The effect of sexual activity on androgen metabolism, androgen-receptor translocation, and glandular weight of ventral prostates of rats

The present study was conducted to determine whether sexual activity exerts an effect on the action of androgen in the rat prostate. Eight-week-old Sprague-Dawley male rats were divided into two groups. Rats were grouped with female rats (sexualactive), or male (sexual-inactive) rats, and sacrificed 6 months later, The ventral prostates were dissected, homogenized and processed into cytosol and nuclei fractions. Testosterone and dihydrotestosterone were quantified by radioimmunoassay, and androgen receptor was determined by 'exchange assay' with radioactive methyltrienolone incubated for 18 h at 15 degrees C. The main result were: 1) The steroid levels of testosterone and dihydrotestosterone in plasma and in the cytosolic fraction of prostate showed no significant difference between the two group of rats. 2) The prostatic nuclear dihydrotestosterone concentration of the sexual-active group (4.3 +/- 0.83 pmol/mg DNA, N = 6) was significantly higher (P less than 0.01) than that of the sexual-inactive group (1.68 +/- 0.43, N = 6). 3) The androgen receptor was significantly higher (P less than 0.05) in nuclear extract (0.64 +/- 0.11 pmol/mg DNA, N = 6) and significantly lower (P less than 0.01) in cytosol (53.4 +/- 5.7 fmol/mg protein, N = 6) of the sexual-active group than those of the sexual inactive group (0.42 +/- 0.13, N = 6 and 74.6 +/- 11.8, N = 6, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of the steroidal androgen receptor antagonist, Win 49,596, on the prostate and testis of beagle dogs.

The effect of the steroidal androgen receptor antagonist Win 49,596 on the prostate and testis was studied in beagle dogs and was compared to the effects of the nonsteroidal androgen receptor antagonist ICI 176,334 and the steroidal 5 alpha-reductase inhibitor MK-906. Win 49,596 was shown to bind to the androgen receptor from normal canine prostate with a Ki of 2.2 microM. After 16 weeks of treatment, prostate size, as estimated by transrectal ultrasonography, was unchanged in intact controls and was 26% of the initial size in castrate controls. Oral doses of Win 49,596 from 0.625-40 mg/kg.day for 16 weeks caused dose-dependent prostatic regression and a dose-related increase in both the incidence and severity of glandular atrophy of the prostate. Prostatic secretory function was also inhibited by Win 49,596 treatment. The effects of Win 49,596 at 40 mg/kg.day on prostatic weight, total DNA, histomorphology, and secretory function were similar to those of castration, while the effects of Win 49,596 at 10 mg/kg.day were similar to those of ICI 176,334 at 0.25 mg/kg.day and MK-906 at 1.0 mg/kg.day. No effects on testicular weight, daily sperm production, or spermatogenesis were observed; however, mild Leydig cell hyperplasia was observed in two dogs treated with 40 mg/kg.day Win 49,596. In addition, at 10 and 40 mg/kg.day Win 49,596, moderate but variable increases in serum testosterone levels were observed. In summary, Win 49,596 caused regression of the hypertrophic canine prostate without effects on spermatogenesis and/or sexual function, supporting its possible use in the treatment of human benign prostatic hypertrophy/hyperplasia.     

The effect of a 5 alpha-reductase inhibitor on androgen-mediated growth of the dog prostate

The administration of testosterone cypionate (0.4 mg/kg BW . day) to castrated male dogs caused a doubling of prostate weight within 4 weeks and an increase in the content of testosterone and dihydrotestosterone in the prostate. When the 5 alpha-reductase inhibitor 17-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (3 mg/kg BW . day) was administered simultaneously with testosterone cypionate, prostatic testosterone content increased from 0.5 +/- 0.2 to 4.1 +/- 1.3 ng/mg DNA, the increase in prostatic dihydrotestosterone content was prevented, and prostatic size decreased to half the starting weight. These results suggest that dihydrotestosterone formation plays a role in prostatic growth.     

