Effect of Inhibition of  5,3 -Hydroxysteroid Dehydrogenase upon Pituitary and Serum Radioimmnoassayable Luteinizing Hormone in the Adult Male Rat

Goldman, Armond S.; Aw, Root; Rd, Russ; Bt, Rudd

doi:10.3181/00379727-136-35337

Cited by 5 publications

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“…Although steroidogenic inhibitors such as Elipten (aminoglutethimide phosphate) acting on cholesterol desmolase, cyanoketone (2a-cyano-4,4,17a-trimethyl-androst-5-en-17/?-ol-3-one) acting on the 3ß-hydroxysteroid dehydrogenase-A5^4-3-oxosteroid isomerase system and SU 10603 acting on 17a-hydroxylase and C17-20 lyase, prevent ovulation in vitro (Rondell, 1970) or in the immature gonadotrophin-primed female rat (Lipner & Greep, 1970), cyanoketone ad¬ ministered to male rats does not affect spermatogenesis (Lupo di Prisco, Materazzi & Scattolini, 1972). Since the inhibitors acting selectively at enzyme sites produce a compensa¬ tory rise in gonadotrophin output from the pituitary (Goldman, Root, Russ & Rudd, 1971), it seemed reasonable that compounds which block production of gonadal hormones and/or hormone antagonists which block hormone action at the target organs including the pituit¬ ary may be more effective in controlling spermatogenesis, if they also depress gonadotro¬ phins. Consequently, six new synthetic steroids without intrinsic hormonal action were initially selected, because they produced inhibition of testicular microsomal conversion of pregnenolone to androgens in vitro, to determine whether they affect male fertility as measured by quantitation of spermatogenesis and the ability of male rats to produce viable offspring in females.…”

Section: Introductionmentioning

confidence: 98%

Effects of New Multi-Site Hormone Blockers on the Fertility of Male Rats

Goldman¹,

Bh²,

Aw³

1976

Journal of Endocrinology

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The effects on the fertility of adult male rats of six new synthetic steroids: I, 3-cyano-5alpha-androst-1-en-17-one; II, the 17beta-acetate form of I; III, 17beta-hydroxy-5beta-cyano-androstan-3-one; IV, 6-methylpregnenolone; V, 17beta-hydroxy-17alpha-ethynyl-5beta-cyano-19-norandrostan-3-one; and VI, 19-norspiroxenone (oestr-4-en-3-one-spiro-17alpha-2'-[tetrahydrofuran]) have been tested. After 6 weeks of treatment with daily doses of 5 mg (I, II, III), 15 mg (IV) or 10 mg (V, VI) only steroid VI blocked the completion of spermatogenesis and reduced the number of foetuses sired in at least five females/male. Steroid VI also diminished seminal vesicular, prostatic, testicular and epididymal weights. It inhibited the testicular enzymes, 3beta-hydroxysteroid dehydrogenase-delta4-5-3-oxosteroid isomerase system, 17alpha-hydroxylase, and C17-20 lyase markedly, but did not affect the adrenal dehydrogenase-isomerase system. It depressed, strikingly, testicular and serum levels of testosterone and 5alpha-dihydrotestosterone and reduced pituitary and serum levels of FSH and LH. Although marked depression of target organ weights also occurred with steroids II, IV and V, and reduction of androgen levels and LH in the circulation with III, IV and V, only VI was a potent blocker of male fertility with the exception of a slight block of the siring of viable foetuses by steroids IV and V. The major difference in site of action of steroid VI from the others was the depression of pituitary and serum levels of FSH along with a marked diminution of testicular content of both testosterone and 5alpha-dihydrotestosterone. 19-Norspiroxenone in the rat is a potent anti-oestrogen without inherent oestrogenicity and is anti-uterotrophic. Thus, VI may affect male fertility by virtue of its potent anti-oestrogenic action in the hypothalamus or testis.

