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.     

Altered metabolism of androgens in elderly men with benign prostatic hyperplasia.

Kinetics of testosterone, dihydrotestosterone (DHT) and 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) were studied in 7 elderly healthy men (ages 61 to 80 years) with benign prostatic hyperplasia (BPH). Clearance rates were determined by the constant infusion technique with labeled testosterone and DHT. Metabolic clearance rate (MCR), conversion ratio (CR), the transfer constants (rho) and production rates (PB) were calculated. Plasma androgens were measured by specific radioimmunoassay. Plasma testosterone was 516 +/- 314 (SD) ng/dl, plasma DHT was 74.6 +/- 19.6 (SD) ng/dl and plasma 3alpha-diol was 16.4 +/- 4.1 (SD) ng/dl. An elevated DHT level in elderly men with BPH wasconfirmed. MCRT was 620 +/- 65 (SD) liter/day and MCRDHT was 393 +/- 50 (SD) liter/day. Both MCRT and MCRDHT in elderly men were significantly lower than in young men. PBT was 3.2 +/- 2.1 (SD) mg/day and PBDHT was 291 +/- 87 (SD)migrogram/day. PBDHT was the same in elderly and young men. DHT production is maintained in elderly men despite reduction of testosterone production. From the data, it was claculated that in contrast to young men where greater than 80% of blood DHT is from secreted testosterone, over 50% in elderly men is derived from secretion or production of DHT by the testis or even more likely the prostate.     

Altered blood androgens in elderly men with prostate hyperplasia.

Plasma testosterone (T) and dihydrotestosterone (DHT) were measured in the plasma of otherwise healthy men ages 60-90 who had prostate hyperplasia. The androgens were measured by specific radioimmunoassays using paper and celite column chromatography. In the elderly subjects, plasma T was 466+/-35 (SE) ng per 100 ml which is reduced (p less than 0.05) as compared with values from younger men. In contrast, DHT levels were elevated when compared with values from men ages 20-39, 89 (53-152) versus 49 (33-74) 95% confidence ng per 100 ml. Analysis of data by the Mann Whitney U test demonstrates that the groups are different (p less than 0.001). These studies indicate that DHT levels and T/DHT ratios are altered in unstressed elderly men with BPH. Further study is necessary to delineate the source of DHT and whether these altered androgen levels are the cause of prostate hypertrophy or an unrelated effect of aging.     

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.     

Circulating unconjugated 5 alpha-androstane-3 alpha, 17 beta-diol in elderly men and patients with prostatic tumours

Circulating levels of 5 alpha-androstane-3 alpha,17 beta-diol (diol) were measured in 24 elderly men (50-80 years) without prostatic tumours and compared with 32 patients (54-84 years) with benign prostatic hypertrophy (BPH) and 32 patients (51-85 years) with carcinoma of the prostate (Ca). The mean +/- s.e.m. for serum concentrations of diol in patients with BPH, Ca and normals were 813 +/- 43, 524 +/- 35 and 635 +/- 28 pmol/l, respectively. There were significant differences between the mean values of these groups. The increased level of diol in BPH patients, when compared to the normals, corresponds to our previous report of elevated levels of its precursor, namely 5 alpha-dihydrotestosterone (DHT), in these patients. Although the mean values for diol were significantly different between the BPH and Ca patients, the scattered values within each group could not be utilized as an index to differentiate the two groups of patients.     

Production of 3 alpha-androstanediol glucuronide in human genital skin

3 alpha-Androstanediol glucuronide (3 alpha diol-G) is produced extrasplanchnically and is a good clinical marker of androgen action in peripheral tissues. However, the direct formation of androgen glucuronides in peripheral sites such as skin has not been determined in man. Genital skin from 21 premenopausal women and 8 men and foreskin from 6 neonates were incubated with either [14C]testosterone [14C]dihydrotestosterone (DHT) to determine the production of DHT glucuronide and 3 alpha diol-G in skin. After hydrolysis of incubation medium with glucuronidase, followed by extraction and sequential chromatography, constant 3H to 14C ratios of 3 alpha diol confirmed the production of DHT glucuronide and 3 alpha diol-g. The conversion of DHT to 3 alpha diol-G was higher than the conversion from testosterone (P less than 0.05), and conversion was higher in men than in women. These data provide evidence for the direct formation of C19 steroid glucuronides by human skin.     