Endogenous androgen levels in epithelium and stroma of human benign prostatic hyperplasia and normal prostate

5 alpha-Dihydrotestosterone (DHT) and 5 alpha-androstane-3 alpha, 18 beta-diol (3 alpha-diol) were extracted from epithelium and stroma of human benign prostatic hyperplasia (BPH) and of normal prostate and quantified by RIA. The main results were: (1) concerning the BPH, DHT is mainly located in the nuclear fraction of epithelium and stroma, whereas 3 alpha-diol was completely of extranuclear origin, (2) in the nuclei derived from BPH stroma the DHT content (7.1 +/- 0.88 pmol/mg DNA, mean +/- SEM [n = 14]) was significantly higher (P less than 0.01) than in the nuclei derived from BPH epithelium (3.8 +/- 0.38 pmol/mg DNA [n = 14]). The DHT content in the nuclear fraction derived from unseparated, i.e. whole tissue, was 5.6 +/- 0.60 pmol/mg DNA [n =14], (3) the biological significance of the overwhelming DHT accumulation in the stromal nuclei for the BPH tissue is reflected by a significant correlation between the DHT values in the nuclei from stroma and whole tissue (rs = 0.710, P less than 0.01) and (4) in four normal prostates the DHT content in the nuclear fraction of epithelium (1.3 +/- 0.37 pmol/mg DNA) and stroma (2.2 +/- 0.93 pmol/mg DNA) was significantly lower (P less than 0.01, each) compared with the respective BPH fraction. These data support earlier findings which indicate that the stroma of BPH is a preferential tissue for androgen metabolism.     

Androgen 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase activities in ventral prostate epithelial and stromal cells from immature and mature rats

To study androgen-mediated differentiation in the rat ventral prostate, we separated the two principal cell types (epithelial and stromal) derived from prostates of immature and mature rats on two continuous Percoll gradients. Cells were immediately placed in culture medium. Testosterone metabolism by the two prostatic cell types was evaluated using [3H]testosterone and quantifying the formation of 5 alpha-[3H]dihydrotestosterone (5 alpha-DHT) and 5 alpha-[3H]androstane-(3 alpha or 3 beta), 17 beta-diols. In epithelial cells from both immature and mature rat prostates the major testosterone metabolites were 5 alpha-DHT and 5 alpha-androstane-3 alpha, 17 beta-diol. Stromal cells metabolized less testosterone than did the epithelial cells. Differences in the relative levels of the various metabolites were observed for the two age groups. To examine in more detail the changes in testosterone metabolism observed in vitro both types of cells and unfractionated cells from immature and mature rat prostates were assayed for testosterone 5 alpha-reductase (using testosterone as substrate) and 3 alpha-hydroxysteroid dehydrogenase (using 5 alpha-DHT as substrate) activities (expressed as pmol substrate reduced/min per 10(6) cells). In immature rats both 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase activities were localized in the epithelial cell fraction (17 and 52 respectively); stromal cells showed lower 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase activity (4 and 4). Relative to epithelial cells from immature rats epithelial cells from mature rats showed a decrease in 5 alpha-reductase (7) and an increase in 3 alpha-hydroxysteroid dehydrogenase (160) activity while stromal 5 alpha-reductase showed little change (3) and 3 alpha-hydroxysteroid dehydrogenase increased to 22.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical aspects and molecular genetics of the persistent Müllerian duct syndrome

