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Comparison of prostatic cancer tissue dihydrotestosterone levels at the time of relapse following orchiectomy or estrogen therapy.

Dihydrotestosterone concentrations have been measured in prostatic tissue from patients with recurrent advanced prostatic cancer after 1.0 to 5.0 mg. diethylstilbestrol per day or castration with or without estrogen therapy. Although medical or surgical castration usually leads to tissue dihydrotestosterone concentrations of less than 2.4 ng./gm. 2 of 20 surgically castrated and 4 of 9 estrogen-treated patients had values above this level. The difference between the number of patients with dihydrotestosterone levels greater than 2.4 ng./gm. in the surgical castrated and estrogen-treated groups was statistically significant by a chi-square test. These differences suggest that 1) increased tissue dihydrotestosterone levels in diethylstilbestrol-treated patients may be caused by inadequate dosage or decreased compliance, and 2) increased tissue dihydrotestosterone concentrations greater than 2.4 ng./gm. in castrated patients suggest an adrenocortical androgen contribution to the prostatic dihydrotestosterone level. Therefore, patients who are castrated or treated with diethylstilbestrol should have plasma testosterone and tissue dihydrotestosterone measurements at the time of relapse. If plasma and tissue dihydrotestosterone levels are at castrate levels (plasma levels less than 0.5 ng./ml. and tissue levels less than 2.4 ng./gm.) then further hormonal therapy is not indicated. Otherwise, adrenocortical suppression should be done if plasma testosterone is at castrate levels and tissue dihydrotestosterone is elevated. When plasma testosterone is above castrate levels titration with hormonal therapy should be done while plasma testosterone is monitored to achieve plasma testosterone levels below 0.5 ng./ml.

Castration↗

17beta-estradiol enhances vascular endothelial growth factor production and dihydrotestosterone antagonizes the enhancement via the regulation of adenylate cyclase in differentiated THP-1 cells.

We studied the in vitro effects of sex hormones on vascular endothelial growth factor (VEGF) production in differentiated THP-1 monocytic cells. Phorbol-12-myristate-13-acetate differentiated THP-1 into macrophage-like cells. 17beta-estradiol (10 (-9) M) increased VEGF secretion of controls 3.1-fold in differentiated THP-1 and this effect of 17beta-estradiol was antagonized by dihydrotestosterone, although dihydrotestosterone alone did not alter VEGF secretion. 17beta-estradiol increased steady-state mRNA level of VEGF and the increase was counteracted by dihydrotestosterone in differentiated THP-1, although dihydrotestosterone alone did not alter the VEGF mRNA level. Progesterone did not affect the constitutive and 17beta-estradiol-induced VEGF secretion and mRNA level. Transient transfection revealed that 17beta-estradiol enhanced chloramphenicol acetyl transferase expression driven by VEGF promoter and the enhancement was antagonized by dihydrotestosterone. Adenylate cyclase inhibitor suppressed 17beta-estradiol-induced enhancement of VEGF secretion, mRNA level, and promoter activity, whereas dihydrotestosterone-induced suppression on the effects of 17beta-estradiol was counteracted by 3',5'-adenosine cyclic monophosphate (cAMP) analog. 17beta-estradiol increased intracellular cAMP level by activating adenylate cyclase, while dihydrotestosterone reduced the basal and 17beta-estradiol-increased cAMP level by inhibiting adenylate cyclase. Transfection with 5'-deleted VEGF promoters demonstrated that the region between -88 and -66 bp may be involved in the transcriptional regulation by each hormone. The mutation within activator protein-2 element in this region abrogated the transcriptional stimulation and repression by the respective hormones. 17beta-estradiol activated transcription from activator protein-2-responsive reporter plasmid while dihydrotestosterone antagonized the effect of 17beta-estradiol. These results suggest that 17beta-estradiol enhances VEGF production while dihydrotestosterone antagonizes the effect of 17beta-estradiol via up- or downregulation of adenylate cyclase in differentiated THP-1.

Adenylyl Cyclases↗

The source of plasma dihydrotestosterone in man.