Serum androgen levels in adolescents with type 1 diabetes: relationship to pubertal stage and metabolic control

Delayed sexual maturation is still frequently seen in adolescents with type 1 diabetes. A close relationship between insulin and androgen metabolism has been found in a number of studies. Our study was designed to investigate whether or not abnormalities in androgen secretion could play a role in the onset of sexual maturation in adolescents with type 1 diabetes. We have asked whether or not there was a correlation between daily insulin dosage, duration of diabetes, metabolic control, age, pubertal stage, and body mass index (BMI) versus serum androgen concentrations. Basal total and free testosterone, dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), sex hormone binding globulin (SHBG) and 3alpha-androstanediol glucuronide (3alpha diol-G) plasma concentrations were measured in 36 pubertal boys and 31 pubertal girls with type 1 diabetes and in 59 sex- and pubertal stage-matched control subjects without diabetes. Significantly higher serum total testosterone (p<0.01) and free testosterone (p<0.05) levels were found in females and males with type 1 diabetes than in controls at pubertal stage 5. DHEA-S, SHBG, DHT and 3alpha diol G concentrations in patients with diabetes were not significantly different from those in controls. There was no correlation between daily insulin requirements and serum androgen levels. These data suggest that adolescents with diabetes have similar serum levels of DHEA-S, SHBG, DHT and 3alpha diol G as healthy subjects at all stages of puberty. However, there are significant differences in serum testosterone and free testosterone levels in adolescents with diabetes when compared to healthy, sex- and pubertal stage-matched controls in late puberty. We hypothesize that the increased testosterone levels in patients with diabetes could relate to reduced fertility in females, disorders of sexual maturation and an increased risk for cardiovascular complications later in life.     

Androgens and glucuronidated androgen metabolites are associated with metabolic risk factors in men

CONTEXT: Androgens are associated with metabolic risk factors in men. However, the independent impact of androgens and androgen metabolites on metabolic risk factors in men is unclear. OBJECTIVE: Our objective was to determine the predictive value of serum levels of androgens and glucuronidated androgen metabolites for metabolic risk factors. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two Swedish cohorts (1,068 young adult and 1,001 elderly men). MAIN OUTCOME MEASURES: We measured correlation of serum dihydrotestosterone (DHT), testosterone (T), and glucuronidated androgen metabolites with fat mass, fat distribution, serum lipids, and insulin resistance. RESULTS: Both DHT and T were negatively associated with different measures of fat mass in both cohorts (P < 0.001). Further statistical analysis indicated that DHT, but not T, was independently negatively associated with different measures of fat mass and insulin resistance (P < 0.001). The glucuronidated androgen metabolite androstane-3alpha,17beta-diol-17glucuronide (17G) was independently positively associated with fat mass (P < 0.001). Most importantly, the 17G to DHT ratio was strongly correlated, not only with fat mass but also with central fat distribution, intrahepatic fat, disturbed lipid profile, insulin resistance, and diabetes, explaining a substantial part of the total variance in total body fat (12% in young adult men, 15% in elderly men), the homeostasis model assessment index (10%), and high-density lipoprotein cholesterol (7%). CONCLUSION: Our findings demonstrate that 17-glucuronidation of the DHT metabolite androstane-3alpha,17beta-diol is strongly associated with several metabolic risk factors in men. Future longitudinal studies are required to determine the possible impact of the 17G to DHT ratio as a metabolic risk factor in men.     

