TRILOSTANE ON THE PROGESTIN MILIEU IN THE PREGNANT MARE

Trilostane, a competitive inhibitor of 3 beta-hydroxysteroid dehydroge nase, was administered intravenously to pregnant mares (n = 3) between day 277 and day 282 of gestation to determine its effect on the proge stin milieu. In addition, placental tissue from mares at mid-gestation (150-300 days) (n = 4) were exposed to either deuterium-labelled preg nenolone alone or deuterium-labelled pregnenolone and trilostane to ex amine the effect of trilostane on placental metabolism of pregnenolone . Blood samples were collected from indwelling jugular catheters at fr equent intervals for 48 h after infusion. Both plasma samples and incu bation media were quantitatively analysed, after solid phase extractio n and steroid derivitization, for concentrations of eight different pr ogestin metabolites using gas chromatography and mass spectrometry. Tr ilostane infusion differentially affected the progestin milieu in vivo without inducing abortion. Forty-five minutes after infusion, materna l plasma concentrations of pregnenolone, 5-pregnene-3 beta,20 beta-dio l, 5 alpha-pregnane-3 beta,20 beta-diol and 3 beta-hydroxy-5 alpha-pre gnan-20-one increased (P < 0.05) and remained high for 37 h. Concentra tions of 5 alpha-pregnane-3,20-dione, 20 alpha-hydroxy-5 alpha-pregnan -3-one and 5 alpha-pregnane-3 beta,20 alpha-diol decreased 15 min afte r infusion (P < 0.05), yet 1.5 h after infusion, concentrations had in creased and remained high until 37 h after infusion. Trilostane inhibi ted the conversion of pregnenolone to progesterone - in vitro (P < 0.0 01) while mediating an increase (P < 0.05) in concentrations of 5 alph a-pregnane-3,20-dione and 3 beta-hydroxy-5 alpha-pregnan-20-one. These observations demonstrate that the pregnant mare possesses unique ster oid hormone metabolic activity and suggests that another steroid, perh aps 5 alpha-pregnane-3,20-dione and not progesterone, is the important steroid precursor for the other progestin metabolites found in circul ating plasma.