The source of plasma dihydrotestosterone (DHT) (17beta-hydroxy-5alpha-androstan-3-one) in humans has been investigated by infusing two potential peripheral precursors, testosterone (T) and androstenedione (A). Metabolic clearance rates (MCR), conversion ratios (CR), transfer constants (rho), and blood production rates (P(B)) were calculated. Plasma testosterone and dihydrotestosterone were measured by competitive binding techniques. The MCR(DHT) was 652 +/-35 (SD) liters/day in five males and 314 +/-63 (SD) liters/day in four adult females. In each individual, the MCR(DHT) was significantly lower than MCR(T) as predicted by testosterone-binding protein affinity studies. The P(B) (DHT) was 302 +/-65 (SD) mug/day in males and 56 +/-26 mug/day in females. Testosterone and androstenedione are precursors (prehormones) for plasma dihydrotestosterone. The conversion ratio CR(BB) (T-DHT), calculated as the ratio of counts per minute per liter of plasma of product to precursor after infusion of labeled precursor, was 5.6 +/-0.6 (SD)% (six subjects) in the male and 3.5 +/-0.4 (SD)% (four subjects) in the female. CR(BB) (A-DHT) after androstenedione infusion to three female subjects averaged 9.2%. No dihydrotestosterone back conversion was detected (< 0.2%). The transfer constants were [rho]BB(T-DHT), 3.9 +/-1.0% (male) and 1.7 +/-0.6% (female), and [rho]BB(A-DHT) average was 13.3% in three female subjects. Using either plasma testosterone and dihydrotestosterone values from our subjects and mean androstenedione values as reported in the literature, approximate contributions can be calculated. Testosterone conversion accounts for at least 70% of plasma DHT in the male, but less than 20% in the normal female. Androstenedione appears to be a major prehormone of plasma dihydrotestosterone accounting for at least two-thirds plasma dihydrotestosterone by peripheral conversion in adult females. In three normal women undergoing tubal ligation, there was an unimpressive gradient between ovarian vein and peripheral plasma dihydrotestosterone. It is suggested that dihydrotestosterone in the blood does not arise from direct secretion but may reflect events occurring in peripheral androgen target tissues.

17-Hydroxycorticosteroids↗

Tissue content of dihydrotestosterone in human prostatic hyperplasis is not supranormal.

The dihydrotestosterone content of normal peripheral and benign hyperplastic prostates was measured in tissue obtained at open surgical procedures on 29 men of ages 36 to 82 yr. The dihydrotestosterone content in normal prostates (mean +/- SE, 5.1 +/- 0.4 ng/g tissue) and in benign hyperplastic prostates (5.0 +/- 0.4) was similar. In 11 patients in whom both normal and hyperplastic prostatic tissue was harvested simultaneously at the same operation, there was no significant difference in the content of dihydrotestosterone in the two types of tissue. These findings fail to confirm the widespread belief that dihydrotestosterone content is elevated in benign hyperplastic prostates. Our data differ from the reported literature in one major respect: the dihydrotestosterone content of normal peripheral prostate in this study is three to four times higher than previously reported. This difference between the present and earlier studies was resolved by experiments performed on cadavers, which were the source of normal prostatic tissue used by other investigators. Dihydrotestosterone content was measured in seven cadavers ranging in age from 19 to 82 yr of age. The results of this experiment indicate that the dihydrotestosterone content of prostatic tissue removed at autopsy is factitiously low (0.7-1.0 ng/g tissue). This finding was confirmed by in vitro incubations of fresh prostatic tissue at 37 degrees C that demonstrated reduction of dihydrotestosterone content to low levels within 2 h. When taken together, these results indicate that when prostatic tissue is harvested appropriately, the dihydrotestosterone content of normal peripheral and hyperplastic tissues is the same. This finding should influence future research into the etiology of benign prostatic hyperplasia.

Adult↗

Antiestrogenic action of dihydrotestosterone in mouse breast. Competition with estradiol for binding to the estrogen receptor.

