Androgenic correlates of genetic variation in the gene encoding 5α-reductase type 1

Ellis, Justine A.; Panagiotopoulos, Sianna; Akdeniz, Aysel; Jerums, George; Harrap, Stephen B

doi:10.1007/s10038-005-0289-x

Cited by 26 publications

(24 citation statements)

References 16 publications

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“…12 In humans, Type I 5á-reductase is found primarily in the sebaceous glands of most regions of skin including scalp, and in liver, muscle, and brain (31,140), with low levels also present in prostate that may increase in prostate cancer (142). Type I 5á-reductase is responsible for approximately one-third of circulating DHT (58).…”

Section: Pharmacodynamics and Pharmacokinetics 5á-reductase Isozyme Smentioning

confidence: 99%

A New Look at the 5?-Reductase Inhibitor Finasteride

et al. 2006

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Finasteride is the first 5á-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5á-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5á-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3á-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of ã-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA A receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual-and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5á-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely re- 53

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Section: Pharmacodynamics and Pharmacokinetics 5á-reductase Isozyme Smentioning

confidence: 99%

A New Look at the 5?-Reductase Inhibitor Finasteride

et al. 2006

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“…13 Reports of associations between the A49T and V89L polymorphisms and plasma androgen levels, including testosterone and 3a-diolG, have been limited. [14][15][16][17] A single study has reported a null association between the V89L variant and balding patterns in European men.…”

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confidence: 99%

5α‐Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia

Hayes

Severi

Padilla

et al. 2006

Intl Journal of Cancer

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Controversy exists over the significance of associations between the SRD5A2 (5a-reductase type 2) polymorphisms, A49T and V89L, and risk of prostate cancer. These potentially functional polymorphisms may alter life-long exposure to androgens with subsequent effects on male health and aging. The aim of this study was to examine the association of these variants with prostate cancer risk, plasma hormone levels and androgenetic alopecia. Subjects include 827 cases and 736 controls from an Australian population-based case-control study of prostate cancer. Information on prostate cancer risk factors and patterns of balding were collected. Plasma levels of testosterone, 3a-diol glucuronide (3a-diolG), dehydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and estradiol were measured for controls. No associations with the V89L polymorphism were found. Carriers of the rarer A49T A allele were at a 60% higher risk of prostate cancer (OR 5 1.60; 95% CI 1.09-2.36; p 5 0.02) and 50% lower risk of vertex and frontal balding (p 5 0.03) compared with men homozygous for the more common G allele. Although we found little evidence of association between this variant and plasma levels of 5 measured androgens, circulating 3a-diolG levels were 34% lower in A49T A allele carriers (p < 0.0001). Our study provides evidence that the SRD5A2 A49T A variant is associated with an increased risk of prostate cancer, lower levels of circulating 3a-diolG and decreased risk of baldness. These findings raise important questions with respect to previous assumptions concerning hormonal influences on prostate cancer risk in ageing males. ' 2006 Wiley-Liss, Inc.Key words: SRD5A2; polymorphisms; prostate cancer risk; population-based case-control study; plasma androgens; androgenetic alopecia Membrane-bound 5a-reductase type 2 (SRD5A2) is responsible for the irreversible conversion of testosterone into its more active metabolite, dihydrotestosterone (DHT) and is essential for the normal growth and development of the prostate gland.1 This hormone-regulator has been implicated in male pathophysiology, including prostate cancer and balding (androgenetic alopecia). The ratio of DHT to testosterone has been reported to be highest for African-Americans, intermediate for Europeans and lowest for Asian-Americans, which corresponds to reported ethnic-based risk of prostate cancer for these groups, suggesting an association with prostate cancer risk.2 Prostate cancer risk has been associated with vertex pattern balding.3 Increased levels of DHT have been demonstrated in the male balding scalp, 4 while lack of balding is seen in pseudohermaphrodites (men with congenital 5a reductase deficiency) with a concomitant reduced ability to convert testosterone to DHT.5 DHT in turn is metabolized to 5a-androstane-3a-17b-diol glucuronide (3a-diolG), a predictor of both cutaneous and intraprostatic serum 5a-reductase levels. 6 These observations support the ''androgen hypothesis'' that increases in active androgens (and their metabolites) are associ...

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“…Indeed, the previously reported lack of association between diabetes and rs248793 25,26 allowed the use of a single healthy group of controls for both PAD subgroups.…”

Section: Single Nucleotide Polymorphism Rs248793 (G/c) Of the Srd5a1mentioning

confidence: 99%

ICAM-1 and SRD5A1 gene polymorphisms in symptomatic peripheral artery disease

et al. 2014

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The genotype distribution of two gene polymorphisms, previously associated with peripheral artery disease (PAD), has been evaluated in a population of diabetic (DPAD) and non-diabetic (NDPAD) patients affected by symptomatic PAD (stages II-IV). A decreased frequency of the AA genotype of rs5498 (ICAM-1) was observed in the PAD subjects compared to controls but this result did not reach statistical significance (p=0.06 by chi-squared test). On the contrary, a significant increase in the frequency of the GG homozygous genotype of rs248793 (SRD5A1) was observed in the PAD patient group in comparison to controls (p=0.01). These data confirm that the GG genotype of rs248793 in the SRD5A1 gene is significantly associated with symptomatic PAD and show a trend towards a stronger association with the non-diabetic status.

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Androgenic correlates of genetic variation in the gene encoding 5α-reductase type 1

Cited by 26 publications

References 16 publications

A New Look at the 5?-Reductase Inhibitor Finasteride

A New Look at the 5?-Reductase Inhibitor Finasteride

5α‐Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia

ICAM-1 and SRD5A1 gene polymorphisms in symptomatic peripheral artery disease

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