Intraprostatic Dihydrotestosterone Levels Research Articles

Effects of competitive and noncompetitive 5f-reductase inhibitors on serum and intra-prostatic androgens in beagle dogs

Background 5α-Reductase inhibitors (5α-RI) act by inhibiting the conversion of testosterone to dihydrotestosterone (DHT), thereby preventing DHT induced benign prostatic hyperplasia. The existing 5α-RIs can be classified into two types: competitive and noncompetitive. Currently, limited evidence is available concerning the effect differences between the two types of 5α-RI on androgens. The purpose of this study was to assess the effects of competitive and noncompetitive 5α-RIs on serum and intra-prostatic androgens in beagle dogs. Methods Twenty beagles with spontaneous benign prostatic hyperplasia were randomly allocated into two groups: epristeride group (n=10) in which beagles were treated with epristeride at 1 mg/kg once a day for 3 months, and finasteride group (n=10) in which beagles were treated with finasteride at 1 mg/kg once a day for 3 months. The levels of intra-prostatic testosterone and DHT were measured before treatment and on day one after three months medication. Serum levels of testosterone and DHT were measured at the same time points. Changes in androgen levels before and after treatment were analyzed, and comparisons were made within each treatment group and between treatment groups. Results After 3-month treatment, serum and intra-prostatic DHT levels all decreased significantly in both the epristeride and finasteride groups. The change of DHT in serum was significantly higher in the finasteride group (-14% and -43% in epristeride and finasteride groups respectively, with P<0.001); however there was no significant difference in the changes of intra-prostatic DHT between the two groups (-47% and -51% in epristeride and finasteride groups, respectively, P=0.304). The decreases in DHT levels were accompanied by reciprocal increases in serum and intra-prostatic testosterone levels. Changes of testosterone were significantly higher in finasteride group both in serum (20% and 42% in epristeride and finasteride groups, respectively, P<0.001) and in prostate tissue (18% and 29% in epristeride and finasteride groups, respectively, P=0.004). Conclusions Two types of 5T-RI have similar effects in reducing DHT in prostate tissue in beagles. Competitive 5α-RI may reduce serum DHT to a greater scale, and significantly increase testosterone in beagle serum and prostate.

Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer

Androgen deprivation therapy (ADT) and 5-α-reductase (5AR) inhibition are used in the treatment of men with advanced or metastatic prostate cancer and benign prostatic hyperplasia (BPH), respectively. These drugs exert their effect by lowering androgen levels in the serum and allegedly, the prostate gland. It is, however, unknown whether (increased) intraprostatic androgen levels are associated with the pathogenesis of BPH and with the initiation and progression of prostate cancer. Also, it is unclear whether intraprostatic dihydrotestosterone (DHT) levels correlate with a response to initial hormonal therapy or with patient outcome. These uncertainties have resulted from the finding that serum testosterone levels do not necessarily reflect those in the prostate gland. Intraprostatic DHT levels of men being treated with 5AR inhibition, of those treated with ADT for hormone-naive prostate cancer, and of those with castration-resistant prostate cancer are all altered in an equivalent manner because of hormonal manipulation. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels, may lead to treatment that is tailored to the needs of the individual patient, and probably to new therapeutic targets as well.

Genomic Strategy for Targeting Therapy in Castration-Resistant Prostate Cancer

Despite treatments which lower circulating androgens, advanced prostate cancers often maintain androgen receptor (AR) signaling. The variable response to secondary hormonal manipulations in men with castrate-resistant prostate cancer (CRPC) creates a compelling need for strategies to individualize therapy based on the molecular features of each patient's tumor. A transcription-based AR activity signature was developed from an androgen-sensitive prostate cancer cell (LNCaP) and tested on independent data sets of prostate cancer cell lines and human tumors to assess its precision and accuracy in detecting AR activity. The AR signature was applied to multiple sets of prostate specimens to determine how AR activity changes with hormone therapy and progression and oncogenic pathway analysis was used to identify biologic pathways correlating with AR activity. A robust AR signature accurately predicts AR activity in multiple prostate cancer cell lines, has minimal variation between replicate samples, and accurately reflects an individual's hormone status and intraprostatic dihydrotestosterone levels. The AR signature finds AR activity to be high in local, untreated prostate tumors and decreased in prostate tissue after neoadjuvant hormone therapy and in CRPC. Heterogeneity of AR activity exists along the spectrum of prostate cancer progression and decreasing predicted AR activity correlates with increasing predicted Src activity and sensitivity to dasatinib (Src-targeting kinase inhibitor). A transcription-based AR signature can detect AR activity within individual prostate cancer specimens and has the potential to help individualize and improve care for patients with CRPC.