Feminization in men occurs when the effective ratio of androgen to estrogen is lowered. Since sufficient estrogen is produced in normal men to induce breast enlargement in the absence of adequate amounts of circulating androgens, it has been generally assumed that androgens exert an antiestrogenic action to prevent feminization in normal men. We examined the mechanisms of this effect of androgens in the mouse breast. Administration of estradiol via silastic implants to castrated virgin CBA/J female mice results in a doubling in dry weight and DNA content of the breast. The effect of estradiol can be inhibited by implantation of 17 beta-hydroxy-5 alpha-androstan-3-one (dihydrotestosterone), whereas dihydrotestosterone alone had no effect on breast growth. Estradiol administration also enhances the level of progesterone receptor in mouse breast. Within 4 d of castration, the progesterone receptor virtually disappears and estradiol treatment causes a twofold increase above the level in intact animals. Dihydrotestosterone does not compete for binding to the progesterone receptor, but it does inhibit estrogen-mediated increases of progesterone receptor content of breast tissue cytosol from both control mice and mice with X-linked testicular feminization (tfm)/Y. Since tfm/Y mice lack a functional androgen receptor, we conclude that this antiestrogenic action of androgen is not mediated by the androgen receptor. Dihydrotestosterone competes with estradiol for binding to the cytosolic estrogen receptor of mouse breast, whereas 17 beta-hydroxy-5 beta-androstan-3-one (5 beta-dihydrotestosterone) neither competes for binding nor inhibits estradiol-mediated induction of the progesterone receptor. Dihydrotestosterone also promotes the translocation of estrogen receptor from cytoplasm to nucleus; the ratio of cytoplasmic-to-nuclear receptor changes from 3:1 in the castrate to 1:2 in dihydrotestosterone-treated mice. Thus, the antiestrogenic effect of androgen in mouse breast may be the result of effects of dihydrotestosterone on the estrogen receptor. If so, dihydrotestosterone performs one of its major actions independent of the androgen receptor.

Animals↗

Inhibition of luteinizing hormone (LH)-releasing hormone-induced secretion of LH in rat anterior pituitary cell culture by testosterone without conversion to 5 alpha-dihydrotestosterone.

The role of 5 alpha-reduction of testosterone in the inhibition of LH secretion was investigated in rat anterior pituitary cell cultures. Pituitary cells were preincubated with testosterone or dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) for 17 h and then with LHRH for an additional 4 h. Dihydrotestosterone was 6-fold more potent than testosterone in the inhibition of LHRH-induced LH release. Basal LH secretion was not affected by either androgen. The inhibition curves of testosterone and dihydrotestosterone were not shifted by the presence of the 5 alpha-reductase inhibitors 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA) and 17 beta-N,N-diisopropylcarbamoyl-4-aza-androstan-3-one (DIPA). Neither 4-MA nor DIPA alone had an effect on either basal or LHRH-induced LH release. When pituitary cells were incubated with [3H]testosterone for 17 h, the radioactivities were found to be unmetabolized testosterone (66.9 +/- 2.4%), dihydrotestosterone (13.3 +/- 0.5%), androstenedione (15.9 +/- 1.3%), 5 alpha-androstane-3,17-dione (2.8 +/- 0.3%), and 3 alpha (beta), 17 beta-androstanediol (less than 1%). In the presence of 4-MA or DIPA, 5 alpha-reduction of testosterone was completely inhibited; androstenedione was the only metabolite. Androstenedione was only 12% as potent as testosterone in the inhibition of LHRH stimulation of LH release, and conversion of [3H]androstenedione to testosterone and dihydrotestosterone did occur in these cells. When [3H]dihydrotestosterone was incubated with pituitary cells, the radioactivities were dihydrotestosterone (64.4 +/- 0%), 5 alpha-androstanedione (19.3 +/- 1%), 3 alpha (beta), 17 beta-androstanediol (7.7 +/- 1.7%), and unknown polar metabolites. 4-MA and DIPA had no effect on the metabolism of dihydrotestosterone. These results indicate that both testosterone and dihydrotestosterone inhibit LHRH-induced LH release and that this activity of testosterone does not depend on its 5 alpha-reduction.

5-alpha Reductase Inhibitors↗

A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency.

