NEW SYNTHETIC STEROIDS WHICH INHIBIT RAT GONADAL STEROIDOGENIC ENZYMES BOTH IN VITRO AND IN VIVO

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Abstract
Six different steroidal analogues with previously suggested effects on gonadal Δ5,3β-hydroxysteroid oxidoreductase, 17α-hydroxylase and C17-20 lyase were investigated in vitro and in vivo. Testicular microsomal conversion of dehydroepiandrosterone to androstenedione and testosterone and of pregnenolone to progesterone and 5α-pregnane-3,20-dione was used as an index of Δ5,3β-hydroxysteroid oxidoreductase activity. 17α-hydroxylase activity was estimated from testicular microsomal formation of 17α-hydroxyprogesterone, androstenedione and testosterone from progesterone and the activity of C17-20 lyase was determined from the conversion of 17α-hydroxyprogesterone into androstenedione and testosterone. Analysis by gas-liquid chromatography – mass spectrometry of the steroidal excretion patterns in urine and faeces from female rats treated with two inhibitors of 17α-hydroxylase and C17-20 lyase in vivo, (I) 16β-bromo-3β,17α-dihydroxy-5α-pregnane-11,20-dione and (II) 17β-ureido-1,4-androstadien-3-one, and a third inhibitor (VI) 17α-cyano-5-androstene-3β,17β-diol, which also inhibits Δ5,3β-hydroxysteroid oxidoreductase in vitro, demonstrates the absence of C19 steroids of ovarian origin. C19 steroids are not excreted by rats treated with I and II up to 7 days after the last dose suggesting that the effects of these inhibitors are persistent. Two other steroids (III) 17-cyano-5,16-androstadien-3β-ol 3-acetate and (V) 17-cyano-5,16-androstadien-3β-ol, inhibit Δ5,3β-hydroxysteroid oxidoreductase in vitro in addition to 17α-hydroxylase and C17-20 lyase and cause the abnormal appearance of Δ5,3β-hydroxy-C19 steroids in the urines of normal and adrenalectomized females but not in those of ovariectomized or in ovariectomized and adrenalectomized rats. Each of these inhibitors also eliminates urinary 3α,17α-dihydroxy-5α-pregnan-20-one of ovarian origin. The pattern of C21O4 and C21O5 steroids of adrenal origin was only slightly affected or not affected at all by I–III and V and VI. The steroidal excretion patterns obtained in treated animals indicate a predominantly ovarian site of action of these inhibitors in vivo. Thus, the present results indicate three agents which block sex hormone production in the rat and two which inhibit gonadal Δ5,3β-hydroxysteroid oxidoreductase with moderate or no inhibition of the adrenal excretion.

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