Levels of plasma steroid glucuronides in intact and castrated men with prostatic cancer

The levels of plasma dehydroepiandrosterone (DHEA), androst-5-ene-3 beta,17 beta-diol (delta 5-diol), testosterone (T), dihydrostestosterone (DHT), androstane-3 alpha,17 beta-diol (3 alpha-diol), androsterone (ADT), and the related glucuronide (G) derivatives were determined in intact and castrated men with prostatic cancer. The plasma concentrations of DHEA and DHEA-G were not significantly different in intact and castrated men while delta 5-diol as well as delta 5-diol-G were 50% lowered in castrated men. As expected, T and DHT concentrations were markedly lower in castrated men. These low plasma levels of T and DHT were accompanied by a decrease of 3 alpha-diol, ADT, T-G, 3 alpha-diol-G, and ADT-G levels. There was, in unoperated men, a positive correlation between the levels of DHEA and ADT-G as well as DHEA and DHEA-G, while T values were highly correlated with ADT-G and 3 alpha-diol-G levels. Furthermore, a significant relationship was found between DHEA and ADT-G as well as 3 alpha-diol-G in castrated men. Our data clearly demonstrate that ADT-G and 3 alpha-diol-G levels are more affected by castration than are the corresponding unconjugated steroids and suggest that these steroid glucuronides should be good markers of androgen metabolism. Moreover, the significant relationship between DHEA, ADT-G, and 3 alpha-diol-G in castrated men also suggests that approximately 30% of C-19 steroids from the adrenals are converted to T and DHT, which are further transformed into steroid glucuronides.     

Short term androgen production by rat ovarian follicles and long term steroidogenesis by thecal explants in culture

To characterize the aromatizable and 5 alpha-reduced androgens produced by developing ovarian follicles, small antral (SA) and preovulatory (PO) follicles, theca and granulosa cells were incubated for 4 h with or without 8-bromo-cAMP and androstenedione. In addition, thecal explants were cultured for 10 days with or without ovine LH (oLH) to determine if the hormone-induced changes in androgen synthesis by developing follicles could be mimicked in vitro. Short term incubations of SA and PO follicles, theca and granulosa cells in medium alone resulted in limited accumulation of androgen [testosterone, 5 alpha-androstan-17 beta-ol-3-one (DHT), 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha diol), and androsterone], as determined by RIA. In the presence of 8-bromo-cAMP, PO follicles produced large quantities of testosterone (3 ng), DHT (1 ng), 3 alpha diol (15 ng), and androsterone (14 ng), while SA follicles accumulated much less androgen (0.69, 0.05, 1.23, and 1.3 ng, respectively). In the presence of androstenedione and 8-bromo-cAMP, both SA and PO follicles and theca produced large amounts of aromatizable and 5 alpha-reduced androgens. SA and PO granulosa cells required the presence of the substrate androstenedione to produce androgens, primarily testosterone and 3 alpha diol. Therefore, progesterone, androstenedione, and 5 alpha-reduced androgens were used to monitor LH action on thecal cell function in culture. Small antral theca cultured in basic culture medium alone (containing 10% fetal calf serum) displayed an increased ability to accumulate androstenedione by day 6, approximately 3 times that observed on day 2. However, a 5-fold further increase in androstenedione accumulation was observed by day 6 for SA theca cultured in the presence of oLH. Maintenance of progesterone accumulation by SA theca throughout the culture period also was dependent on the presence of LH. In contrast, androstenedione accumulation by PO theca required the presence of LH in the culture medium, while progesterone accumulation in these cultures did not. Little or no 5 alpha-reduced androgen accumulated in the media of SA and PO theca cultured in basic culture medium alone. However, SA and PO theca cultured with oLH accumulated approximately 1 ng androsterone by day 10. We conclude that 1) SA and PO follicles, theca and granulosa cells possess the enzymes required to produce large amounts of 3 alpha diol and androsterone; 2) low concentrations of oLH are required to stimulate SA thecal steroidogenesis and to maintain PO thecal androstenedione accumulation in culture.(ABSTRACT TRUNCATED AT 400 WORDS)     

Representativeness of a single point plasma testosterone level for the long term hormonal milieu in men.

