Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5α-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: New approach for benign prostate hyperplasia

Wenqing Gao, Jeffrey D. Kearbey, Vipin A. Nair, Kiwon Chung, A. F. Parlow, Duane Miller, James T. Dalton

Research output: Contribution to journalArticle

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Abstract

Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both, castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5α-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/ kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator and muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5α-reductase (K1, >20 μM) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited pro-static 5α-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.

Original languageEnglish (US)
Pages (from-to)5420-5428
Number of pages9
JournalEndocrinology
Volume145
Issue number12
DOIs
StatePublished - Dec 1 2004

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Finasteride
Androgen Antagonists
Androgen Receptors
Hyperplasia
Prostate
Oxidoreductases
Pharmacology
Androgens
Anal Canal
Muscles
hydroxyflutamide
Weights and Measures
Seminal Vesicles
Testosterone
Hormones

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5α-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats : New approach for benign prostate hyperplasia. / Gao, Wenqing; Kearbey, Jeffrey D.; Nair, Vipin A.; Chung, Kiwon; Parlow, A. F.; Miller, Duane; Dalton, James T.

In: Endocrinology, Vol. 145, No. 12, 01.12.2004, p. 5420-5428.

Research output: Contribution to journalArticle

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abstract = "Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both, castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5α-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/ kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator and muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5α-reductase (K1, >20 μM) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited pro-static 5α-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.",
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