The efficacy and safety of androgen supplementation in older men remains controversial. Despite biochemical evidence of partial androgen deficiency in older men, controlled studies using T demonstrate equivocal benefits. Furthermore, the importance of aromatization and 5alpha reduction in androgen actions among older men remains unclear. Dihydrotestosterone is the highest potency natural androgen with the additional features that it is neither aromatizable nor susceptible to potency amplification by 5alpha reduction. Therefore, the effects of dihydrotestosterone may differ from those of T in older men. This study evaluated the efficacy and safety of 3 months treatment with transdermal dihydrotestosterone gel on muscle strength, mobility, and quality of life in ambulant, community-dwelling men aged 60 yr or older. Eligible men (plasma T < or =15 nmol/liter) were randomized to undergo daily dermal application of 70 mg dihydrotestosterone gel (n = 18) or vehicle (n = 19) and were studied before, monthly during, and 1 month after treatment. Among 33 (17 dihydrotestosterone, 16 placebo) men completing the study with a high degree of compliance, dihydrotestosterone had significant effects on circulating hormones (increased dihydrotestosterone; decreased total and free testosterone, LH, and FSH; unchanged SHBG and estradiol), lipid profiles (decreased total and low-density lipoprotein cholesterols; unchanged high-density lipoprotein cholesterol and triglycerides), hematopoiesis (increased hemoglobin, hematocrit, and red cell counts), and body composition (decreased skinfold thickness and fat mass; unchanged lean mass and waist to hip ratio). Muscle strength measured by isokinetic peak torque was increased in flexion of the dominant knee but not in knee extension or shoulder contraction, nor was there any significant change in gait, balance, or mobility tests, in cognitive function, or in quality of life scales. Dihydrotestosterone treatment had no adverse effects on prostate (unchanged prostate volumes and prostate-specific antigen) and cardiovascular (no adverse change in vascular reactivity or lipids) safety markers. We conclude that 3 months treatment with transdermal dihydrotestosterone gel demonstrates expected androgenic effects, short-term safety, and limited improvement in lower limb muscle strength but no change in physical functioning or cognitive function.

Administration, Cutaneous↗

The effect of dihydrotestosterone and culture conditions on proliferation of the human prostatic cancer cell line LNCaP.

Cell density, nutritional state, and serum factors modify the growth response of LNCaP human prostatic cancer cells to dihydrotestosterone. Evaluation of growth response to dihydrotestosterone requires logarithmic transformation of cell count or thymidine incorporation data. Under conditions of dose response, growth increases with cell density but no significant interaction of dihydrotestosterone with cell density was found under optimal culture conditions. The frequency of media change was a significant factor in modulating dose response. When cells from cultures maintained at different feeding periods were plated at different cell densities of (trypan blue) viable cells, significant effects of plating density on dihydrotestosterone response were found. Dihydrotestosterone protects cells under the adverse effects of media deprivation. Under the extreme adverse effects of serum deprivation, cells respond to dihydrotestosterone even under conditions of increasing cell loss. The effects of dihydrotestosterone on final cell density were significant. In the absence of serum, the elongated cells of LNCaP assume a round shape, but many remain adherent to the culture dish and can be restored to normal morphology by serum. A number of growth factors fail to restore normal morphology that was completely restored by a combination of fibronectin and dihydrotestosterone. We have not developed a practicable serum-free system for LNCaP.

Biological Factors↗

Interactive effects of insulin with dihydrotestosterone on adrenergic tone in isolated rat tail arterial rings.