OBJECTIVE The 5α-reductase inhibitor, finasteride, provides a logical medical treatment for benign prostatic hyperplasia (BPH). However, the effects of chronic finasteride treatment on prostatic androgen levels, 5α-reductase activity and tissue prostatic specific antigen (PSA) have not been studied. We have examined prostate tissue androgen concentrations and 5α-reductase activity of the gland in men with BPH treated with the drug for 3 months. DESIGN AND PATIENTS Twenty-eight patients with clinically diagnosed BPH, awaiting transurethral resection of the prostate, were entered in a double-blind placebo controlled study. Nineteen patients were randomly allocated to treatment with finasteride (5 mg daily) and 9 received placebo for 3 months. MEASUREMENTS Prostate specimens were collected immediately following surgery and analysed for testosterone, dihydrotestosterone (DHT), androstenedione, 5α-reductase activity and PSA. Blood specimens obtained before the start and immediately following treatment were also tested for steroid hormone concentrations and PSA levels. RESULTS There was no significant difference in the median levels of intraprostatic testosterone (P = 0.77), DHT(P= 0.46) and androstenedione (P = 0.09) between the finasteride and placebo groups. However, the 5α-reductase activity of the placebo group (237.9 pmol DHT/g tissue/30 min) was approximately 10 times that of the finasteride group (21.5 pmol DHT/g tissue/30 min; P = 0.0008). Although we were unable to detect any differences in the PSA concentrations of the prostate glands, there was a significant difference (P = 0.0002) in the median percentage change of serum PSA concentrations for the two patient groups. Serum DHT levels were also depleted (P = 0.038) whilst serum testosterone was increased (P = 0.054) in the finasteride patients when compared to the placebo group. Furthermore our study demonstrated no correlation between the in vitro 5α-reductase activity of the gland and tissue DHT concentrations. CONCLUSIONS Whilst finasteride treatment induced a reduction in serum dihydrotestosterone and prostatic specific antigen levels with a concomittant increase in blood testosterone concentrations, the impact of the drug on tissue androgen concentrations varied considerably from one patient to another. The differential effect of the drug on tissue androgen concentrations suggests that in the human prostate there are possibly more than one isoform of 5α-reductase responsible for the accumulation of DHT in the gland.     

Hormonal control of prostatic thyrotropin-releasing hormone (TRH) testosterone modulates prostatic TRH concentrations

The presence of extremely high concentrations of authentic TRH in the rat prostate prompted us to examine whether prostatic TRH concentrations were under hormonal control. Both the immunoreactive TRH content per prostate and TRH immunoreactivity expressed per 100 mg prostatic protein were lower in animals 2 weeks after hypophysectomy than in sham-operated and calorically restricted weight-matched controls. Since many of the prostatic functions are testosterone dependent, we assessed the possibility that testosterone modulated prostatic TRH concentrations. We measured prostatic TRH concentrations in the following four groups of sexually mature male Sprague-Dawley rats: group I, sham operated; group II, castrated; group III, castrated animals with 5-mm Silastic testosterone implants; and group IV, castrated animals with 20-mm testosterone implants. Prostatic TRH concentrations in these four groups 2 weeks after surgery were 600.5 +/- 33.3, 65.1 +/- 22.6, 169.4 +/- 55.3, and 609.5 +/- 144.3 (+/-SE) ng/100 mg protein. There was good linear correlation between prostatic TRH concentrations and serum testosterone concentrations (r = 0.65; P less than 0.01). By subjecting the pooled prostatic extracts from each group to ion exchange chromatography on a SP-Sephadex C-25 column and measuring the proportion of immunoreactivity coeluting with authentic TRH, it was shown that the fall in prostatic TRH immunoreactivity after castration and hypophysectomy was indeed due to a loss of authentic TRH. We conclude that the prostatic TRH concentrations are under hormonal control and appear to be modulated by serum testosterone concentrations. This is the first demonstration of hormonal regulation of a neuropeptide in a mammalian extrahypothalamic site and suggests a physiological role for this neuropeptide at this site.     

Androgen-binding proteins in human benign prostatic hypertrophy.

