The 5 Alpha-Reductase Isozyme Family: A Review of Basic Biology and Their Role in Human Diseases

Department of Urology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Advances in Urology 01/2012; 2012(1687-6369):530121. DOI: 10.1155/2012/530121
Source: PubMed

ABSTRACT Despite the discovery of 5 alpha-reduction as an enzymatic step in steroid metabolism in 1951, and the discovery that dihydrotestosterone is more potent than testosterone in 1968, the significance of 5 alpha-reduced steroids in human diseases was not appreciated until the discovery of 5 alpha-reductase type 2 deficiency in 1974. Affected males are born with ambiguous external genitalia, despite normal internal genitalia. The prostate is hypoplastic, nonpalpable on rectal examination and approximately 1/10th the size of age-matched normal glands. Benign prostate hyperplasia or prostate cancer does not develop in these patients. At puberty, the external genitalia virilize partially, however, secondary sexual hair remains sparse and male pattern baldness and acne develop rarely. Several compounds have been developed to inhibit the 5 alpha-reductase isozymes and they play an important role in the prevention and treatment of many common diseases. This review describes the basic biochemical properties, functions, tissue distribution, chromosomal location, and clinical significance of the 5 alpha-reductase isozyme family.

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Available from: Alejandro Godoy, Sep 29, 2015
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    • "In addition to converting testosterone to DHT [12], 5ARs can act upon other substrates including progesterone , androstenedione, cortisol, aldosterone and deoxycorticosterone [13]. The effects of dutasteride upon PCa risk reduction in men with increased PCa risk, and in men with low-risk localised PCa, are well characterised [14] [15]. "
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    ABSTRACT: Bicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA). Prostate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18months. Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline's RandAll System. Subjects who completed 18months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blinded. Primary end-point was time to disease progression (TDP) up to 42months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer or receipt of rescue medication). There was no statistically significant difference in TDP in 127 men treated with bicalutamide/dutasteride (n=62) compared with bicalutamide/placebo (n=65) (hazard ratio (HR)=0.94 [95% confidence interval (CI) 0.61, 1.46]; p=0.79). The estimated median TDP was 425days (95% CI 302, 858) in the bicalutamide/placebo group and 623days (95% CI 369, 730) in the bicalutamide/dutasteride group. There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response. In the multivariate analysis, age, non-White race, higher baseline testosterone and lower baseline PSA were associated with longer TDP. Adverse events were comparable between treatment groups. In men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 06/2015; 120(12). DOI:10.1016/j.ejca.2015.04.028 · 5.42 Impact Factor
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    • "In comparison to TEST, TREN's trophic effects are reduced in tissues expressing the enzyme 5a- reductase [29] indicating either a lower affinity for this enzyme or an altered metabolic conversion resulting in reduced bioconversion to dihydrotestosterone (DHT). This is of particular benefit in prostatic tissue where 5a-reductase is most notably expressed [30] [31]. Additionally, the removal of the methyl group at position 19 of the steroid backbone broadly reduces the susceptibility of 19-nor androgens to aromatisation [26]. "
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    ABSTRACT: Trenbolone (TREN) is used for anabolic growth-promotion in over 20 million cattle annually and continues to be misused for aesthetic purposes in humans. The current study investigated TREN's effects on body composition and cardiometabolic risk factors; and its tissue-selective effects on the cardiovascular system, liver and prostate. Male rats (n = 12) were implanted with osmotic infusion pumps delivering either cyclodextrin vehicle (CTRL) or 2mg/kg/day TREN for six weeks. Dual Energy X-ray Absorptiometry assessment of body composition; organ wet weights and serum lipid profiles; and insulin sensitivity were assessed. Cardiac ultrasound examinations were performed before in vivo studies assessed myocardial susceptibility to ischemia-reperfusion (I/R) injury. Circulating sex hormones and liver enzyme activities; and prostate and liver histology were examined. In six weeks, fat mass increased by 34±7% in CTRLs (p<0.01). Fat mass decreased by 37±6% and lean mass increased by 11±4% with TREN (p<0.05). Serum triglycerides, HDL and LDL were reduced by 62, 57 and 78% (p<0.05) respectively in TREN rats. Histological examination of the prostates from TREN-treated rats indicated benign hyperplasia associated with an increased prostate mass (149% compared to CTRLs, p<0.01). No evidence of adverse cardiac or hepatic effects was observed. In conclusion, improvements in body composition, lipid profile and insulin sensitivity (key risk factors for cardiometabolic disease) were achieved with six week TREN treatment without evidence of adverse cardiovascular or hepatic effects that are commonly associated with traditional anabolic steroid misuse. Sex hormone suppression and benign prostate hyperplasia were confirmed as adverse effects of the treatment. Copyright © 2014. Published by Elsevier Inc.
    Steroids 12/2014; 94. DOI:10.1016/j.steroids.2014.12.017 · 2.64 Impact Factor
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    • "Both 5-AR1 and 5-AR2 are expressed throughout human life.1718 5-AR1 is detected at quite low levels in the fetal scalp and nongenital skin, while 5-AR2 is expressed in the external genital skin early in gestation.91019 "
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    ABSTRACT: The development of human benign or malignant prostatic diseases is closely associated with androgens, primarily testosterone (T) and dihydrotestosterone (DHT). T is converted to DHT by 5-alpha reductase (5-AR) isozymes. Differential expression of 5-AR isozymes is observed in both human benign and malignant prostatic tissues. 5-AR inhibitors (5-ARI) are commonly used for the treatment of benign prostatic hyperplasia (BPH) and were once promoted as chemopreventive agents for prostate cancer (PCa). This review discusses the role of the differential expression of 5-AR in the normal development of the human prostate and in the pathogenesis and progression of BPH and PCa.
    Asian Journal of Andrology 01/2014; 16(2). DOI:10.4103/1008-682X.123664 · 2.60 Impact Factor
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