Reversal of sex-related differences in incidence of vascular diseases in Type II diabetics suggests that high circulating insulin may reverse normal differences in vascular actions of sex steroids. We have found that a high concentration of insulin can reverse small inhibitory actions of low estradiol on adrenergic tone in isolated arterial rings. Thus, we measured effects of high insulin on actions of dihydrotestosterone on adrenergic tone and specificity of these effects with respect to time of exposure to the steroid and its concentration. In the first of two studies, tail arterial rings from 16 male rats were incubated for 2 h with either dihydrotestosterone (0.0012 mumol/ L), insulin (0.5 mU/mL), dihydrotestosterone plus insulin, or vehicles. Rings were then contracted with norepinephrine administered cumulatively from 10(-9) to 10(-4) mol/L. Contractile responses to norepinephrine from 10(-7) to 10(-4) mol/L were increased by dihydrotestosterone in the absence (P < .05) but not in the presence of insulin. Also, norepinephrine's EC50 was reduced by dihydrotestosterone in the absence (P < .05) but not in the presence of insulin. In a second study (with rings from 12 more rats), the same low level of dihydrotestosterone failed to affect norepinephrine contractions acutely (that is, within 6 min), whereas much higher levels (12 and 120 mumol/L) rapidly inhibited the same contractions, independent of 2-h preincubation with insulin. Thus, prolonged exposure to a low physiological level of dihydrotestosterone enhances adrenergic tone, whereas acute exposure to high levels inhibits it. In addition, a high level of insulin specifically blunts the delayed enhancing effect of the low dihydrotestosterone. These results suggest possible mechanisms underlying sex-related differences in arterial vascular tone and the potential impact of hyperinsulinemia on such differences.

Animals↗

[Serum dihydrotestosterone versus total testosterone values of patients with laryngeal carcinomas and chronic laryngitis].

BACKGROUND: Paradoxically, the highest incidence of laryngeal carcinomas occurs in the presence of reduced gonadal androgen levels associated with ageing, while the stimulating effects of androgens on the laryngeal mucosa and their tumors have been reported in the literature. The decrease of testosterone values and nearly unchanged values of dihydrotestosterone in serum and tissues of elderly men have been documented in recent endocrinological literature. This trial was performed in an effort to resolve this apparent contradiction. METHODS: Twenty-two male laryngeal cancer patients and ten patients with chronic laryngitis were examined, and their dihydrotestosterone and total testosterone values in serum recorded. Blood sampling was performed for each patient between 7 and 10 a.m. before commencement of tumor therapy. An enzyme immunoassay (Serono automat SR 1) was used to determine the values of total testosterone, whereas a 5 alpha dihydrotestosterone (H 3)- radio-immuno-assay was carried out after serum extraction. RESULTS: The total testosterone values of the laryngeal cancer patients were found to be significantly lower than the values in the laryngitis group, but the mean levels of dihydrotestosterone were found to be comparable within both groups. However, the scattering of dihydrotestosterone values was much higher in the group of laryngeal cancer patients than in the laryngitis group. CONCLUSIONS: The average age of the cancer patients examined was 10 years higher than in the laryngitis group. The present results partially correspond to the reports in the endocrinological literature. Together with experimental results regarding the effects of pure substances of testosterone and dihydrotestosterone on permanent laryngeal cancer cell lines, the current results confirm the importance of the imbalance between testosterone and dihydrotestosterone as a cofactor in the development of squamous cell carcinomas of the larynx. Testosterone substitution as well as blocking of 5 alpha-reductase, the enzyme which facilitates formation of dihydrotestosterone from testosterone, are regarded as promising therapeutic opportunities for the future, especially for patients with laryngeal preneoplasias or as recurrence prophylaxis after primary tumor therapy.

Aged↗

Decreased 5alpha-dihydrotestosterone catabolism suppresses T lymphocyte functions in males after trauma-hemorrhage.

Trauma-hemorrhage produces profound immunosuppression in males but not in proestrus females. Prior castration or flutamide treatment of males following trauma-hemorrhage prevents immunosuppression, implicating 5alpha-dihydrotestosterone for the immunosuppressive effects. 5alpha-dihydrotestosterone, a high-affinity androgen receptor-binding steroid, is synthesized in tissues as needed and seldom accumulates. The presence of steroidogenic enzymes in T lymphocytes suggests both synthesis and catabolism of 5alpha-dihydrotestosterone. We hypothesized, therefore, that the basis for high 5alpha-dihydrotestosterone activity in T lymphocytes of males following trauma-hemorrhage is due to decreased catabolism. Accordingly, catabolism of 5alpha-dihydrotestosterone was assessed in splenic T lymphocytes by examining the activity and expression of enzymes involved. Analysis showed increased synthesis and decreased catabolism of 5alpha-dihydrotestosterone in intact male T lymphocytes following trauma-hemorrhage. In contrast, reduced 5alpha-reductase activity and increased expression of 17beta-hydroxysteroid dehydrogenase oxidative isomers suggest inactivation of 5alpha-dihydrotestosterone in precastrated males. Thus our study suggests increased synthesis and decreased catabolism of 5alpha-dihydrotestosterone as a reason for loss of T lymphocyte functions in intact males following trauma-hemorrhage, as evidenced by decreased release of interleukin-2 and -6.