Effect of Dutasteride on Intraprostatic Androgen Levels in Men With Benign Prostatic Hyperplasia or Prostate Cancer

Dutasteride exerts its beneficial effects on the prostate through suppression of intraprostatic dihydrotestosterone (DHT). The aim of this analysis was to assess the effects of the approved dose of dutasteride (0.5 mg/d), given for 2 weeks to 4 months, on the serum and intraprostatic DHT and testosterone levels in 3 randomized studies. Intraprostatic androgen levels were measured in benign prostatic tissue collected during transurethral resection of the prostate (benign prostatic hyperplasia studies, n = 256) or radical prostatectomy (prostate cancer study, n = 51), performed after 2 weeks, or 1, 3, or 4 months of treatment with dutasteride or with placebo or surgery alone. The serum androgen levels were assessed at the same points during treatment. Data from the control groups were pooled to provide 1 comparison group. Dutasteride reduced the intraprostatic DHT levels by 83%, 90%, 92%, and 93% after 2 weeks and 1, 3, and 4 months of treatment, respectively, compared with placebo/surgery alone. Dutasteride reduced the serum DHT levels from baseline by 84% at 2 weeks and by approximately 90% at 1, 2, 3, and 4 months compared with a 5.2% increase in the control group. The decrease in DHT levels with dutasteride was accompanied by a reciprocal increase in the serum and intraprostatic testosterone levels. However, the intraprostatic testosterone levels in the dutasteride groups generally remained lower than the intraprostatic DHT levels in the control group. The results of our study have shown that dutasteride provides near-maximal suppression of both serum and intraprostatic DHT levels in men with benign prostatic hyperplasia or prostate cancer at all points assessed.

The effect of dutasteride on intraprostatic dihydrotestosterone concentrations in men with benign prostatic hyperplasia

The dual 5alpha-reductase inhibitor, dutasteride has been shown to suppress serum dihydrotestosterone (DHT) by >90%. In the present study, the effect of dutasteride 0.5 mg/day on intraprostatic DHT levels was investigated. In this multicenter, double-blind trial, 43 men with benign prostatic hyperplasia (BPH) scheduled to undergo transurethral resection of the prostate (TURP) were randomized to receive dutasteride, 0.5 mg/day or placebo for 3 months before surgery. Intraprostatic DHT, testosterone and dutasteride levels were determined at the time of TURP. Changes in serum DHT and testosterone from baseline, and both serum and intraprostatic dutasteride levels at the time of TURP were also assessed. Dutasteride reduced intraprostatic DHT by 94% relative to placebo (P<0.001); the adjusted mean intraprostatic DHT concentration was 3.23 and 0.209 ng/g in the placebo and dutasteride groups, respectively. In the dutasteride group, serum DHT was reduced from baseline by 93% at month 3, a significantly greater reduction (P<0.001) than the 15% decrease observed in the placebo group. There was a reciprocal increase in intraprostatic testosterone but the level of intraprostatic testosterone in the dutasteride group tended to be lower than the intraprostatic DHT level in the placebo group (P=0.06). Significant intraprostatic DHT suppression was achieved in all subjects who received dutasteride, regardless of the level of intraprostatic dutasteride. There was a strong positive correlation between serum and intraprostatic dutasteride concentrations (R(2)=0.73). After 3 months of treatment, dutasteride 0.5 mg/day provided near-complete suppression of both intraprostatic and serum DHT in men with BPH.