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Section: Introductionmentioning

confidence: 98%

Effects of New Multi-Site Hormone Blockers on the Fertility of Male Rats

Goldman¹,

Bh²,

Aw³

1976

Journal of Endocrinology

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“…Administration of this drug to female rats results in the excretion of 3p-hydroxy-A5-CI9 and C,, steroids in urine and feces [4]. This inhibitor has been successfully administered to preg- nant rats to disturb fetal sexual differentiation of male and female fetuses [3], but little has been studied of its effects in the adult male [5]. Despite the wealth of information that now exists about various biological effects of this potent compound (for references see [3]), little is known about the quantitative changes in steroid excretion in treated animals, the rapidity of onset of action, the relative contribution of gonads and adrenals to the excretion of 3p-hydroxy-A5-steroids, or the duration of the defect in steroid excretion.…”

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confidence: 99%

Sex‐Dependent Differences in Derangements of Biliary‐Steroid‐Excretion Patterns Produced by Cyanoketone in Rats

Begué

Goldman

Gustafsson

et al. 1973

European Journal of Biochemistry

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Intramuscular injections of 25 mg/kg body weight of 2a-cyano-4,4,17a-trimethyl-5-androsten17p-ol-3-one (cyanoketone) produces an immediate cessation of excretion of practically all corticosteroid metabolites (3a, 11~,15a,21-tetrahydroxy-5a-pregnan-20-one and 301-and 38,l lp, 21-trihydroxy-5a-pregnan-20-one) in bile from female rats. Instead, large amounts of 3p-hydroxy-5-pregnen-20-one, 3p,i6a-dihydroxy-5-pregnen-20-one and 5-pregnene-3B,20a-diol are excreted. The total daily excretion of steroids in bile from treated female animals is 2580 f 580 pg compared to 850 pg in a female rat injected with solvent only. When ovariectomized rats are treated with cyanoketone, the principal biliary metabolites are 3j3-hydroxy-5-pregnen-20-one and 3/3, 16a-dihydroxy-5-pregnen-20-one and the total daily excretion of steroids measured is 1186 f 197 pg indicating that ovaries contribute about 50 O/ , , of the total output of 3~-hydroxy-A5-steroids in treated, intact female rats. As late as 28 days after a single injection of cyanoketone 3p-hydroxy-A5-steroids (44 pg/24 h) are excreted in bile and the total excretion of corticosteroid metabolites is still low (72 pg/24 h) a t this time. 130 days after a single dose, no 3~-hydroxy-A5-steroids can be identified in bile but the total corticosteroid excretion is still less than 2 standard deviations below values of untreated intact animals (315 pg/24 h). Thus, in females cyanoketone has both an immediate enzyme-inhibiting effect reflected by rapid onset of action after administration and, in addition, a long-term depressing action on enzyme biosynthesis manifested by low total steroid excretion values measured a t least as long as 130 days after injection of inhibitor.Administration of cyanoketone to male rats gives rise to a small biliary excretion of 31s-hydroxy-A5-steroids (3/3,lBa-dihydroxy-5-pregnen-2O-one, 5-pregnene-3~,17a,2Ool-tmol and 5-pregnene-3p,20a-diol) and a decrease in corticosteroid (mainly 3fl,llp,2l-trihydroxy-5a-pregnan-20-one) excretion. Corticosteroid output reaches normal values about 24 h after injection of inhibitor. Testectomy eliminates biliary 3p-hydroxy-A5-~teroids. These findings indicate that cyanoketone produces biliary 3p-hydroxy-A5-steroids mainly of testicular origin. Moreover, it appears that the 3p-hydroxy-A5-steroid oxidoreductase system in the adrenals and testes of the male rat is inhibited by cyanoketone considerably less efficiently and for a shorter duration than that in the adrenals and ovaries of the female.One of the most efficient inhibitors of adrenal and gonadal steroidogenesis is the steroidal cyanoketone, 2u-cyano-4,4,17u-trimethyl-5-androsten-1~~-o~-3-one, a substrate analog that inhibits 3p-hydroxy-A5-steroid oxidoreductase [i -31. Administration of this drug to female rats results in the excretion of 3p-hydroxy-A5-CI9 and C,, steroids in urine and feces [4]. This inhibitor has been successfully administered to preg- nant rats to disturb fetal sexual differentiation of male and female fetuses [3], but little has been studied of it...

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