17-Hydroxysteroid Dehydrogenases↗

The metabolic clearance rate and origin of plasma dihydrotestosterone in man and its conversion to the 5-alpha-androstanediols.

Dihydrotestosterone metabolism was studied with a constant infusion technique in three men, three women, five hirsute women, and four estrogen-treated hirsute women. The mean dihydrotestosterone metabolic clearance rate was higher in men (336 liters/24 hr per m(2) [range, 239-448]) than in women (153 liters/24 hr per m(2) [range, 108-184]). The metabolic clearance rates in hirsute patients were intermediate between those men and women and were decreased by estrogen treatment. These observations demonstrate similarities in the metabolic rates of testosterone and dihydrotestosterone. The conversion of plasma testosterone and androstenedione to dihydrotestosterone was studied in men and hirsute women. Approximately 4 and 2% of plasma testosterone and androstenedione, respectively, were converted to plasma dihydrotestosterone in both groups. From these observations it was determined that a major fraction of plasma dihydrotestosterone was derived from these plasma precursors rather than from glandular secretion. Both 5alpha-androstan-3alpha,17beta-diol (3alpha-diol) and 5alpha-androstan-3beta,17beta-diol (3beta-diol) were identified in plasma during dihydrotestosterone and testosterone infusions. The conversion ratio of dihydrotestosterone to 3alpha-diol (C(BB) (DHT-3alpha)) was greater than the conversion ratio to the 3beta-isomer (C(BB) (DTH-3beta)) in all the patients studied. Both C(BB) (DHT-3alpha) and C(BB) (DHT-3beta) were higher in men (mean values of 0.151 [range, 0.110-0.222] and 0..031 [range, 0.022-0.042]) than in women (means of 0.044 [range, 0.037-0.048] and 0.012 [range 0.010-0.013]). A smaller fraction of testosterone was converted to 3alpha-diol and 3beta-diol.

Adrenocortical Hyperfunction↗

Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone.

Testosterone and dihydrotestosterone are believed to exert their androgenic effects by interacting with a single intracellular receptor protein in androgen target tissues. During fetal life, however, testosterone mediates the virilization of the Wolffian ducts into the epididymis, vas deferens, and seminal vesicles, whereas the urogenital sinus and external genitalia require the in situ conversion of testosterone to dihydrotestosterone to undergo male development. The reason why the signal provided by testosterone needs to be amplified in some androgen target tissues but not in others remains an enigma. To provide insight into the different actions of these androgens we studied their interaction with the human androgen receptor in fibroblasts cultured from the genital skin of a patient with 5 alpha-reductase deficiency. Dihydrotestosterone was formed in negligible amounts in these cells, and in some experiments the residual 5 alpha-reductase activity was further blocked with the 5 alpha-reductase inhibitor finasteride. Saturation analysis in fibroblast monolayers disclosed similar amounts of binding with testosterone and dihydrotestosterone, and the affinity of binding of dihydrotestosterone was, on the average, about 2-fold greater than that of testosterone. [3H]Testosterone also exhibited a 5-fold faster dissociation rate from the receptor than [3H]dihydrotestosterone. In thermolability experiments the [3H]testosterone-receptor complex displayed marked instability at 42 C with 2 nM [3H] testosterone, whereas with 20 nM [3H]testosterone, receptor stability was similar to that seen with [3H]dihydrotestosterone. In up-regulation experiments, 2 nM [3H]testosterone produced a 34% increase in specific androgen receptor binding after 24 h, whereas 20 nM [3H]testosterone produced an average increase of 64%. Our results suggest that the weaker androgenic potency of testosterone compared to that of dihydrotestosterone resides in its weaker interaction with the androgen receptor, most clearly demonstrable as an increase in the dissociation rate of testosterone from the receptor. When present in relatively high concentrations, however, testosterone overcomes this defect by mass action.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia.