Prostatic samples were surgically removed from 7 patients suffering from benign prostatic hypertrophy. High-speed supernatants (cytosol) containing 20-25 mg of protein/ml were prepared. Glycerol gradient ultracentrifugations were performed, using cytosol labeled at 0 C with 2-5 nM 3H-17beta-hydroxy-androstan-3-one (androstanolone or dihydrotestosterone) alone, or in the presence of 50-250-fold excess of androstanolone, estradiol, or androstane-3alpha, 17beta-diol (androstanediol). Two high-affinity saturable binding components were observed. One binding component was the androgen receptor. Its sedimentation coefficient was 8 S in low-salt medium. It had a high affinity for androstanolone. The binding of 3H-androstanolone was strongly completed by androstanolone itself, less by estradiol, and not by androstanediol. In one case, endogenous androstanolone found in the 8 S region of glycerol gradients was measured by radioimmunoassay, and it was calculated that more than 90% of the cytosol receptor binding sites might be occupied by this steroid while the total binding capacity of the 8 S receptor was estimated to approximate 2.6 pmol of androstanolone/g of prostate. No testosterone was found in the receptor fraction. The second binding component was attributable, at least in part, to the sex steroid-binding plasma protein (SBP), as indicated by its sedimentation coefficient (congruent to 4 S in low salt medium), its high affinity for androstanolone and androstanediol and its lower affinity for estradiol, and finally, its migration on polyacrylamide gel electrophoresis. In one instance, the concentration of the SBP-like protein in prostate cytosol was measured by equilibrium dialysis, and it was calculated that the binding capacity of the prostate SBP-like component corresponded to 4 pmol of androstanolone/g of prostate, a small (less than 5%) value with regard to SBP concentration in the plasma of the same patient. The blood contamination of the cytosol, as obtained from the measurement of hemoglobin, did not account for the amount of SBP found in the prostate sample. Since SBP-like protein is probably of plasma origin, to determine whether SBP was located in the extracellular space or inside the prostate cells, BPH slices from another patient were incubated in the presence of 3H-testosterone, the cytosol was prepared, and was fractionated by Sephadex G-150 column chromatography. The androstanolone/testosterone ratio in the receptor-containing peak was high (1.7), whereas in the incubation medium it was very low (0.08). In the peak containing the SBP-like protein, the ratio was 0.74, which may suggest that all or part had been exposed to the predominant androstanolone environment inside the prostatic cell.     

Dihydrotestosterone accumulation in genital skin fibroblasts derived from elderly men with prostatic hyperplasia.

The conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase and the interconversion between DHT and 5 alpha-Androstane-3 alpha,17 beta-diol (3 alpha-diol) by 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSOR) were studied in fibroblasts derived from the genital skin of 15 prepubertal boys (2-10 yr), 17 young men (20-40 yr), 13 elderly men (60-78 yr) without clinically evident prostatic pathology, and 17 elderly men (61-88 yr) with benign prostatic hyperplasia (BPH). Respective DHT formations from testosterone (5 alpha-reduction) and 3 alpha-diol (3 alpha-HSOR oxidation) were not different among genital skin fibroblasts of the 4 groups. However, DHT degradation to 3 alpha-diol (3 alpha-HSOR reduction) was significantly lower in fibroblasts from elderly men with BPH than in those from the prepubertal boys (P less than 0.01), the young men (P less than 0.01), and the elderly men without BPH (P less than 0.05). 3 beta-HSOR reduction in fibroblasts of the BPH group was significantly lower (P less than 0.05) than in those of the elderly men without BPH; however, it did not differ from values for the prepubertal boys and the young men. (3 alpha + 3 beta)-HSOR reduction was also significantly lower (P less than 0.05) in the BPH group than respective values of the three other groups. These results indicate that DHT accumulation may occur in genital skin fibroblasts from elderly men with BPH, resulting from a shift in the overall balance of androgen metabolism, which favors the net formation of DHT.     

Nuclear accumulation of androgens in perfused rat accessory sex organs and testes.

The uptake of androgens into the nuclei of caput epididymis, ventral prostate, seminal vesicle and testis was studied by recirculating physiological and pharmacological concentrations of [3H]testosterone in an artificial medium through the lower half (hemicorpus) of castrated or hypophysectomized rats. The accumulation of dihydrotestosterone in accessory sex organ nuclei was saturable, inhibited by perfusion of excess testosterone or cyproterone acetate, and associated with binding to 3S salt-extractable molecules. In castrated preparations the mean saturation levels (pmol/mg DNA) were different in the three organs: seminal vesicle, 2.8; ventral prostate, 1.8; caput epididymis, 0.9. The saturation level was significantly lower in ventral prostate of hypophysectomized rats (1.2) treated with testosterone to regenerate the accessory sex organs. Testosterone was the major nuclear androgen in the testes of mature hypophysectomized preparations perfused with testosterone. Although there was a large amount of nonspecific accumulation, testosterone binding to 3S molecules was shown by sucrose gradient centrifugation. Binding of dihydrotestosterone to 3S molecules in testicular nuclei was also demonstrated. The ratio of dihydrotestosterone to testosterone was different in immature and mature testicular nuclei and was altered by treatments known to affect testicular 5 alpha-reductase activity. The results suggest that in rat accessory sex organs and immature testis the major active androgen is dihydrotestosterone, whereas in mature testis it is testosterone. The shift in the predominant nuclear androgen in the testis from dihydrotestosterone to testosterone is most simply explained by the maturational change in 5 alpha-reductase activity.     

