The role of the prostate in androgen metabolism

The androgenic steroid hormones are essential for the physiological development of the prostate gland and are also implicated in pathological processes such as benign prostatic hyperplasia and prostate cancer. The systemic effect of endocrine activity in the prostate gland has so far been considered of minor importance. The overall aim of this thesis is to further investigate the role of the prostate in androgen bio-activation and inactivation and relate these processes to prostate cancer susceptibility. Conjugation by UDP-glucuronosyl transferases (UGTs) is considered a major inactivation route for androgens in the prostate. Of these UGT2B15 and UGT2B17 are expressed in the prostate. Functional polymorphisms have been identified in both of these enzymes and were associated with intraprostatic androgen glucuronide levels (Paper IV). In paper I we investigated the UGT2B17 deletion polymorphism and found a 2.2-fold increased risk for prostate cancer for individuals with the deletion allele. In order to evaluate these findings we repeated the genotype association in a considerably larger population-based case-control study (paper II). In contrast to our previous results no association between the UGT2B17 deletion polymorphism and prostate cancer rate was found. The dihydrotestosterone (DHT) metabolite 5 -androstane-3 ,17 -diol (3 Adiol) has been proposed as an intraprostatic ligand of the estrogen receptor (ER ) promoting anti-proliferative activity. For the first time significant 3 Adiol levels were detected in human prostate tissue (paper IV). The cytochrome P450 7B1 (CYP7B1) enzyme is a putative regulator of intraprostatic 3 Adiol levels. In paper III we demonstrated increased CYP7B1 protein expression in malignant areas in the prostate and that the CYP7B1/ER mRNA ratio was increased in prostate cancer compared to benign tissue. The transcriptional activity of the CYP7B1 gene is regulated by methylation. Many studies have investigated the association between circulating sex hormones and prostate cancer risk, but the conclusion from these studies may be wrong since the correlation between intraprostatic androgen metabolism and systemic androgens is poor. In paper IV we measured peripheral and local peri-prostatic androgen and gonadotropin levels in men undergoing radical prostatectomy (RP) for localized prostate cancer. There was an almost two-fold higher DHT concentration and a fifteen percent lower luteinizing hormone (LH) concentration in local prostatic serum compared to peripheral serum levels. A significant positive correlation between prostate weight and local DHT levels was observed. The correlation studies also indicate that 28 % of the systemic DHT variance can be explained by prostatic DHT production. In paper V we investigated the serum and urine hormonal changes after RP. We measured serum levels of testosterone, DHT, sex hormone binding globulin (SHBG), luteinizing hormone LH, follicle stimulating hormone (FSH) and inhibin B preoperatively and 90 days postoperatively. Steroid urine profile was also determined preand postoperatively in 18 patients. There were significant increases in serum LH and FSH and a 13 % decrease in DHT levels. Urinary levels of DHT glucuronides (DHT-G) decreased by 67% while Androsterone-G and 3 Adiol-G increased. Inhibin B levels correlated inversely with both FSH and LH. Thus RP leads to significant DHT decrease in both serum and urine and we conclude that the observed increase in gonadotropin levels is a consequence of the DHT changes. LIST OF PUBLICATIONS This thesis is based on the following papers, referred to in the text by their Roman