PubMed · 16149549
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Akira Komiya, Hiroyoshi Suzuki, Tomohiko Ichikawa. 2005. [5alpha-dihydrotestosterone (DHT)].. https://pubmed.ncbi.nlm.nih.gov/16149549/
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Controversy exists over the significance of associations between the SRD5A2 (5alpha-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, 3alpha-diol glucuronide (3alpha-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 = 1.60; 95% CI 1.09-2.36; p = 0.02) and 50% lower risk of vertex and frontal balding (p = 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 3alpha-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 3alpha-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.
Previous in vitro studies demonstrated that bioactive androgen 5alpha-dihydrotestosterone (DHT) exerted antiproliferative effects through an interaction with androgen receptor (AR) in breast carcinoma cells. However, AR status has not been examined in association with DHT concentration in breast carcinoma tissues, and significance of androgenic actions remains unclear in breast carcinomas. Therefore, in our study, we first examined intratumoral DHT concentrations in 38 breast carcinoma tissues using liquid chromatography/electrospray tandem mass spectrometry. Intratumoral DHT concentration was positively associated with 5alpha-reductase type 1 (5alphaRed1), and negatively correlated with aromatase. We then examined clinical significance of AR and 5alphaRed1 status in 115 breast carcinoma tissues by immunohistochemistry. Breast carcinomas positive for both AR and 5alphaRed1 were inversely associated with tumor size or Ki-67. These patients showed significant associations with a decreased risk of recurrence and improved prognosis for overall survival, and the AR / 5alphaRed1 status was demonstrated an independent prognostic factor. Moreover, we examined possible regulation of DHT production by aromatase in in vitro studies. DHT synthesis from androstenedione in MCF-7 cells was significantly inhibited by coculture with aromatase-positive stromal cells, which was significantly reversed by addition of aromatase inhibitor exemestane. These results suggest that intratumoral DHT concentration is mainly determined by 5alphaRed1 and aromatase in breast carcinoma tissues, and antiproliferative effect of DHT may primarily occur in the cases positive for both AR and 5alphaRed1. Aromatase inhibitors may be more effective in these patients, possibly due to increasing local DHT concentration with estrogen deprivation.
OBJECTIVES: Bone mineral density (BMD) is a complex trait resulting from the interplay of genetic and acquired factors. The objective of this study was to explore the influence of several anthropometric, lifestyle, genetic, and hormonal factors on BMD and analyze the possible differences in men and women. METHODS: We studied 572 individuals over 50 years of age (381 postmenopausal women and 191 men). Lumbar spine and femoral neck BMD were measured by dual energy x-ray absorptiometry. The free estrogen index (FEI) was calculated as the ratio of serum estradiol to sex hormone binding globulin in 241 individuals. Three polymorphisms in the genes coding for 17-hydroxylase/liase, sulfotransferase, and 5alpha-reductase were studied in DNA isolated from blood cells. RESULTS: Body mass index was strongly correlated to spine and femoral BMD both in women and in men (r = 0.32-0.49; P < 0.001). FEI was also independently correlated with spine BMD in both sexes (r = 0.23 and 0.34, P < 0.01), and with femoral neck in women (r = 0.30). Women with G alleles of the sulfotransferase gene tended to have higher spine BMD than those with C alleles (P = 0.025). No other genotype-related differences in BMD were found. CONCLUSIONS: In conclusion, the results of this study point toward body weight and estradiol levels as major factors determining BMD both in women and in men. A common polymorphism of the sulfotransferase gene also appears to be associated to spine BMD in women.