The oral administration of finasteride, a 4-aza-steroid inhibitor of 5 alpha-reductase, decreases serum dihydrotestosterone levels, but has little effect on serum testosterone. The current study was designed to assess the effect of finasteride on dihydrotestosterone levels in the prostates of men with benign prostatic hyperplasia. In a double blind, placebo-controlled study, 69 men with symptomatic prostatic hyperplasia were treated with placebo or 1, 5, 10, 50, or 100 mg/day finasteride for 7 days before transurethral resection of the prostate. In the placebo group the mean concentration of prostatic dihydrotestosterone was 10.3 +/- 0.6 nmol/kg (+/- SE), and the mean concentration of testosterone was 0.7 +/- 0.1 nmol/kg. After 7 days of treatment with all doses of finasteride, prostatic dihydrotestosterone declined to 15% or less of control levels, and the testosterone concentration increased in a reciprocal fashion. Compared to the placebo group, there was no significant difference in the mean prostatic dihydrotestosterone level achieved in any of the finasteride-treated groups. However, prostatic dihydrotestosterone levels were lower in the groups receiving higher doses of the drug. In two additional patients, finasteride treatment for 2 days also caused a decrease in prostatic dihydrotestosterone levels. No significant adverse experiences occurred during the study. We conclude that finasteride causes profound decrease in prostatic dihydrotestosterone.

5-alpha Reductase Inhibitors↗

Effect of dihydrotestosterone on turnover of alcohol dehydrogenase in rat hepatocyte culture.

Dihydrotestosterone decreased alcohol dehydrogenase (ADH) activity and enzyme-protein in rat hepatocytes in culture. This effect was observed after the hepatocytes had been exposed to dihydrotestosterone for 3 days at concentrations of 0.5 micromol/L or higher. Dihydrotestosterone did not decrease alcohol dehydrogenase messenger RNA (mRNA) but, rather, resulted in small increases in ADH mRNA after 3 days of exposure. To further determine the mechanism for the effects of dihydrotestosterone in decreasing the enzyme, the turnover of ADH was determined after incorporation of [3H]-leucine into the enzyme protein. Dihydrotestosterone did not alter the initial 2-hour incorporation of [3H]-leucine into the enzyme protein. Dihydrotestosterone, however, resulted in an increase in the fractional rate of degradation (Kd) of the enzyme from 0.12 +/- 0.013 to 0.23 +/- 0.004 per hour (P < .001) accompanied by a much smaller increase in the fractional rate of synthesis (Ks) from 0.12 +/- 0.028 to 0.17 +/- 0.031 per hour (P > .05). Hence, the mechanism for the fall in ADH in the presence of dihydrotestosterone is an increase in enzyme degradation which is not accompanied by a sufficient increase in enzyme synthesis.

Alcohol Dehydrogenase↗

Possible mechanism of induction of benign prostatic hyperplasia by estradiol and dihydrotestosterone in dogs.

A mechanism of induction of canine benign prostatic hyperplasia (BPH) by androgen-stimulated growth of prostatic cells exposed to estrogen-induced toxicity. Estrogen is thought to be activated by redox cycling of catechol metabolites, a mechanism of generation of active radicals. Mongrel dogs, 4 animals/group, were sham-operated (controls) or were treated for 60 days with implants of 5 alpha-dihydrotestosterone and/or estradiol-17 beta. The activities of drug and hormone metabolizing enzymes (aryl hydrocarbon hydroxylase, 7-ethoxycoumarin O-deethylase, and estradiol-17 beta-2- and -4-hydroxylase) in prostate were significantly elevated by chronic treatment with either estradiol-17 beta or 5 alpha-dihydrotestosterone plus estradiol-17 beta, but not in kidney or liver which are not targets of hormone-induced hyperplasia. Activities of the detoxifying enzymes catalase and glutathione peroxidase I in prostate were increased by estradiol-17 beta treatment, whereas in kidney or liver they were not affected or changed to a lesser degree than observed in prostate. Free radial-induced damage (carbonyl content) of proteins was observed in prostate of dogs treated with either estradiol-17 beta or 5 alpha-dihydrotestosterone plus estradiol-17 beta and in liver protein by treatment with either 5 alpha-dihydrotestosterone or 5 alpha-dihydrotestosterone plus estradiol-17 beta. It was concluded that the patterns of estradiol-17 beta- or 5 alpha-dihydrotestosterone plus estradiol-17 beta-induced increases in activities of catechol estrogen synthase and of other drug metabolizing enzymes were consistent with the postulated free radical generation by redox cycling of catechol estrogen specifically in the prostate. The increases in activities of detoxifying enzymes may represent an (albeit insufficient) response to prostatic free radical damage to protein in prostate is consistent with a postulated induction of BPH via injury by estrogen metabolites followed by 5 alpha-dihydrotestosterone-stimulated growth of altered prostatic cells.