Androgen receptor expression and 5 alpha-reductase activity along the proximal-distal axis of the rat prostatic duct.

The rat prostate consists of a series of branched ducts that eminate from the urethra. Heterogeneity of rat prostatic growth, secretory activity, and cell turnover has been observed along the proximal-distal axis of the branched ductal network. In addition, there are regional differences in androgen sensitivity along the ducts, with the distal ductal tips being highly androgen dependent and the proximal regions being relatively androgen independent. To determine the underlying mechanisms that may regulate these regional differences in androgen responsiveness, androgen receptor (AR) levels and 5 alpha-reductase activity were examined along the proximal-distal axis of microdissected ventral prostatic ducts from 15-, 30-, and 100-day-old rats. As in the murine prostate, DNA synthetic activity was concentrated in the distal tip region of the 15- and 30-day ducts. Immunocytochemistry and autoradiography with [3H] dihydrotestosterone were used to examine AR expression and functional ability to bind ligand, respectively. The results revealed no discernable differences in AR levels or binding activity in any cell type along the ductal length in prepubertal, pubertal, or adult rats. In addition, 5 alpha-reductase activity was the same in the distal and proximal ductal regions. We conclude that regional heterogeneity in prostatic growth and function is not a result of differences in levels of AR and 5 alpha-reductase. Rather, other region-specific structural, intracellular, or paracrine factors may be responsible for the differences in androgen responsiveness along the prostatic duct.     

The presence of androgen-binding protein in the guinea-pig testis, epididymis and epididymal fluid

Androgen-binding protein (ABP) is present in the guinea-pig testis, epididymis and epididymal fluid. Guinea-pig ABP sediments as an approx. 4.6S species on sucrose gradients containing 0.01 M KCl. Electrophoresis on non-denaturing polyacrylamide gels indicated that specific androgen binding was present in epididymal cytosol, but not in plasma. Time-course studies indicated that binding equilibrium is approached in about 2.5 h; the dissociation half-time of [3H]5 alpha-DHT from guinea-pig ABP is 5.64 +/- 0.62 h (n = 6) at 4 degrees C. The relative affinities of some steroids for guinea-pig ABP in relation to 5 alpha-DHT = 1 are: testosterone = 0.55 +/- 0.13 (n = 4), estradiol = 0.14 +/- 0.03 (n = 4), the anti-androgen cyproterone acetate = 0.0025 +/- 0.0002 (n = 3). Guinea-pig ABP exhibited an equilibrium dissociation constant of 6.34 +/- 0.52 nM (n = 3) at 4 degrees C and there were 3.43 +/- 0.78 (n = 3) pmoles of binding sites per mg of protein when homogenates of the whole epididymis were assayed. The concentration of ABP was lowest in the caput-corpus region of the epididymis, highest in the proximal cauda, and intermediate in the distal cauda. Essentially all of the ABP present in the distal cauda was intraluminal, as evidenced by the fact that flushing of the duct eliminated most of the [3H]5 alpha-DHT binding activity.     

Endogenous androgen levels of human prostatic tissues

Endogenous androgen levels of prostatic tissues in patients with benign prostatic hypertrophy (BPH) and untreated prostatic cancer (PC) were determined by radioimmunoassay using sephadex LH-20 column chromatography. By this assay procedure, it was possible to measure tissue androgen levels with only 30 approximately 40 mg weight of tissues. In BPH (n=20) the concentrations of steroids (mean +/- standard deviation, ng/g. tissue weight) were 5 alpha-androstane 3 alpha, 17 beta diol (A-diol), 2.31 +/- 1.29; dihydrotestosterone (DHT), 4.97 +/- 2.17; testosterone (T), 0.62 +/- 0.33. In PC (n=17) the concentrations were 5.51 +/- 3.23; 3.94 +/- 3.16; and 0.93 +/- 0.38; respectively. The concentrations of DHT were raised and the levels of A-diol were reduced significantly (P less than 0.01) in BPH compared with PC. Tissue DHT levels of PC were variable, but they could be classified in to two groups. One was below 2 ng levels (n=8) similar to those of non-androgen target tissues and the other was over 2 ng (n=19). The relationships between histological differentiation and tissue DHT levels in prostatic cancer were examined. In poorly differentiated cancer (n=4), DHT levels were low in all cases, furthermore even in well differentiated ones there were 4 cases with levels below 2 ng. Thus, the measurement of endogenous DHT levels of prostatic tissues was considered to be valuable for the judgment of androgen dependency in prostatic cancer.     