To test the reliability of a single plasma testosterone (T) or dihydrotestosterone (DHT) level, respectively, as a parameter of the long term hormonal milieu, plasma T and DHT levels were measured eight times, over a period of 50 weeks, in 169 middle-aged and elderly men with symptomatic benign prostatic hyperplasia, who were otherwise healthy. The results show an excellent correlation (r = 0.849) between plasma androgen levels at first sampling and the mean of the 7 samples taken subsequently over 1 yr. Of the 22 subjects with plasma testosterone levels below the lower limit of normal (10 nmol/L) at first sampling, none had an annual plasma T value greater than 13.5 nmol/L, i.e. the annual mean was also below the normal limit or in the low normal range, whereas of the 18 subjects with a T level at first sampling above 25 nmol/L (+/- 90th percentile), none had a mean plasma T level below 19.0 nmol/L (70th percentile). Similar results were obtained for DHT. When plasma testosterone levels at first sampling were subdivided into groups, with a concentration interval of 5 nmol/L from 5 to more than 25 nmol/L, multifactor analysis of variance showed no significant difference between the values within the same group at each sampling, whereas at each sampling the groups remained highly significantly (P less than 0.001) different from each other. The same applies to DHT levels when subdivided into groups with a concentration interval of 0.5 nmol/L. It is concluded that in healthy middle-aged and elderly men, single point plasma androgen measurements reflect fairly reliably the annual mean androgen level.     

Hormone blood levels and their inter-relationships in normal men and men with benign prostatic hyperplasia (BPH).

In 128 non-hospitalized men (age range 36-65 years) rectal palpation revealed in 54 cases an enlargement of the prostate (group II), which was very distinct in 20 cases (group III). The measurement of testosterone (T), 5alpha-dihydrotestosterone (DHT), 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) oestradiol (Oe2), sex-hormone-binding-globulin binding capacity (SHBG), luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (Prl) in the blood of normal men (group I) and those with BPH (group II or III) demonstrated no significant differences between the three groups when respective age ranges were compared. A significant increase of FSH and decrease of 3alpha-diol with age was seen in the normal group (I), which was similar but less pronounced in BPH (groups II and III). A distinct increase of DHT with age was found in BPH (group II), which was not so dominant in normal men (group I). From these data it is concluded that the conversion of DHT to 3alpha-diol might be reduced in older males independent from the occurrence of BPH and that the hyperplastic prostate possibly secretes significant amounts of DHT into the circulation. These results are discussed with respect to their possible role in the pathogenesis of BPH.     

Contribution of plasma androstenedione to 5 alpha-androstanediol glucuronide in women with idiopathic hirsutism

To confirm that plasma delta 4 androstenedione (delta 4) is the main precursor for 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide (Adiol G) in patients with idiopathic hirsutism (IH), delta 4 was cutaneously applied to five normal women and five women with IH. Several parameters of androgen metabolism were assayed basally and throughout the studies. Those included plasma delta 4, testosterone, and dihydrotestosterone as well as urinary Adiol G and testosterone glucuronide excretion. Under basal conditions plasma testosterone, delta 4, and dihydrotestosterone did not differ significantly between the two groups of subjects. Urinary Adiol G excretion was significantly higher (P less than 0.01) in IH patients [123 +/- 36 (SE) micrograms/24 h] than in the normal women group (45 +/- 20 micrograms/24 h). After percutaneous administration of delta 4, plasma delta 4 increased in both groups by nearly 600% and there was a 300% increase in Adiol G excretion in IH patients (336 +/- 57 micrograms/24 h), whereas only a 50% increase occurred in normal women (65 +/- 17 micrograms/24 h). We postulate that plasma delta 4 may be the main precursor accounting for the increased production of urinary Adiol G in women with IH, in whom hirsutism may be due to a high 5 alpha-reductase activity. Indeed, 5 alpha-reductase as measured in vitro in pubic skin was significantly higher in hirsute patients (224 +/- 66 fmol/mg skin X h) than in normal women (45 +/- 15 fmol/mg skin X h).     