7-Alkoxycoumarin O-Dealkylase↗

Synthesis of 16 alpha-[125I] iodo-5 alpha dihydrotestosterone and evaluation of its affinity for the androgen receptor.

Analogs of 5 alpha-dihydrotestosterone, halogenated at carbon 11, were synthesized as potential gamma-emitting ligands for the androgen receptor. These compounds, were chosen for synthesis because estradiol, similarly substituted, is strongly bound to the estrogen receptor, and both androgen and estrogen receptors have generally similar structural requirements for the D-ring. The 16 alpha-halogenated steroids, including 16 alpha-]125I] iodo-5 alpha-dihydrotestosterone were synthesized from 16 beta-bromo-5 alpha-dihydrotestosterone by halogen exchange. The cis-beta-bromohydrin substrate was synthesized from 5 alpha-androstane-3,17-dione by selective ketalization, dibromination at C-16 and stereoselective reduction, 16 alpha-iodo dihydrotestosterone was devoid of androgen activity in vivo at concentrations at which 5 alpha-dihydrotestosterone was fully stimulatory. The 16-alpha-iodo, 16 alpha-bromo, and 16-beta-bromo analogs were allowed to compete with [3H]-dihydrotestosterone for binding to the androgen receptor; the 16 alpha-iodo compound had a relative binding affinity 1/100th and both bromo compounds 1/30th that of dihydrotestosterone. In addition, no specific binding was detected when the 16 alpha-[125I]iodo analog was incubated with prostatic cytosol.

Animals↗

Dihydrotestosterone and 3 alpha-androstanediol dynamics in the normal, involuted, and hyperplastic canine prostate.

Perfusion of canine prostatic tissue with [1, 2-3H] 5 alpha-androstane-3 alpha, 17 beta-diol and [4-14C] dihydrotestosterone and the measurement of the isotopic concentrations at the steady state were used to calculate the metabolic dynamics of these steroids by prostatic tissue obtained from normal, castrated or androgen-treated dogs. From the results it was concluded that: Entry of both steroids into the tissue was similar, and no saturation was observed with increasing concentrations of these androgens in the perfusion medium. In contrast, the entry of both steroids was reduced when the perfusion buffer was replaced with diluted plasma. Dihydrotestosterone in prostatic tissue was present in a diffusible form, whereas 3 alpha,17 beta-androstanediol was not. The conversion of 3 alpha, 17 beta-androstanediol to dihydrotestosterone was always higher than the conversion of dihydrotestosterone to 3 alpha, 17 beta-androstanediol; thus, the oxidative pathway was favored. The entry and uptake of both androgens was greatly reduced in those prostates excised from castrated dogs. The uptake of dihydrotestosterone by normal prostatic tissue was 3- to 6-fold higher than the uptake of 3 alpha, 17 beta-androstanediol. However, higher intratissular concentrations of dihydrotestosterone were obtained by increasing the concentration of 3 alpha, 17 beta-androstanediol perfused over that observed by increasing the concentration of dihydrotestosterone perfused. In the hyperplastic tissue, the entry, uptake and metabolism of the two androgens were similar to those observed in the normal gland, but their intratissular concentrations were found to be higher.

Androstane-3,17-diol↗