The epidemiology of sex steroid hormones and their signaling and metabolic pathways in the etiology of prostate cancer

The purpose of this review is to discuss the epidemiologic literature on the association of sex steroid hormones and components of their signaling and metabolic pathways with prostate cancer and to describe data evaluating racial variation in sex steroid hormone pathways as a possible explanation for the notably higher risk of prostate cancer in African-American men compared to white or Asian men. Although sex steroid hormones likely contribute to the growth and progression of prostate cancer, associations between hormones and prostate cancer risk across the range of normal levels have been difficult to reliably demonstrate epidemiologically. Methodologic issues no doubt have made the detection of these associations difficult. Of particular importance are (1) the inadequacy of measuring circulating hormones in middle age as a surrogate for the exposure in the target cells in the prostate at the relevant time in life and (2) the current inability to integrate across components of the sex steroid hormone signaling pathway to fully capture target cell androgenic and estrogenic stimulation. Although the approach of evaluating polymorphisms in genes involved in sex steroid hormone signaling or metabolism as a way to minimize some of the issues in the direct measurement of hormones is logical, the findings among these studies are somewhat difficult to reconcile as well. The problems of the changing case mix due to screening for elevated PSA, small sample sizes increasing the likelihood of false negative and false positive results, the controls and their allele frequencies not being representative of the population at risk, and lack of knowledge of the functional consequence of a polymorphism in relation to other polymorphisms in that gene or without consideration of other genes involved in the same pathway may be contributory. The primary result of the Prostate Cancer Prevention Trial confirms that intraprostatic dihydrotestosterone levels in the normal range indeed do contribute to the growth of prostate adenocarcinoma. However, the secondary result of higher-grade disease in cases in the finasteride arm coupled with clinical studies showing higher grade disease in non-metastatic cases with lower serum androgens, if not a pathological artifact or detection bias in the finasteride arm, possibly suggests a complex relationship between androgens and the growth versus differentiation of a prostate tumor. Finally, racial variation in components of the sex steroid hormone pathway do appear to exist, but whether the extent of the variation is adequately great such that it accounts for some of the substantial differences in prostate cancer incidence among blacks, whites, and Asians is unclear.

Induction of apoptosis in rat ventral prostate by finasteride is associated with alteration in MAP kinase pathways and Bcl-2 related family of proteins

Finasteride is widely used in treatment of symptomatic benign prostatic hyperplasia. Treatment of rats with finasteride caused a significant decrease in ventral prostate weight and intraprostatic dihydrotestosterone levels while intraprostatic testosterone levels were increased. Finasteride inhibited Akt-1 and MAPK expression while expression of PTEN was significantly increased only at 100 mg dose. Basal phosphorylation of c-Raf, MEK1/2, MAPK and the transcription factor Elk-1 was significantly reduced by finasteride. The rate of prostate epithelial apoptosis is equivalent to 0.1+/-0.03, 0.6+/-0.18%, 0.92+/-0.24% and 1.42+/-0.3% on treatments with 0, 1, 10 and 100 mg finasteride per kg body weight, respectively. Concomitantly, these treatments led to a 2.5-, 4.0- and 4.0-fold increase in Bad while a slight decrease in Bax was observed. Similar elevations were also observed in Bcl-xs levels which increased by 9.8-, 10- and 12-fold respectively in the finasteride treatments as compared to controls. Bcl-xL levels in ventral prostates treated with 1, 10 and 100 mg finasteride were approximately 30, 30 and 26% of control, respectively. Significant reduction in Bcl-2 expression was observed only at the dose of 100 mg/kg body weight. These findings suggest that modulation of MAP kinase and Akt expression, Bcl-xL, Bcl-xs, Bcl-2 and Bad proteins by finasteride may be, in part, responsible for the anti-proliferative and apoptotic effect of this drug seen clinically and in animal models.

Androgen-Induced Regrowth in the Castrated Rat Ventral Prostate: Role of 5 -Reductase

