In 1965, Shimazaki et al. first found that incubation of radiolabled testosterone with tissue extracts of rat prostate or minced tissues of normal and pathological human prostates formed radiolabled DHT and androst-4-ene-3,17-dione.20'21 Three years later, Bruchovsky and Wilson found that DHT could be detected in isolated prostatic nuclei 2 hours after administration of 3H-testosterone to rats.22 Several months later, Anderson and Liao confirmed that nuclei of both rat ventral prostate and seminal vesicles selectively retained 3H-DHT.23 The metabolic rate of DHT formation is high in hyperplastic tissues, moderate in normal tissues, and low in cancerous tissues.20'21 Reduced activity of 5a-reductase in the cancerous tissues was further confirmed by various procedures: incubation with minced tissues24 and with homogenate,25'26 RT-PCR,11'27 and microarray.10 Poorly differentiated cancerous tissues showed less activity than well differentiated ones. Metabolic foci in lymph nodes revealed scant activity28 and no expression of SRD5A1 or SRD5A2 mRNA.29 Although a few opposing findings are present,8,9 decreased 5a-reductase activity in cancer tissues has been indicated in many other reports. In this context, hormone concentrations (pM/dry weight) in normal, benign hyperplastic, and cancerous prostate tissues were: 12.6 ± 2.3, 14.1 ± 2.4, and 39.6 ± 6.2 of testosterone; 12.9 ± 1.9, 45.5 ± 5.8, and 22.4 ± 2.4 of DHT; and no detectable level, 30.0 ± 7.6, and 42.0 ± 7.9 of androst-4-ene-3,17-dione, respectively.30
DHT is further metabolized to 5a-androstane-3a,17^-diol and, to a lesser extent, 5a-androstane-3p,17^-diol in the prostate. The former is converted to androsterone.31 To assess the activity of 5a-reductase, measurements of 5a-androstane-3a,17^-diol glucuronide and androsterone glucuronide in serum are commonly used. The oxidative reaction of 5a-androstane-3a,17^-diol has been discussed, since dog prostate hyper-plasia can effectively be induced with this steroid, perhaps by its conversion to DHT. However, in cases of prostate cancer, this reaction does not seem to be substantial.32
Percutaneous administration of dehydroepiandrosterone to healthy aged male volunteers caused an increase of androst-4-ene-3,17-dione and conjugated metabolites of DHT (glucuronides of androsterone, 5a-androstane-3a,17^-diol and 5a-androstane-3p,17^-diol) in serum, despite unchanged levels of testosterone and DHT.33 In patients who underwent castration, the serum ratio of DHT/testosterone increased,34 and 58% of DHT remained in the serum, in contrast to the 92% reduction of serum testosterone,35 suggesting that adrenal androgen is a precursor of DHT. The prostate contains metabolizing enzymes for the conversion of dehydroepiandrosterone and its sulfate, and androst-4-ene-3,17-dione to DHT, including sulfatase,36 3 P-hydroxysteroid dehydrogenase,37 and 17P-hydroxysteroid dehydrogenase.38'39 An estimated 30%-50% of total androgens in men are synthesized in peripheral tissues, including the prostate, from inactive adrenal precursors.40 In a 14-year follow-up of 1008 men, the total testosterone, estrone, estradiol, and sex hormone-binding globulin levels did not correlate with the incidence of prostate cancer, but androst-4-ene-3,17-dione showed a positive dose-response gradient, suggesting an adrenal contribution.41 Although the proportion of adrenal androgen acting as precursors of DHT is uncertain, adrenal androgen must be considered in striving for complete block of DHT formation for prostate cancer treatment. It is a clinical issue whether endocrine therapy can be achieved by suppression of the testicular hormone alone or whether elimination of influence from adrenal androgens is necessary.
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