Influence of age on steroid concentrations in skin and striated muscle in women and in cardiac muscle and lung tissue in men

In order to investigate whether androgen concentrations vary as a function of age in all tissues and organs and whether the sexual differences in plasma androgen levels are reflected in tissue concentrations, testosterone (T), 5 alpha-androstane-17 beta-ol, 3-one (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (Adiol), and 4-androstene-3,17-dione (Adion) concentrations were measured postmortem in lung tissue and myocardium of men aged 16-87 yr. The results were compared to values obtained previously in other tissues. Similar measurements were made in various tissues (labia majora, clitoris, pubic skin, thigh skin, striated muscle) from women aged 16-87 yr. In cardiac tissue of men, T was quantitatively the most important androgen and concentrations of DHT and Adiol were low, reflecting low 5 alpha-reductase activity; in lung tissue, T and Adion were found in similar concentrations, with lower levels of 5 alpha-reduced metabolites. In both cardiac and lung tissue, androgen concentrations decreased significantly with age. In women, androgen concentrations were highest in specific androgen target tissues (labia majora, clitoris) and lowest in thigh skin and striated muscle. The ratios of the 5 alpha-saturated metabolites (DHT plus Adiol) to T or to T + Adion, respectively, parallel total androgen concentrations, whereas the Adiol to DHT ratio, a parameter of 3 alpha-reductase activity, was highest in striated muscle and thigh skin and lowest in androgen target tissues (labia majora and clitoris). In women tissue concentrations of all androgens decreased significantly with age in nearly all tissues studied. As expected tissue androgen concentrations were lower in women than in men, but in androgen target tissues such as the clitoris or labia majora, concentrations were little lower than in scrotal skin. We conclude that in both men and women androgen target tissues contain high androgen concentrations and high 5 alpha-reductase activity; moreover androgen concentrations in target tissues are similar in both sexes. In both sexes tissue androgen concentrations decreased with age in most tissues, but in target tissues the decrease was more pronounced in women than in men.     

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.     

Decreased bioavailable testosterone in aging normal and impotent men

Tissue available (bioavailable) testosterone (T) includes circulating free T (FT) and albumin-bound T. A reasonable assessment of bioavailable T can be made by using 50% ammonium sulfate to precipitate sex hormone-binding globulin (SHBG)-bound T. The supernatant non-SHBG-bound T (non-SHBG-T) correlates well with physiological androgen activity. To assess bioavailable T in normal aging men, we analyzed serum samples from seven healthy aged men (65-83 yr old) and compared the results to samples from 13 young men (22-39 yr old). Mean serum T, FT, and LH concentrations were not significantly different in the 2 groups. However, the mean absolute non-SHBG-T level was significantly lower (P less than 0.005) in the older group. In a separate population of 20 impotent but otherwise healthy men (5 27-37 yr old, 10 48-64 yr old, and 5 66-69 yr old), the mean absolute non-SHBG-T concentration was lower in middle-aged (P less than .01) and elderly men (P less than 0.001) than in young men. The absolute FT was lower only in the elderly group (P less than 0.05), while mean LH and T levels were similar in all 3 age groups. These data suggest that serum concentrations of tissue available T are decreased in aged men and that non-SHBG-T measurement is a more sensitive indicator of this decrease than are serum T or serum FT measurements. These changes appear to begin by middle age.     

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.     

Elevated production and metabolic clearance rates of androgens in morbidly obese women

