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


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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    • "The RT-PCR results revealed the expression of only 5α-R1 (Fig. 1), which is consistent with the results of previous studies[6,313233. Therefore, the non-radioactive HHDPC-based assay system was first evaluated with a positive control, dutasteride, which is a well-known specific 5α-R1 inhibitor[6]. The compound demonstrated complete inhibition of the enzyme activity at a final concentration of 10 μg/ml with an IC 50 value of 9.7 nM (Fig. 3). "
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    ABSTRACT: Background: Androgenic alopecia (AGA) is a major type of human scalp hair loss, which is caused by two androgens: testosterone (T) and 5aα-dihydrotestosterone (5aα-DHT). Both androgens bind to the androgen receptor (AR) and induce androgen-sensitive genes within the human hair dermal papilla cells (HHDPCs), but 5aα-DHT exhibits much higher binding affinity and potency than T does in inducing the involved androgen-sensitive genes. Changes in the induction of androgen-sensitive genes during AGA are caused by the over-production of 5aα-DHT by the 5aα-reductase (5aα-R) enzyme; therefore, one possible method to treat AGA is to inhibit this enzymatic reaction. Methods: RT-PCR was used to identify the presence of the 5aα-R and AR within HHDPCs. A newly developed AGA-relevant HHDPC-based assay combined with non-radioactive thin layer chromatography (TLC) detection was used for screening crude plant extracts for the identification of new 5aα-R inhibitors. Results: HHDPCs expressed both 5aα-R type 1 isoform of the enzyme (5aα-R1) and AR in all of the passages used in this study. Among the thirty tested extracts, Avicennia marina (AM) displayed the highest inhibitory activity at the final concentration of 10 μg/ml, as the production of 5aα-DHT decreased by 52 % (IC50 = 9.21 ± 0.38 μg/ml). Conclusions: Avicennia marina (AM) was identified as a potential candidate for the treatment of AGA based on its 5aα-R1-inhibitory activity.
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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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    • "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.
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