Blood testosterone threshold for androgen deficiency symptoms

There are few systematic studies of the relationship between blood testosterone concentrations and the symptoms of overt androgen deficiency. Because most testosterone preparations are relatively short-term, the rapid changes in blood testosterone concentrations they cause make it difficult to define any testosterone threshold. By contrast, subdermal testosterone implants provide stable blood testosterone concentrations over days to weeks, while gradually declining to baseline over 5-7 months. Hence, this provides an opportunity to define a blood testosterone threshold for androgen deficiency symptoms by observing androgen-deficient men as their familiar androgen deficiency symptoms return as testosterone pellets slowly dissolve. Among 52 androgen-deficient men who underwent 260 implantations over 5 yr, at the time of return of androgen deficiency symptoms the blood total and free testosterone concentrations were highly reproducible within individuals (F = 0.8, P = 0.49 and F = 1.4, 0.24, respectively) but varied markedly between men (F = 167 and F = 138, both P < 0.001), indicating that each person had a consistent testosterone threshold for androgen deficiency symptoms that differed markedly between individuals. The most reported symptoms of androgen deficiency were lack of energy, lack of motivation, and reduced libido. The symptomatic threshold was significantly lower in men with secondary hypogonadism compared with men with primary or mixed hypogonadism (total, 9.7 +/- 0.5 nmol/liter vs. 11.7 +/- 0.4 nmol/liter and 10.2 +/- 0.3 nmol/liter, P = 0.006; free, 146 +/- 10 pmol/liter vs. 165 +/- 6 pmol/liter and 211 +/- 18 pmol/liter, P = 0.002) but was not affected by the underlying cause of hypogonadism or by specific symptoms of any severity. Despite a wide range in individual thresholds for androgen deficiency symptoms, the mean blood testosterone threshold corresponded to the lower end of the eugonadal reference range for young men. The implications of these observations for the development of more specific quality-of-life measures, as well as for other potential androgen deficiency states such as chronic diseases and aging, remain to be determined.     

Prostatic involution in rats induced by a novel 5 alpha-reductase inhibitor, SK&F 105657: role for testosterone in the androgenic response.

Within the prostate, androgen stimulates glandular cell secretion and proliferation while inhibiting glandular cell death. Due to its predominant nuclear localization, higher affinity for the androgen receptor, and more than 10-fold higher intracellular concentration than testosterone, dihydrotestosterone (DHT), not testosterone, appears to be the active intracellular androgen within the prostate of intact male hosts. The issue has remained unanswered, however, whether testosterone itself, without irreversible conversion to DHT by the 5 alpha-reductase enzyme, is capable of androgenic effects in the prostate. To address this issue, a novel dead end (i.e. product) inhibitor of the 5 alpha-reductase enzyme, SK&F 105657, was administered to intact or castrated male rats treated with either exogeneous testosterone or DHT. When administered twice a day orally at 25 mg/kg.dose, SK&F 105657 reduced the prostatic DHT content of either intact or castrated rats maintained with exogeneous testosterone to the same low level as that produced by surgical castration. Unlike castration, however, such SK&F 105657 treatment increased the prostatic testosterone content by more than 5-fold. The decrease in prostatic DHT coupled with a raise in testosterone are specifically due to the in vivo inhibition of the 5 alpha-reductase activity, since they were not observed in castrated rats maintained with exogeneous DHT. Treatment of intact or castrated male rats with exogeneous testosterone and oral SK&F 105657 (25 mg/kg, twice daily) resulted in a substantial inhibition of prostatic secretion, an inhibition of prostatic glandular cell proliferation, and an increase in prostatic glandular cell death. The magnitude of the changes, however, was not as great as that observed after surgical castration. The results are, however, specific for 5 alpha-reductase inhibition, since they were not observed in castrated rats given exogeneous DHT. These results demonstrate that if the prostatic testosterone content is elevated to sufficient levels, androgenic effects are induced without a requirement for an elevation in prostatic DHT content. Thus, the conversion of testosterone to DHT appears to function as a means of amplifying androgenic stimulation in the prostate.     