Testosterone (T), the major circulating androgen, must be converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase (5α-R) to be maximally active in the prostate. The present study was designed to determine the relative potency of T and DHT on regrowth of the involuted prostate and to elucidate the role of 5α-R in the growing prostate. To create dose-response curves for intraprostatic T or DHT, rats were castrated for 2 weeks to allow their prostates to fully regress and then given T implants of various sizes in the presence or absence of the 5α-R inhibitor, finasteride. Markers for androgen effects on regrowth of the prostate were prostate weight, duct mass (a measure of secretory activity) and DNA content (a measure of cell number). To assess the relative uptake of T and DHT by the prostate, a comparison was made of intraprostatic DHT levels resulting from T and DHT implants. In the prostate, 1.6–1.9 times more T than DHT was required to achieve a half-maximal response for each of the three markers of prostate regrowth. The dose-response curves revealed that thresholds for intraprostatic T and DHT had to be attained before significant growth was observed. The threshold for T was 2- to 3-fold greater than that for DHT. However, at high intraprostatic concentrations, the effects of T mimicked those of DHT. When the relationship between serum T levels and prostate regrowth was considered, 13 times more serum T was required for half-maximal prostate regrowth when its conversion to DHT was blocked by finasteride. This is partly due to decreased androgen accumulation in the prostate when T was the major intraprostatic androgen. Finally, T or DHT implants in the absence of finasteride resulted in similar intraprostatic DHT levels, indicating that uptake of each serum androgen into the prostate was similar. However, to achieve similar levels of DHT or T in serum, much larger DHT pellets were needed, suggesting more rapid metabolism of DHT in tissues other than the prostate. We conclude that the role of 5α-R is 2-fold: it converts testosterone into a modestly more potent androgen and enhances prostatic accumulation of androgen. DHT, in principle, could serve equally well as T as the circulating androgen, although the rate of DHT production would have to be considerably higher to counter the apparent rapid clearance from serum. In addition, we hypothesize that T has arisen as the major circulating androgen instead of DHT because it can be aromatized to estradiol, which itself has important roles in male reproductive function and bone physiology.

Androgen-induced regrowth in the castrated rat ventral prostate: role of 5alpha-reductase.

Testosterone (T), the major circulating androgen, must be converted to dihydrotestosterone (DHT) by the enzyme 5alpha-reductase (5alpha-R) to be maximally active in the prostate. The present study was designed to determine the relative potency of T and DHT on regrowth of the involuted prostate and to elucidate the role of 5alpha-R in the growing prostate. To create dose-response curves for intraprostatic T or DHT, rats were castrated for 2 weeks to allow their prostates to fully regress and then given T implants of various sizes in the presence or absence of the 5alpha-R inhibitor, finasteride. Markers for androgen effects on regrowth of the prostate were prostate weight, duct mass (a measure of secretory activity) and DNA content (a measure of cell number). To assess the relative uptake of T and DHT by the prostate, a comparison was made of intraprostatic DHT levels resulting from T and DHT implants. In the prostate, 1.6-1.9 times more T than DHT was required to achieve a half-maximal response for each of the three markers of prostate regrowth. The dose-response curves revealed that thresholds for intraprostatic T and DHT had to be attained before significant growth was observed. The threshold for T was 2- to 3-fold greater than that for DHT. However, at high intraprostatic concentrations, the effects of T mimicked those of DHT. When the relationship between serum T levels and prostate regrowth was considered, 13 times more serum T was required for half-maximal prostate regrowth when its conversion to DHT was blocked by finasteride. This is partly due to decreased androgen accumulation in the prostate when T was the major intraprostatic androgen. Finally, T or DHT implants in the absence of finasteride resulted in similar intraprostatic DHT levels, indicating that uptake of each serum androgen into the prostate was similar. However, to achieve similar levels of DHT or T in serum, much larger DHT pellets were needed, suggesting more rapid metabolism of DHT in tissues other than the prostate. We conclude that the role of 5alpha-R is 2-fold: it converts testosterone into a modestly more potent androgen and enhances prostatic accumulation of androgen. DHT, in principle, could serve equally well as T as the circulating androgen, although the rate of DHT production would have to be considerably higher to counter the apparent rapid clearance from serum. In addition, we hypothesize that T has arisen as the major circulating androgen instead of DHT because it can be aromatized to estradiol, which itself has important roles in male reproductive function and bone physiology.

Morphological and hormonal changes in the ventral and dorsolateral prostatic lobes of rats treated with finasteride, a 5-alpha reductase inhibitor.

