Prostatic Dihydrotestosterone Concentration Research Articles

Effects of Steroidal Antiandrogen or 5-alpha-reductase Inhibitor on Prostate Tissue Hormone Content.

The effects of a steroidal antiandrogen (AA) and 5-alpha-reductase inhibitor (5ARI) on prostate tissue hormone content and metabolism are not fully elucidated. The objective of this study is to investigate the hormone content and metabolism of the prostate tissues of patients treated with AA or 5ARI using the ultra-sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Thirty-nine patients with benign prostatic hyperplasia (BPH) undergoing transurethral surgery were included. Serum and prostate tissue hormone and prostate tissue hormone metabolism analyses were performed using LC-MS/MS after 1 month of treatment with chlormadinone acetate (CMA; steroidal AA, 50 mg/day) or dutasteride (DUTA; dual 5ARI, 0.5 mg/day). Serum testosterone (T), dihydrotestosterone (DHT), and adrenal androgen levels were lower in the CMA group than the control group. Prostate tissue T and DHT levels were also lower in the CMA group than the control group. In the DUTA group, only serum and prostate DHT concentrations were reduced compared to the control group; in contrast, those of other hormones, especially T and 4-androstene-3,17-dione in the prostate tissue, showed marked elevations up to 70.4- and 11.4-fold normal levels, respectively. Moreover, the hormone metabolism assay confirmed that the conversion of T to DHT was significantly suppressed while that of T to 4-androstene-3,17-dione was significantly accelerated in the prostate tissue of DUTA-treated patients. Although treatment with AA and 5ARI show similar clinical outcomes, their effect on tissue hormone content and metabolism varied greatly. Prostate 77: 672-680, 2017. © 2017 Wiley Periodicals, Inc.

Inhibition of androgen synthesis in human testicular and prostatic microsomes and in male rats by novel steroidal compounds.

The C(17,20)-lyase and 5alpha-reductase are key enzymes in the biosynthesis of androgens. The effects of novel steroidal compounds were evaluated as inhibitors against both human C(17,20)-lyase and 5alpha-reductase in vitro. The concentrations of testosterone (T) and dihydrotestosterone (DHT) in the prostate, testis and serum and changes in the tissue weights were also determined in rats treated with the novel inhibitors. L-12 and L-26 showed potent inhibition of human testicular C(17,20)-lyase with IC50 values of 50 and 25 nM, respectively. L-12, L-38, and I-47 showed moderate inhibition of human testicular C(17,20)-lyase with IC50 values of 75, 108, and 70 nM, respectively similar to ketoconazole (78 nM). Interestingly, L-6, L-26, and L-38 also showed some inhibitory activity against 5alpha-reductase with IC50 values of 75, 125, and 377 nM, respectively. Finasteride, an inhibitor of 5alpha-reductase had an IC50 value of 33 nM. However, ketoconazole did not inhibit 5alpha-reductase nor did finasteride inhibit C(17,20)-lyase. Treatment of normal male rats with several of these novel inhibitors (50 mg/kg x day, s.c., for 14 consecutive days) caused about 45-91% decrease in serum, testicular and prostatic T concentration. Similarly, serum and prostatic DHT concentration were significantly decreased in rats treated with these novel compounds by 50-90% compared with controls. Surgical castration caused almost complete elimination of circulating T and DHT concentration in rat tissues. L-6 and L-12 were the most effective and reduced the wet weight of the prostate by 50%. Although future improvements in their bioavailability are necessary, these novel steroidal compounds show promise as potential agents for reducing T and DHT levels in patients with androgen dependent diseases.

Castration levels of plasma testosterone have potent stimulatory effects on androgen-sensitive parameters in the rat prostate

In order to assess the biological significance of low serum androgens comparable to those which remain after castration in men treated for prostate cancer, Silastic depots continuously releasing predetermined doses of testosterone (T) have been implanted into castrated adult male rats in the absence or presence of simultaneous treatment with the pure antiandrogen Flutamide. Quite remarkably, a 3- to 5-fold increase in prostate weight ( P ≤ 0.01) was observed at plasma T concentrations comparable to those found in the serum of castrated men. Although of lower magnitude, castration levels of plasma T also caused a significant stimulation of seminal vesicle weight ( P < 0.01). This dramatic stimulatory influence of “castration” levels of plasma T on ventral prostate and seminal vesicle weight can be explained by the 13- to 15-fold higher intraprostatic level of the active androgen dihydrotestosterone (DHT) compared to the plasma T concentration. In fact, a near-maximal intraprostatic concentration of DHT is reached at concentrations of plasma T of 0.2–0.5 ng/ml and a positive correlation was found between prostatic DHT concentration and ventral prostate weight. Prostatic growth and DHT concentrations were also positively correlated with ornithine decarboxylase (ODC) activity, an enzyme highly sensitive to androgens in the rat ventral prostate. In fact, a dramatic (30-fold) increase in ODC activity was observed at plasma T values corresponding to those found in castrated men. The level of prostatic β 2-adrenergic receptors fell within 10 days of castration and an increase in β 2-adrenergic receptor concentration was observed with low doses of T, thus indicating that β 2-adrenoreceptor levels are also a sensitive parameter of androgenic activity in the rat prostate. Concomitant treatment with the pure antiandrogen Flutamide, while having no effect by itself, completely prevented the stimulatory effect of T on prostate weight, ODC activity and β 2-adrenergic receptor levels in the rat prostate. The present data clearly demonstrate that plasma T levels in the range found in castrated men (0.2–0.5 ng/ml) have major androgenic activity in the rat prostate. Such findings strongly suggest that, in addition to the blockade (by treatment with LHRH agonist) or removal (by orchiectomy) of testicular androgens, an improved therapy of prostatic carcinoma requires simultaneously blockade of the so-far neglected but biologically important androgens of adrenal origin which, otherwise, are left free to stimulate prostatic cancer after castration.

Dihydrotestosterone concentration of beagle prostatic tissue: effect of age and hyperplasia.

Dihydrotestosterone (DHT) concentration was measured in prostatic tissue obtained from castrate or intact beagles treated with androgens and/or estradiol-17 beta. Also DHT concentration was measured in prostatic tissue of beagles ranging from 0.7-9.2 yr; some with and others without spontaneously occurring benign prostatic hyperplasia (BPH). Three major results were forthcoming. First, a linear, positive correlation was observed between prostatic weight and DHT concentration in castrated or intact beagles treated with 11 of 15 steroid hormone regimens. Four additional treatments including intact or castrated beagles treated with either DHT or 5 alpha-androstan-3 alpha,17 beta-diol alone resulted in high concentrations of prostatic DHT but not equally high prostatic weight. Thus, prostatic DHT concentration is not always tightly coupled with prostate weight in the beagle. Second, there was no significant (P greater than 0.25) difference in prostatic DHT concentration between dogs with histologically normal prostates and those with spontaneous BPH. Thus, contrary to earlier reports, the tissue concentration of DHT in dog prostatic hyperplasia is not supranormal. Third, there was a dramatic change in prostatic DHT concentration which peaked at 3.8 yr. We conclude that steroid hormone treatment regimens which caused elevated prostatic DHT concentrations did not always result in equally high prostatic weight in the beagle. Also, if androgens like DHT are related causally to BPH in the dog, they probably play a permissive rather than an inductive role in the disease process.