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.
We evaluated the association between 21 polymorphisms in hormone and DNA repair pathway genes and survival among 454 Australian women diagnosed with invasive epithelial ovarian cancer. The cohort was followed for mortality using personal identifiers which were linked to state cancer registry records and the Australian National Death Index. The mean follow-up time after ovarian cancer diagnosis was 4.63 years (all women) and 8.07 years for the censored group (those alive or dead from non-ovarian cancer causes). Two hundred and eighty-eight (63%) ovarian cancer deaths occurred during the follow-up period. No association was observed for the vast majority of polymorphisms, but there was suggestive evidence for altered risk of ovarian cancer death associated with the CYP17 5'UTR C allele (HR 1.30; 95% CI=1.02-1.68, p= 0.04), and for the SRD5A2 V89L C allele (HR 0.79; 95% CI=0.62-1.01, p=0.06). These results are interesting given tentative evidence that both of these variants are also associated with increased predisposition to ovarian cancer in our extended Australian study, and in other published studies. However, given the marginal significance of these associations and the large number of tests performed, independent replication will be necessary to validate these novel findings.