In rats, the prostate is divided into three distinct lobes, and the lobes are dependent on androgens [testosterone (T) and dihydrotestosterone (DHT)] as trophic hormones. However, the reasons for the difference in the incidence of proliferative changes reported are not well-understood. Administration of finasteride, a 5-alpha reductase (5alphaR) inhibitor which selectively inhibits the conversion of T to DHT, results in elevated intraprostatic T levels. However, long-term (2 years) administration of finasteride results in no increase in proliferative changes in the ventral lobes of the rat prostate. Therefore, studies were designed to determine the differences in intraprostatic hormonal levels, morphology, and 5alphaR activity in different lobes of the rat prostate. Sexually mature male Sprague-Dawley rats were used in all studies. Finasteride was administered orally to rats. The methodology included determination of intraprostatic T and DHT levels by radioimmunoassay, qualitative and quantitative evaluation of prostatic morphology, and in vitro determination of 5alphaR activities in rat prostatic lobes. A significant amount of 5alphaR activity was observed in the dorsal, ventral, and lateral lobes of the rat prostate. Both 5alphaR isozymes (types 1 and 2) were present in all lobes, based on 5alphaR activities observed at both acidic and neutral pH. Oral administration of finasteride (160 mg/kg/day) for 15 days resulted in significant (P < or = 0.001) decreases in intraprostatic DHT levels and increases in T levels; when compared to controls, the mean decrease in DHT levels in the ventral and the dorsolateral lobes was 86% and 94%, respectively, and the mean increase in T levels in the ventral and the dorsolateral lobes was approximately 3 times and 20 times, respectively, higher than in controls. Chronic administration of finasteride (80 mg/kg/day) for 6 months resulted in significant (P < or = 0.001) decreases in the weights of the prostatic lobes, which correlated with significant (P < or = 0.001) decreases in the total number of epithelial and stromal cells per gland in both the ventral and dorsolateral lobes of the prostate. There were no qualitative differences in prostatic morphology between the control and finasteride-treated groups. A short-term study in control rats exposed to bromodeoxyuridine (Brdu) showed that the number of Brdu-labeled cells in the dorsolateral lobe was significantly (P < or = 0.05) greater than in the ventral lobe. This first comparative study has highlighted some of the similarities and differences among the prostatic lobes of the rat. Inhibition of conversion of T to DHT with finasteride resulted in a significant increase in intraprostatic T levels and a significant decrease in DHT levels in rats; despite a significant increase in intraprostatic T levels, the prostate remained atrophic, indicating that DHT alone has a trophic effect on the prostate.

Blockade of androstenedione-induced stimulation of androgen-sensitive parameters in the rat prostate by combination of Flutamide and 4-MA

In order to mimic the human situation in which adrenal steroid precursors are converted to the active androgen dihydrotestosterone (DHT) in prostatic tissue, we have used castrated rats supplemented with the precursor steroid androstenedione ( Δ 4-dione) released from Silastic implants. While it is well known that the action of DHT can be partially neutralized by antiandrogens which compete for binding to the androgen receptor, we have used 17 β- N, N-diethylcarbamoyl-4-methyl-4-aza-5 α-androstan-3-one (4-MA), an inhibitor of 5α-reductase, the enzyme which converts testosterone into DHT, in order to decrease intraprostatic DHT levels and thus facilitate the action of the antiandrogen. Animals were treated for 7 days with Flutamide (FLU, 2 mg) or 4-MA (4 mg) injected subcutaneously, twice daily, alone or in combination. 4-MA administered alone caused a 54% inhibition of Δ 4-dione-stimulated ventral prostate weight while FLU exerted a 74% inhibitory effect and 4-MA + FLU further improved inhibition to 81%. We then measured, by in situ hybridization, the levels of prostatic mRNAs encoding the C1 and C3 components of the prostatic binding protein (PBP) which are highly specific and sensitive markers of androgen action. PBP-C3 mRNA levels fell by 95% following castration while treatment with Δ 4-dione completely reversed the effect of castration. Administration of FLU or 4-MA independently caused 33% and 10% decreases, respectively, of PBP-C3 mRNA levels stimulated by Δ 4-dione while the combination of both compounds further inhibited PBP-C3 mRNA levels to reach a 55% inhibition. Similar effects were observed on PBP-C1 mRNA levels. Moreover, while FLU or 4-MA alone caused 72 and 75% decreases in intraprostatic DHT levels, respectively, the combined treatment caused a 89% decrease in the intraprostatic concentration of the androgen. The present data show that the combination of a pure antiandrogen and a 5α-reductase inhibitor has greater inhibitory effects than either compound used alone on androgen-sensitive parameters in the rat ventral prostate. It is likely that an important part of the beneficial effect of the antiandrogen is due to its blockade of access to the androgen receptor of the high intraprostatic levels of testosterone resulting from the action of the 5α-reductase inhibitor used alone.

Differential Effect of 5α-Reductase Inhibition and Castration on Androgen-Regulated Gene Expression in Rat Prostate

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)