Sex steroids and their relationship to binding proteins in the serum of the marmoset monkey (Callithrix jacchus)

A sex hormone binding globulin (SHBG) similar to human SHBG was identified in marmoset serum based on its gel electrophoretic mobility, isoelectric point and steroid binding properties. Levels of serum SHBG were measured in immature and mature males, immature females and females during the luteal phase and pregnancy; serum progesterone, 5 alpha-dihydrotestosterone (5 alpha-DHT), testosterone, oestradiol-17 beta and oestrone were also measured. Mean (+/- S.E.M.) concentrations of SHBG in immature males (336 +/- 19 nmol/l) were higher (P less than 0.01) than those in mature males (251 +/- 13 nmol/l), whereas values in the groups of females were similar (359 +/- 12, 395 +/- 17, 397 +/- 39 nmol/l in immature, non-pregnant and pregnant females respectively). There was an inverse relationship between SHBG and the levels of testosterone (r = -0.67) and 5 alpha-DHT (r = -0.86) in males, but the correlation was significant (P less than 0.05) only for 5 alpha-DHT. There was no correlation between levels of SHBG and oestrogens in males or between levels of SHBG and any of the steroids measured in females. Equilibrium dialysis was used to assess the percentage of steroid in serum in the unbound form. Mean percentage values for unbound testosterone and 5 alpha-DHT were lower in immature males than in mature males (P less than 0.01) and negatively correlated with levels of SHBG (r = -0.78, testosterone; r = -0.56, 5 alpha-DHT).     

Three-month treatment with a long-acting gonadotropin-releasing hormone agonist of patients with benign prostatic hyperplasia: effects on tissue androgen concentration, 5 alpha-reductase activity and androgen receptor content

The intraprostatic concentrations of testosterone (T) and dihydrotestosterone (DHT) have been measured in only a few men. We measured, in prostatic tissue obtained at surgery from seven men with benign prostatic hyperplasia, the effects of 3-month treatment with a long-acting GnRH agonist on 1) the intraprostatic concentrations of T, DHT, and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol); 2) prostatic 5 alpha-reductase activity; and 3) the prostatic content of androgen receptors (AR). Plasma T, DHT, and 3 alpha-diol levels also were measured. Prostatic tissue samples obtained at surgery from a group of untreated men with benign prostatic hyperplasia also were studied. The mean DHT and 3 alpha-diol concentrations in the prostatic tissue of the treated men were about 10% of those in untreated men (n = 19; P less than 0.01 for DHT and P less than 0.05 for 3 alpha-diol), and the mean intraprostatic T concentration in the treated men was about 25% of that in the control group (0.10 greater than P greater than 0.05). The mean in vitro formation of DHT by the prostatic tissue of the treated men was about 50% lower (P less than 0.05) than that by prostatic tissue of the untreated men (n = 9). The mean cytosolic AR content in the prostatic tissue of the treated men was significantly higher (P less than 0.05), whereas the mean nuclear content of both salt-extractable and salt-resistant AR was significantly lower (P less than 0.05) than that in the prostatic tissue of the untreated men (n = 8). The mean plasma T levels in treated men decreased from 4.77 +/- 1.79 (SD) ng/mL (16.5 +/- 6.2 nmol/L) to 0.27 +/- 0.42 ng/mL (0.9 +/- 1.5 nmol/L) after 1 month of therapy and remained in the castrate range thereafter. We conclude that pharmacological castration resulting from 3-month treatment with a long-acting GnRH agonist decreases the intraprostatic T concentration to about one fourth and those of DHT and 3 alpha-diol to about one tenth of the levels in untreated men. Thus, GnRH agonist treatment may not completely abolish intraprostatic androgen concentrations in metastatic prostatic cancer patients. The decrease in prostatic 5 alpha-reductase activity as well as the decrease in nuclear receptors are probably secondary to the decrease in plasma T concentrations.