Blood production rates of testosterone, dihydrotestosterone (DHT), and 3 alpha-androstanediol (3 alpha-diol) were found to be approximately 2-fold elevated in morbidly obese, nonhirsute, normally menstruating women. Values were intermediate between those found in normal women and those in a group of nonobese normally menstruating women with idiopathic hirsutism. Elevated androgen production rates in obese women were associated with 2- to 3-fold increases in MCRs, presumably due to decreased levels of sex hormone-binding globulin. Thus, increased production rates were offset by increased MCRs, resulting in plasma testosterone, DHT, and 3 alpha-diol concentrations that were similar in the obese and normal women. By contrast, women with hirsutism had increased production rates associated with elevated plasma androgens as well as increased MCRs. Urinary excretion of testosterone glucuronide and 3 alpha-diol glucuronide (3 alpha-diol G) were elevated in both obese and hirsute women, paralleling the increased androgen production rates. Despite increased production rates and excretion of androgens, obese women exhibited no menstrual abnormalities, hirsutism, or other signs of virilism. To explore the apparent ineffectiveness of increased androgen production to produce virilizing symptoms, we measured plasma 3 alpha-diol G levels as a measure of peripheral androgen action. The mean +/- SE plasma 3 alpha-diol G was 53 +/- 8 ng/dl in obese women and 36 +/- 6 in normal women; by contrast, women with idiopathic hirsutism had levels of 440 +/- 99, a 12-fold elevation. Plasma testosterone glucuronide in obese and hirsute women were only 2- to 3-fold elevated, while plasma DHT glucuronide was not increased in obese women and was only 2-fold elevated in hirsute women. Thus, obesity is a state of increased androgen production and accelerated clearance. 3 alpha-diol G levels in obese women were only minimally elevated, in contrast to values in the hirsute women, perhaps reflecting the apparent androgen ineffectiveness.     

Serum androgen levels in black, Hispanic, and white men

CONTEXT: Racial/ethnic differences in androgen levels could account for differences in prostate cancer risk, body composition, and bone loss. OBJECTIVE: The objective of the study was to investigate racial/ethnic variations in testosterone, bioavailable testosterone, dihydrotestosterone (DHT), SHBG, and dehydroepiandrosterone sulfate (DHEAS) levels. DESIGN: The Boston Area Community Health (BACH) Survey was a multistage stratified cluster random sample, recruiting from 2002 to 2005. SETTING: The study was a community-based sample of Boston. PARTICIPANTS: Participants included black, Hispanic, or white individuals, aged 30-79 yr, competent to sign informed consent and literate in English/Spanish. Of 2301 men recruited, 1899 provided blood samples (538 black, 651 Hispanic, 710 white). INTERVENTION: Intervention consisted of data obtained during in-person at-home interview, conducted by a bilingual phlebotomist/interviewer. MAIN OUTCOME MEASURE(S): Testosterone, bioavailable testosterone, DHT, DHT to testosterone ratio, SHBG, and DHEAS were measured. RESULTS: With or without adjustment for covariates, there were no significant differences in testosterone, bioavailable testosterone, or SHBG levels by race/ethnicity. DHEAS levels differed by race/ethnicity before covariate adjustment; after adjustment this difference was attenuated. Before adjustment, DHT and DHT to testosterone ratios did not significantly differ by racial/ethnic group. After adjustment, there was evidence of racial/ethnic differences in DHT (P = 0.047) and DHT to testosterone (P = 0.038) levels. Black men had higher DHT levels and DHT to testosterone ratios than white and Hispanic men. CONCLUSIONS: Because there are no racial/ethnic differences in testosterone levels, normative ranges need not be adjusted by race/ethnicity for androgen deficiency diagnosis for men aged 30-79 yr. Further investigation is needed to determine whether differences in DHT levels and DHT to testosterone ratio can help explain racial/ethnic variations in prostate cancer incidence, body composition, and bone mass.     

Comparison of androgen metabolites in benign prostatic hypertrophy (BPH) and normal prostate.

5 alpha-Dihydrotestosterone (DHT) and androstanediols (diols) have been measured in human prostate tissue. DHT levels in surgical specimens of prostate from 8 patients with BPH averaged 5.6 +/- 0.93 S.E. ng/g and were significantly greater than (P less than 0.01) values of 2.1 +/- 0.32 S.E. ng/g in 6 normal prostates obtained post-mortem from males less than 50 yrs old. Androstanediols averaged 2.3 +/- 0.35 S.E. ng/g in the BPH specimens compared to values of 10.2 +/- 2.4 S.E. ng/g in the normal prostates (P less than 0.01). This significantly higher (P less than 0.001) ratio of diols/DHT in the normal (5.1 +/- 0.93 S.E.) compared to the BPH prostate (0.45 +/- 0.08 S.E.) suggests that a decrease in 3-hydroxysteroid oxido-reductase, which converts DHT to diol, may be an important clue to the pathogenesis of BPH.