Associations of serum sex steroid hormone and 5α-androstane-3α,17β-diol glucuronide concentrations with prostate cancer risk among men treated with finasteride.

Finasteride, an inhibitor of 5α-reductase (type II), lowers intraprostatic dihydrotestosterone (DHT), which is reflected in serum as reduced 5α-androstane-3α,17β-diol glucuronide (3α-dG). It also modestly increases serum testosterone (T), estrone (E(1)), and estradiol (E(2)). In this altered hormonal milieu, it is unknown whether serum concentrations of these hormones are associated with prostate cancer risk. In this nested case-control study of men in the finasteride arm of the Prostate Cancer Prevention Trial, sex steroid hormones and sex hormone binding globulin were measured at baseline and approximately 3-year posttreatment in 553 prostate cancer cases and 694 controls. Median posttreatment changes in concentrations of 3α-dG, T, E(1), and E(2) were -73.8%, +10.1%, +11.2%, and +7.5% (all P < 0.001), respectively. Neither the pre- nor posttreatment concentrations of 3α-dG, nor its change, were associated with risk. Pretreatment, high concentrations of E(1) and low concentrations of T were associated with increased cancer risk [OR; 95% confidence interval (CI) quartile 4 vs. 1: 1.38 (0.99-1.93) P(trend) = 0.03; 0.64 (0.43-0.93) P(trend) = 0.07, respectively]. Posttreatment, high concentrations of both E(1) and E(2) were associated with increased cancer risk [OR; 95% CI quartile 4 vs. 1: 1.54 (1.09-2.17) P(trend) = 0.03; 1.49 (1.07-2.07) P(trend) = 0.02, respectively]. Among finasteride-treated men, concentrations of 3α-dG were not associated with total or Gleason grades 2 to 6, 7 to 10, or 8 to 10 cancer. High serum estrogens may increase cancer risk when intraprostatic DHT is pharmacologically lowered. Low posttreatment serum estrogens may identify men more likely to benefit from use of finasteride to prevent prostate cancer.

Kristal AR ，Till C ，Tangen CM ，Goodman PJ ，Neuhouser ML ，Stanczyk FZ ，Chu LW ，Patel SK ，Thompson IM ，Reichardt JK ，Hoque A ，Platz EA ，Figg WD ，Van Bokhoven A ，Lippman SM ，Hsing AW ... -  《-》

Effect of finasteride on serum levels of androstenedione, testosterone and their 5α-reduced metabolites in men at risk for prostate cancer.

Studies show that treatment of men with 5α-reductase inhibitors such as finasteride is effective for the primary prevention of prostate cancer. Although it is known that finasteride treatment suppresses serum levels of dihydrotestosterone (DHT) and its distal metabolite, 5α-androstane-3α,17β-diol glucuronide (3α-diol G), and increases serum testosterone (T) levels, little is known about its effect on other precursors and metabolites of DHT, as well as on the relationship of these androgens to prostate specific antigen (PSA), a marker of prostatic intraepithelial neoplasia. The present study provides new data on the effect of finasteride on precursors and metabolites of DHT. Fifty-three men, ages 57-79 years, with elevated PSA levels (>4ng/ml), were randomized to treatment with finasteride (5mg/day) or observation (controls) for 12 months. Blood samples were obtained at baseline, 1, 3, 6 and 12 months for measurement of PSA, androstenedione (A), T, DHT, 3α-diol G, androsterone glucuronide (ADT G) and DHT sulfate (DHT S) in serum by validated, highly specific radioimmunoassays. Statistical analysis was carried out using mixed model ANOVA and t-tests. In the control group, PSA and androgen levels were unchanged throughout the 12 months of treatment. In the finasteride group, PSA, DHT, DHT S, 3α-diol G and ADT G decreased from baseline to 1 month by 23.2%, 78.7%, 71.0%, 75.7% and 43.0%, respectively. The change in PSA decreased further to 46.1% and 55.1% at 3 and 12 months of treatment, respectively, whereas the decrease in androgens observed at 1 month did not change by more than 6.9% for DHT, DHT S and 3α-diol G in the subsequent months of sampling. However, the decline in ADT G was only 22.2% at month 3, and remained essentially at this level after that time. In contrast, T and A increased significantly from baseline, and the increase in A of approximately 34.5% was about 1.9 times the increase in T (approximately 18.3%). The present data suggest that either 3α-diol G or DHT S may serve as a potential diagnostic marker of intraprostatic 5α-reductase activity during treatment of patients with 5α-reductase inhibitors.

Stanczyk FZ ，Azen CG ，Pike MC 《-》

Serum steroid and sex hormone-binding globulin concentrations and the risk of incident benign prostatic hyperplasia: results from the prostate cancer prevention trial.

Kristal AR ，Schenk JM ，Song Y ，Arnold KB ，Neuhouser ML ，Goodman PJ ，Lin DW ，Stanczyk FZ ，Thompson IM ... -  《-》

Prospective study of sex hormone levels and risk of prostate cancer.

Gann PH ，Hennekens CH ，Ma J ，Longcope C ，Stampfer MJ ... -  《JNCI-Journal of the National Cancer Institute》

MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen.

Schwartz JI ，Tanaka WK ，Wang DZ ，Ebel DL ，Geissler LA ，Dallob A ，Hafkin B ，Gertz BJ ... -  《JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM》