Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Azasteroids”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 433 records · Page 24Linked to original sources
PubMed2005

Oral testosterone in oil plus dutasteride in men: a pharmacokinetic study.

Testosterone (T) is not administered orally, because it has been reported to be rapidly metabolized by the liver. We hypothesized that sufficient doses of T or T enanthate (TE), administered orally in oil, would result in clinically useful elevations in serum T. We also hypothesized that coadministration of dutasteride (D) with T or TE would minimize increases in serum DHT seen previously with oral administration. Therefore, we conducted a pharmacokinetic study of oral T and TE in oil, with and without concomitant D, in normal men whose T production had been temporarily suppressed by the GnRH antagonist acyline. Thirteen healthy men (mean age, 24 +/- 6 yr) were enrolled and assigned to oral T (n = 7) and oral TE (n = 6) groups and were administered 200, 400, or 800 mg of either T or TE in sesame oil in the morning on 3 successive days 24 h after receiving acyline. Blood samples for measurement of serum T and dihydrotestosterone were obtained before T or TE administration and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h after administration. Subjects were then administered D for 4 d before repeating the sequence of T or TE doses with D. Serum T was significantly increased in a dose-dependent fashion with the administration of oral T or TE in oil. Coadministration of D with oral T or TE significantly increased the 24-hr average serum T levels compared with administration of T or TE alone [average serum T after 400 mg dose, 8.7 +/- 3.0 nmol/l (T) and 8.3 +/- 5.7 nmol/l (TE) vs. 16.1 +/- 5.8 nmol/l (T +D) and 15.0 +/- 8.8 nmol/l (TE + D); P < 0.05 for T vs. T and D]. The administration of oral T or TE in oil combined with D results in unexpected and potentially therapeutic increases in serum T. Additional studies of this combination as a novel form of oral androgen therapy are warranted.

Administration, Oral↗
PubMed2005

Effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or gonadotropin-releasing hormone antagonist on spermatogenesis and intratesticular steroid levels in normal men.

CONTEXT: Combination of a GnRH antagonist (acyline), types I and II, 5alpha-reductase inhibitor (dutasteride) or levonorgestrel (LNG) with testosterone (T) treatment may augment the suppression of spermatogenesis and intratesticular (iT) steroids. OBJECTIVE: The objective of this study was to assess the effects of combined hormonal contraceptive regimens on germ cell populations and iT steroids. DESIGN, SETTING, AND PARTICIPANTS: Twenty-nine normal health men enrolled in this prospective, randomized, 14-wk study at the University of Washington. INTERVENTION(S): Twenty-two men (n = 5-6/group) received 8 wk of T enanthate (TE; 100 mg, i.m., weekly) combined with 1) 125 microg LNG daily, orally; 2) 125 microg LNG plus 0.5 mg dutasteride daily, orally; 3) 300 microg/kg acyline twice weekly, s.c.; or 4) 125 microg LNG daily, orally, plus 300 microg/kg acyline twice weekly, s.c. Subjects then underwent a vasectomy and testicular biopsy. Control men (n = 7) proceeded directly to surgery. MAIN OUTCOME MEASURE(S): The main outcome measures were germ cells and iT steroids [T, dihydrotestosterone, 3alpha- and beta-androstanediol (Adiol), and estradiol (E2)]. RESULTS: High iT levels of all androgens (6- to 123-fold serum levels) and E2 (407-fold serum levels) were found in control men. iTT (1.9-2.6% control; P < 0.001) and iT3betaAdiol (16-34% control; P < 0.05) levels decreased with all treatments. iT dihydrotestosterone (13-29% control; P < 0.05) and iT3alphaAdiol (44-47% control; P < 0.05) levels decreased with all but the TE plus LNG treatment. iTE2 levels decreased only in the TE plus acyline group (28% control; P = 0.01). Germ cells from type B spermatogonia onward were suppressed, with no differences between groups found. Variable sites of impairment of germ cell progression were evident between men (spermagonial maturation, meiosis 1 entry, and spermiation). Other than a negative correlation between iT3alphaAdiol and haploid germ cell number (P < 0.006), no correlations between germ cell number and gonadotropins, sperm concentration, or iT steroids were found. CONCLUSIONS: A similar high testicular:serum gradient exists for E2 and T in normal men, and 8 wk of gonadotropin suppression markedly reduces iTT, with 5alpha-reduced androgens and E2 levels decreasing to a much lesser degree. The heterogeneity of the germ cell response, regardless of treatment, gonadotropins or iT steroids, points to the individual sensitivity of sites in germ cell development, which is worthy of additional exploration.

5-alpha Reductase Inhibitors↗
PubMed2006

Relationship among serum testosterone, sexual function, and response to treatment in men receiving dutasteride for benign prostatic hyperplasia.

CONTEXT: Although benign prostatic hyperplasia (BPH) is an androgen-dependent disorder, little is known regarding the influence of serum testosterone levels on sexual or prostate function or clinical response to dutasteride. OBJECTIVE: The objective of the study was to explore these relationships in a large cohort of men treated with dutasteride for BPH. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: Among 4254 men with BPH participating in 2-yr placebo-controlled dutasteride trials, 27% had a pretreatment serum testosterone less than 300 ng/dl. These 1162 men were divided into seven groups based on their serum testosterone level (<150, 150-174, 175-199, 200-224, 225-249, 250-274, and 275-299 ng/dl) and compared with men with normal baseline serum testosterone (BST; > or = 300 ng/dl). Questionnaires were used to assess sexual function, prostate-specific antigen (PSA), and prostate volume to assess androgenic stimulation of the prostate and the American Urological Association Symptom Index to assess clinical responses. RESULTS: Although lower BST was associated with increased sexual dysfunction, this increase was not seen until BST was less than 225 ng/dl. There was no decrease in baseline PSA and prostate volume at low BST levels. Dutasteride was effective at decreasing PSA and prostate volume and improving BPH symptoms at all BST levels. CONCLUSIONS: In men with BPH, the frequency of sexual dysfunction increases at serum testosterone concentrations less than 225 ng/dl. However, PSA and prostate volume were similar at all testosterone levels, explaining why BPH can occur in men that would otherwise be considered hypogonadal. The fact that dutasteride is also effective in men with normal and low testosterone levels suggests that the high levels of 5alpha-reductase and dihydrotestosterone in the prostate allow the development and progression of prostatic hyperplasia, even at low circulating testosterone levels.

Aged↗
PubMed1986

In vitro effects of an aromatase inhibitor on 5 alpha-reductase activity in human hypertrophic prostatic tissue.

To determine the effects of 4-hydroxy-4-androstene-3,17-dione (4-OH-A) on the in vitro conversion of testosterone (T) to 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone, DHT), 5 alpha-androstan-3 alpha, 17 beta-diol and 5 alpha-androstan-3 beta, 17 beta-diol (diols), human benign hypertrophic prostatic (BPH) tissue was incubated with 4-14C-T as substrate, in the presence of 4-OH-A (10(-8) to 10(-6) M); the amounts of the 5 alpha-reduced metabolites formed were quantitated. The effects of 4-OH-A were compared with those of 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), a known inhibitor of the 5 alpha-reductase. In the absence of 4-OH-A and 4-MA, human BPH tissue converted T to DHT and the diols readily. Both 4-OH-A and 4-MA induced significant and dose-related decreases in the formation of both DHT and the diols. The degree of inhibition induced by the different concentrations of 4-OH-A and 4-MA were 31, 41, 72% and 57, 87, 97%, respectively. The decreased formation of the diols was a consequence of the decreased availability of DHT (the immediate precursor of the diols) and was not due to direct effects of the inhibitors on the 3-hydroxysteroid dehydrogenases; both 4-OH-A and 4-MA were totally unable to modify the conversion of DHT to the diols, when 4-14C-DHT was used as substrate. Thus, 4-OH-A inhibits the process of 5 alpha-reduction of T in BPH tissue. This molecule might represent a potential new agent for the prevention and/or treatment of human BPH.

5-alpha Reductase Inhibitors↗
PubMed1987

The effects of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide, a 5 alpha-reductase inhibitor and antiandrogen, on the development of baldness in the stumptail macaque.

We used a primate model of male-pattern baldness to test the efficacy of a topically applied 5 alpha-reductase inhibitor and antiandrogen (4-MA) in the prevention of baldness. Six periadolescent stumptail macaques were given daily topical applications of either 4-MA in dimethylsulfoxide or dimethylsulfoxide alone for 27 months. The three control monkeys developed varying degrees of baldness, while the three 4-MA-treated monkeys retained their juvenile pattern of hair growth. The percentage of actively growing hair follicles in the frontal scalp did not change in the 4-MA-treated group [46 +/- 6 (+/- SE) vs. 48 +/- 4], while a significant decrease occurred in the control group (63 +/- 6 vs. 25 +/- 12; P less than 0.025). Skin 5 alpha-reductase activity was reduced in the scalp of the 4-MA-treated monkeys. We conclude that topical 4-MA can prevent the development of baldness in the stumptail macaque, a primate model of androgen-dependent baldness.

Alopecia↗
PubMed1990

C19 and C21 5 beta/5 alpha metabolite ratios in subjects treated with the 5 alpha-reductase inhibitor finasteride: comparison of male pseudohermaphrodites with inherited 5 alpha-reductase deficiency.

Male subjects administered the 5 alpha-reductase inhibitor finasteride were studied to determine its effect on C19 and C21 5 alpha-metabolism. Plasma testosterone (T) and 5 alpha-dihydrotestosterone (DHT) were measured and T/DHT ratios determined at doses of 0.2-80 mg. Urinary etiocholanolone (5 beta)/androsterone (5 alpha) ratios and 5 beta/5 alpha metabolite ratios of cortisol, 11 beta-hydroxyandrostenedione, and corticosterone were also measured. The steroid profile was compared to male pseudohermaphrodites with inherited 5 alpha-reductase deficiency who have a global defect in C19 and C21 5 alpha-metabolism. The mean plasma DHT levels were decreased at all doses, resulting in elevated T/DHT ratios. The mean urinary etiocholanolone/androsterone, 11 beta-hydroxyetiocholanolone/11 beta-hydroxyandrosterone, tetrahydrocortisol/allotetrahydrocortisol, and tetrahydrocorticosterone/allotetrahydrocorticosterone ratios were elevated compared to pretreatment levels and placebo control values. The mean ratios appeared to be dose dependent for plasma T/DHT, urinary etiocholanolone/androsterone tetrahydrocorticosterone/allotetrahydrocorticosterone ratios. The mean 11 beta-hydroxyetiocholanolone-hydroxyandrosterone ratio was maximally elevated at the lowest doses. The results indicate that finasteride has a broad steroid spectrum inhibiting C19 and C21 5 alpha-steroid metabolism and affecting hepatic and peripheral 5 alpha-metabolism. These results suggest that a single gene codes for a single 5 alpha-reductase enzyme with affinity for multiple steroid substrates. The steroid profile is strikingly similar to that of male pseudohermaphrodites with inherited 5 alpha-reductase deficiency.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1990

Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers.

Finasteride, a 5 alpha-reductase inhibitor, was administered to normal male volunteers in a blinded placebo-controlled study at daily oral doses of 25, 50, and 100 mg for 11 days (part 1) and daily oral doses of 0.04, 0.12, 0.2, and 1.0 mg for 14 days (part 2). Results from part 1 showed a significant reduction in dihydrotestosterone (DHT) at all doses and a significant increase in both testosterone (T) and delta 4-androstenedione at the 50- and 100-mg doses. No change was seen in LH, FSH, cortisol, or estradiol levels. Serum lipids, including total cholesterol, low density lipoprotein, high density lipoprotein, and triglycerides were not affected by treatment. Results from part 2 again showed significant reduction in DHT at all doses. DHT levels returned to pretreatment values within 14 days of discontinuing treatment. Significant increases in T were observed only in the 1.0 mg group and only during the first 8 days of treatment. The T/DHT ratio increased with all doses and returned to baseline when drug was discontinued. The DHT metabolites and androstanediol glucuronide and androsterone glucuronide were significantly reduced at all doses. There were no significant adverse experiences reported during part 1 or 2. In conclusion, finasteride is well tolerated by normal volunteers and results in significant suppression of serum DHT at all doses tested.

Adult↗
PubMed1990

Effect of finasteride, a 5 alpha-reductase inhibitor on prostate tissue androgens and prostate-specific antigen.

Whole tissue dihydrotestosterone (DHT) and testosterone (T) concentrations have been measured after finasteride, a 5 alpha-reductase inhibitor, and this was compared to other methods of androgen inhibition. In 10 patients treated for 1 week with finasteride, whole tissue DHT decreased to a mean of 0.302 ng/g. This value was significantly less than DHT values in control patients (mean, 4.5 ng/g) and patients treated with either surgical castration (mean, 1.14 ng/g), megestrol (160 mg/day) plus diethylstilbestrol (0.1 mg), or megestrol plus ketoconazole (1200 mg/day; mean, 0.609). Tissue T levels were significantly increased in finasteride-treated patients (1.18 ng/g) compared to a mean of 0.171 ng/g in controls and 0.105 ng/g in megestrol-treated patients. Part of the prostate tissue obtained at surgery was mechanically separated into epithelium and stroma. The epithelial cells were homogenized, the supernate was assayed for prostate-specific antigen (PSA), an androgen-dependent protein, and the pellet was assayed for DHT and DNA. Epithelial cell PSA and DHT values significantly decreased in finasteride- and megestrol- plus estrogen-treated patients compared to controls. However, the slope and position of the regression lines for DHT vs. PSA in patients treated with megestrol plus low dose estrogen (r = 0.79) differed significantly (P less than 0.05) from the regression line relating epithelial DHT to PSA in patients treated with finasteride (r = 0.82). Since the regression slope for finasteride described a greater increase in PSA per unit change in DHT compared to the slope for megestrol plus estrogen, which lowers both DHT and T, finasteride, despite its drastic lowering of DHT, may have a modest residual androgenic effect related to its effect on tissue T.

5-alpha Reductase Inhibitors↗
PubMed1990

Anti-5 alpha-reductase autoantibodies in the serum of patients with prostatic cancer.

Human sera were tested for their ability to inhibit 5 alpha-reductase binding of a potent inhibitor of the enzyme. Thirty one of 227 serum samples from patients diagnosed or suspected of prostatic cancer had a significant inhibitory activity, whereas 128 serum samples from other patients were inactive. The majority of the inhibitory activity was in the IgG fraction purified by chromatography on a protein A-Sepharose affinity column and an anti-human IgG-agarose column. IgG fractions from non-inhibitory sera were inactive. Inhibitory IgG also inhibited the enzymatic activity of microsomal 5 alpha-reductase from liver, ventral prostate and preputial gland of rat, and liver, prostate, and facial skin of human. The inhibitory IgG had no effect on NADH-menadione reductase or 17 beta-hydroxysteroid dehydrogenase. These results suggest that 5 alpha-reductase autoantibodies are present in the blood of some prostatic cancer patients.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque.

A 5 alpha-reductase inhibitor, finasteride, was administered orally at 0.5 mg/day, alone or in combination with topical 2% minoxidil, for 20 weeks to determine the effects on scalp hair growth in balding adult male stumptail macaque monkeys. A 7-day dose-finding study showed that both 0.5- and 2.0-mg doses of the drug produced a similar diminution in serum dihydrotestosterone (DHT) in male stumptails. Hair growth was evaluated by shaving and weighing scalp hair at baseline and at 4-week intervals during treatment to obtain cumulative delta hair weight (sum of the 4-week changes in hair weight from baseline) for the 20-week study. The activity of the 5 alpha-reductase enzyme was assessed by RIA of serum testosterone (T) and DHT at 4-week intervals. The combination of finasteride and minoxidil generated significant augmentation of hair weight (additive effect) compared to either drug alone. Finasteride increased hair weight in four of five monkeys. When the data of the one nonresponsive monkey were excluded, finasteride elicited a significant elevation in hair weight compared to topical vehicle alone. Minoxidil also evoked a significant increase in hair weight compared to vehicle alone. Serum T was unchanged, whereas serum DHT was significantly depressed in monkeys that received either finasteride or the combination of finasteride and minoxidil. These data suggest that inhibition of the conversion of T to DHT by this 5 alpha-reductase inhibitor reverses the balding process and enhances hair regrowth by topical minoxidil in the male balding stumptail macaque.

5-alpha Reductase Inhibitors↗
PubMed1992

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↗
PubMed1992

Effect of finasteride, a 5 alpha-reductase inhibitor, on serum gonadotropins in normal men.

Testosterone exerts negative feedback control on gonadotropin secretion either directly, after aromatization to estradiol, or after 5 alpha-reduction to dihydrotestosterone (DHT). Conflicting data exist as to the role of DHT in the modulation of this negative feedback. To determine whether suppression of endogenous DHT alters gonadotropin secretion, we gave the selective 5 alpha-reductase inhibitor finasteride (5 mg daily), or placebo, to 20 healthy men for 28 days. Basal and GnRH-stimulated LH, bioactive LH, FSH, testosterone, and DHT levels were measured before and after 14 and 28 days of treatment. Basal DHT fell from 1.1 +/- 0.2 to 0.15 +/- 0.04 nmol/L after 28 days of finasteride treatment. A significant rise in baseline testosterone from 17.6 +/- 2.0 to 18.3 +/- 2.3 nmol/L was seen at 14 days (P = 0.046), but not at 28 days. No significant changes were seen in either basal or GnRH-stimulated gonadotropin levels on any day. We conclude that suppression of serum DHT levels with 5 mg finasteride daily in healthy young men has no discernible effect on serum gonadotropin levels.

Adult↗
PubMed1993

The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity.

To evaluate the androgen control of sebum, subjects with complete androgen insensitivity and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency and decreased dihydrotestosterone (DHT) production had sebum production studied. A hydrophobic polymeric film applied to the forehead was used to measure sebum production through the use of air filled micropores. Sebum scores of normal preadrenarchal children (ages 2-6), and normal age-matched adult males and females, were studied as well as males treated with the 5 alpha-reductase inhibitor, finasteride, for benign prostatic hyperplasia who were studied at baseline and after drug therapy. Androgen insensitive subjects had no sebum production by this methodology, and the results were identical to preadrenarchal children. In contrast, adult male pseudohermaphrodites with 5 alpha-reductase deficiency and a selective decrease in DHT production had sebum production scores identical to normal age-matched males. Males with benign prostatic hyperplasia treated with the 5 alpha-reductase inhibitor, finasteride, to lower DHT levels did not decrease the sebum score from baseline values. The lack of demonstrable sebum in androgen-insensitive subjects clearly demonstrates the absolute androgen control of sebum production. The DHT dependency of the sebaceous gland, however, could not be demonstrated in this study. Two 5 alpha-reductase isoenzymes 1 and 2, have been described. 5 alpha-reductase-2 is the gene responsible for inherited 5 alpha-reductase deficiency. Although the degree of inhibition of DHT in utero and in adulthood in male pseudohermaphrodites with a defect in 5 alpha-reductase-2 enzyme activity caused severe impairment of external genital and prostate differentiation and decreased facial and body hair, it had no demonstrable effect on sebaceous gland development or function. Furthermore, lowering DHT levels in adulthood had no effect on sebum production. If the gland is rich in the enzyme 5 alpha-reductase-2, it is proposed that the sebaceous gland is either exquisitely sensitive to DHT, requiring only small amounts for normal development and function, or that male levels of testosterone compensate for DHT and maintain normal sebaceous gland activity throughout life. It is also possible that 5 alpha-reductase-1 is the enzyme of the sebaceous gland and is unaffected in the inherited condition and by finasteride.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1996

Effect of MK-386, a novel inhibitor of type 1 5 alpha-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men.

Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.99.5), with differential tissue distribution, have been identified in humans. These enzymes catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Finasteride, a selective inhibitor of type 2 5 alpha R, lowers circulating DHT levels by approximately 70% in men after treatment with 5 mg daily. MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one) is a new selective inhibitor of type 1 5 alpha R. A single rising dose, alternating panel, trial in 16 healthy males (age range, 21-25 yr) studied the effect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relative to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttreatment (P < 0.01 vs. placebo). No consistent effect on T concentrations was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age range, 24-47 yr); a 25-mg dose of MK-386 was added for 2 days of combination therapy after at least 10 days of finasteride treatment. Withdrawal of MK-386 was followed by 5-6 days of finasteride follow-up treatment. Finasteride alone reduced DHT, on the average, by 68.7% (SE = 3.4%). Addition of MK-386 suppressed DHT by 89.5% (SE = 1.4%) relative to baseline (P < 0.01 vs. effect of finasteride alone). Small increases in serum T were observed with finasteride alone and in combination with MK-386 (approximately 10% and 19%, respectively). These data are consistent with selective 5 alpha R type 1 inhibition in man by MK-386 and the prediction that types 1 and 2 5 alpha R account for all, or nearly all, of circulating DHT. Further clinical trials are needed to assess the therapeutic utility of type 1 5 alpha R inhibition as well as that of combined inhibition of types 1 and 2 5 alpha R.

Adult↗
PubMed1999

Characterization of aromatase cytochrome P450 activity in the human temporal lobe.

Local aromatase-mediated conversion of androgens plays an important role in androgen action on the brain. To characterize estrogen formation in the human brain, we measured the microsomal aromatase activity of temporal lobe biopsies and compared it to that of human placenta using a highly sensitive 3H2O assay with [1beta-3H]androstenedione as substrate. Brain tissue was removed neurosurgically from 23 patients with epilepsy. Data of kinetic studies were analyzed with a computer-assisted, nonlinear, curve-fitting method using the Michaelis-Menten plus a nonspecific metabolism model. In contrast to data for placental aromatase activity, that for brain always had to be corrected for nonspecific tritium release. The mean K, values were 22.2 nmol/L in brain and 49.6 nmol/L in placenta. Inhibition experiments with atamestane, an inhibitor of aromatase cytochrome P450, revealed specific, dose-responsive, and competitive inhibition of both brain and placental aromatase activities. Placental aromatase activity was completely suppressible by atamestane, whereas in brain tissue there remained a residue of nonspecific tritium release. Subsequent experiments with cerebral cortex and subcortical white matter specimens of children and adults revealed a significantly higher aromatase activity in cerebral cortex than in subcortical white matter, but no sex or age differences were found.

Adolescent↗
PubMed2001

Characterization of the 5alpha-reductase-3alpha-hydroxysteroid dehydrogenase complex in the human brain.

Although androgen metabolism in the human brain was discovered almost 30 yr ago, conclusive studies on the enzymes involved are still lacking. We therefore investigated 5alpha-reductase and colocalized 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity in cerebral neocortex (CX) and subcortical white matter (SC) specimens neurosurgically removed from 44 patients suffering from epilepsy. We could demonstrate the presence of the 5alpha-reductase-3alpha-HSD complex in the biopsies of all patients under investigation. Inhibition experiments with specific inhibitors for 5alpha-reductase type 1 and type 2 revealed strong evidence for the exclusive activity of the type 1 isoform. We detected a significantly higher 5alpha-reductase activity in CX than in SC (P< 0.0001), but no sex-specific differences were observed. Furthermore, we found that, in contrast to liver, only 3alpha-HSD type 2 messenger RNA is expressed in the brain and that its expression is significantly higher in SC than in CX without sex-specific differences. The present study is the first to systematically characterize the 5alpha-reductase-3alpha-HSD complex in the human brain. The lack of sex-specific differences and also the colocalization of both enzymes at all life stages suggest a more general purpose of the complex, e.g. the synthesis of neuroactive steroids or the catabolism of neurotoxic steroids, rather than control of reproductive functions.

3-Hydroxysteroid Dehydrogenases↗
PubMed1991

Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate.

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

5-alpha Reductase Inhibitors↗