5α-Reductase inhibitory and anti-androgenic activities of some 4-azasteroids in the rat

Brooks, J. R.; Berman, Charles L.; Primka, R. L.; Reynolds, G. F.; Rasmusson, Gary H.

doi:10.1016/0039-128x(86)90072-3

Cited by 98 publications

(35 citation statements)

References 18 publications

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“…Finasteride, an azasteroid, is a pure, competitive inhibitor of 5a-reductase, with almost no affinity for the androgen receptor. In experiments in dogs and cats, finasteride has been shown to reduce prostate size sig nificantly [1,2].…”

Section: Hormonal Effects Of Finasteridementioning

confidence: 99%

Hormonal Effects of a 5α-Reductase Inhibitor (Finasteride) on Hormonal Levels in Normal Men and in Patients with Benign Prostatic Hyperplasia

Vermeulen

Giagulli²,

Schepper³

et al. 1991

Eur Urol

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Section: Hormonal Effects Of Finasteridementioning

confidence: 99%

Hormonal Effects of a 5α-Reductase Inhibitor (Finasteride) on Hormonal Levels in Normal Men and in Patients with Benign Prostatic Hyperplasia

Vermeulen

Giagulli²,

Schepper³

et al. 1991

Eur Urol

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“…To determine whether testosterone or dihydrotestosterone is responsible for the control of this crucial process for androgen-mediated prostate growth, we evaluated the effect of the 4-azasteroid finasteride, a potent competitive inhibitor of the enzyme (15)(16)(17), on the level of expression of 5a-reductase and its mRNA in the rat ventral prostate. The findings demonstrate the existence of a dihydrotestosteronemediated feed-forward control of prostate growth.…”

mentioning

confidence: 99%

Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase.

George

Russell

Wilson

1991

Proc. Natl. Acad. Sci. U.S.A.

120

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Dihydrotestosterone, the primary mediator of prostate growth, is synthesized in target tissues from the circulating androgen testosterone through the action of steroid Sa-reductase (EC 1.3.99.5). The expression of 5a-reductase and the level of 5a-reductase messenger RNA in rat ventral prostate are regulated by androgens. To determine whether this control is mediated by dihydrotestosterone or testosterone, we investigated the effect of rmasteride, a potent inhibitor of steroid 5a-reductase, on the expression of 5a-reductase in the prostate. The administration of rmasteride to intact rats for 7 days caused a 55% decrease in prostate weight and an 87% decrease in 5a-reductase enzyme activity. Furthermore, the restoration ofprostate growth after castration and the enhancement in 5a-reductase enzyme activity and 5a-reductase messenger RNA level by testosterone administration were blocked by finasteride, whereas the inhibitor had no effect on dihydrotestosterone-mediated increases in 5a-reductase activity or messengerRNAlevel. Thesefindingsindicatethatdihydrotestosterone itself controls prostate growth and Sa-reductase activity. They further suggest that prostate growth is controlled by a feed-forward mechanism by which formation of trace amounts of dihydrotestosterone induces 5a-reductase, thereby increasing dihydrotestosterone synthesis and triggering a positive developmental cascade.Both the differentiation of the prostate gland during male embryogenesis (1) and the subsequent growth of the tissue during postnatal life (2) are controlled by androgenic hormones synthesized in the testes. Some androgen actions, such as the promotion of spermatogenesis and the enhancement of muscle growth, are believed to be mediated by the testicular androgen testosterone (2). In other target tissues, including the prostate, testosterone is converted to dihydrotestosterone by the enzyme steroid Sa-reductase (EC 1.3.99.5) (3, 4). Dihydrotestosterone is a more potent androgen than testosterone in some bioassay systems (5), and dihydrotestosterone formation is believed to be essential for many androgen actions. For example, studies of subjects with hereditary steroid Sa-reductase deficiency (6) and investigations of the effects of inhibitors of steroid Sareductase (7-11) indicate that dihydrotestosterone formation is necessary for both the embryonic differentiation and the postnatal growth of the prostate. Furthermore, unregulated dihydrotestosterone action is believed to cause hyperplastic prostate growth in aging dogs and men (12).In addition to the role in the control of differentiation and growth, androgens also control the expression of a number of genes in the prostate, including the gene for steroid 5a-reductase (13). In the ventral prostate of the rat both the steady-state level and the recovery of 5a-reductase after castration are regulated by androgens (13), and this regulation is mediated at the level of transcription of Sa-reductase mRNA (14).To determine whether testosterone or dihydrotestosterone is responsible for...

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“…Finasteride, the first 5·-reductase inhibitor developed [13], was subsequently discovered to be a selective inhibitor of type II human 5·-reductase [14]. The compound has recently been made available for the therapy of symptomatic benign prostatic hyperplasia [15,16].…”

Section: Discussionmentioning

confidence: 99%

Effect of the 5α-Reductase Inhibitor PNU 156765, Alone or in Combination with Flutamide, in the Dunning R3327 Prostatic Carcinoma Model in Rats

Zaccheo¹,

Giudici²,

Panzeri³

et al. 1998

Chemotherapy

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The efficacy of treatment with the 5α-reductase inhibitor PNU 156765 (FCE 28260) was investigated in the Dunning R3327 prostatic tumor in rats. The compound, given orally at the doses of 10 and 50 mg/kg/day, for 8 weeks, reduced the growth of established tumors by 49–50%, an effect similar to that of flutamide at 5 mg/kg/day (46% inhibition). In a further experiment, the combination of PNU 156765 10 mg/kg/day and flutamide 5 mg/kg/day resulted in greater inhibition than either treatment alone (70 vs. 20% in PNU-156765-treated and 51% in flutamide-treated groups). The effect of the combination was similar to that of castration (75% inhibition). Ventral prostate weight was more markedly reduced by PNU 156765 than by flutamide, and combined treatment was as effective as castration. Prostatic dihydrotestosterone content was markedly reduced by PNU 156765 while prostatic testosterone increased. Concomitant treatment with flutamide antagonized the testosterone increase induced by PNU 156765. These data indicate a role for 5α-reductase inhibitors in the therapy of prostate cancer, in combination with antiandrogens, in order to achieve adequate androgen blockade with minimal side effects.

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5α-Reductase inhibitory and anti-androgenic activities of some 4-azasteroids in the rat

Cited by 98 publications

References 18 publications

Hormonal Effects of a 5α-Reductase Inhibitor (Finasteride) on Hormonal Levels in Normal Men and in Patients with Benign Prostatic Hyperplasia

Hormonal Effects of a 5α-Reductase Inhibitor (Finasteride) on Hormonal Levels in Normal Men and in Patients with Benign Prostatic Hyperplasia

Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase.

Effect of the 5α-Reductase Inhibitor PNU 156765, Alone or in Combination with Flutamide, in the Dunning R3327 Prostatic Carcinoma Model in Rats

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