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PubMedDate not supplied

Comparison of current alkylating agents with a homo-aza-steroidal ester for antineoplastic activity.

The modified steroidal alkylating agent, 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-bis(2-chloroethyl)aminophenoxyacetate++ + has been tested against L1210 and P388 leukemias, and Lewis lung cancer, on DNA synthesis of EAT, L1210, P388, and BHK cell cultures, and on the induction of sister chromatid exchange. Comparable studies in vivo and in vitro were also done with p-bis(2-chloroethyl)aminophenoxyacetic acid, cyclophosphamide, melphalan, and chlorambucil.

Alkylating Agents↗
PubMed1991

5 alpha-metabolism in finasteride-treated subjects and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency. A review.

Male pseudohermaphrodites (MPHs) with inherited 5 alpha-reductase deficiency and decreased dihydrotestosterone production have a global defect in 5 alpha-metabolism affecting both C19 androgen metabolism and C21 steroid metabolism. However, the decreased 5 alpha-reduction of testosterone to dihydrotestosterone is the only impaired steroid conversion to have clinical consequences, e.g., ambiguous genitalia, impaired prostate differentiation and development, and decreased facial and body hair. The 5 alpha-steroid metabolite profile in the MPHs was compared with that of men with benign prostatic hyperplasia who were administered varying doses of the 5 alpha-reductase inhibitor finasteride. Finasteride was found to be a potent inhibitor of both C19 androgen and C21 5 alpha-steroid metabolism affecting both hepatic and peripheral 5 alpha-metabolism. The 5 alpha-steroid metabolite profile was strikingly similar to that of MPHs with inherited 5 alpha-reductase deficiency. The data suggest that a 5 alpha-reductase gene codes for an enzyme with affinity for multiple steroid substrates.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1991

Hormonal effects of a 5 alpha-reductase inhibitor (finasteride) on hormonal levels in normal men and in patients with benign prostatic hyperplasia.

Finasteride is a potent competitive 5 alpha-reductase inhibitor, active at a dose as low as 1 mg/day. After a single dose, the effects on 5 alpha-reductase last as long as 7 days. Both hepatic and target tissue 5 alpha-reductase are inhibited. Plasma testosterone and estradiol are unaffected and luteinizing hormone levels do not change. During chronic treatment with finasteride 5 mg/day, the effects on 5 alpha-reductase are maintained. Since the only significant effect of chronic finasteride therapy appears to be 5 alpha-reductase inhibition, and testosterone or estradiol levels are not affected, neither libido nor potency is lost. Testosterone is the active androgen at the muscular level; therefore, muscular catabolism is not expected.

5-alpha Reductase Inhibitors↗
PubMed1993

Long-term urodynamic effects of finasteride in benign prostatic hyperplasia: a pilot study.

A group of 69 men with bladder outflow obstruction due to benign prostatic hyperplasia (BPH) were treated in a double-blind placebo-controlled study with finasteride (Proscar), a 5 alpha-reductase inhibitor, 5 mg or 10 mg/day, or an identical placebo for 3 months; subsequently, 20 patients received finasteride 5 mg/day in an open extension study. Ten of these patients have now completed 3 years of therapy and have been reevaluated with pressure/flow urodynamics. In finasteride-treated patients dihydrotestosterone (DHT) declined by over 60%, remaining unchanged with placebo. Symptom scores fell in both groups of patients, maximum flow rate values decreased on placebo but improved by a mean of 1.5 ml/s in the 10-mg group and 3.3 ml/s in the 5-mg group. After 1 year of therapy, the reduction in symptom score was well maintained and the flow rate had increased by a mean of 2.7 ml/s; the mean prostate volume was reduced by 14% and prostate-specific antigen (PSA) had declined by 28%. In the 10 patients treated for 3 years who consented to further urodynamic study, the maximum urinary flow rate had improved from a mean baseline value of 8.7 ml/s to a mean of 13.8 ml/s, while maximum subtracted voiding pressure had decreased from a mean baseline value of 72 cm H2O to an unobstructed mean value of 44 cm H2O. Side effects were minimal and reversible on stopping the medication.(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha Reductase Inhibitors↗
PubMed1992

Scandinavian clinical study of finasteride in the treatment of benign prostatic hyperplasia.

The effects of finasteride, a potent 5 alpha-reductase inhibitor, were assessed in patients with benign prostatic hyperplasia. Patients were treated with finasteride or placebo for 24 weeks in a double-blind multicenter study followed by a 12-month open-extension period. After 24 weeks, finasteride-treated patients, when compared to placebo-treated patients, showed a significant reduction in prostate volume (22.5% median decrease) and prostate significant antigen (32.4% median decrease), a significant increase in maximum urinary flow (1.6 ml/s mean increase from baseline) and a significant improvement in their obstructive symptom scores (two-point decrease from baseline). Finasteride was well tolerated, and the improvements in prostate volume, maximum urinary flow rate and obstructive symptom scores observed in the controlled study were maintained throughout the extension study.

5-alpha Reductase Inhibitors↗
PubMed2003

New evidence of similarity between human and plant steroid metabolism: 5alpha-reductase activity in Solanum malacoxylon.

The physiological role of steroid hormones in humans is well known, and the metabolic pathway and mechanisms of action are almost completely elucidated. The role of plant steroid hormones, brassinosteroids, is less known, but an increasing amount of data on brassinosteroid biosynthesis is showing unexpected similarities between human and plant steroid metabolic pathways. Here we focus our attention on the enzyme 5alpha-reductase (5alphaR) for which a plant ortholog of the mammalian system, DET2, was recently described in Arabidopsis thaliana. We demonstrate that campestenone, the natural substrate of DET2, is reduced to 5alpha-campestanone by both human 5alphaR isozymes but with different affinities. Solanum malacoxylon, which is a calcinogenic plant very active in the biosynthesis of vitamin D-like molecules and sterols, was used to study 5alphaR activity. Leaves and calli were chosen as examples of differentiated and undifferentiated tissues, respectively. Two separate 5alphaR activities were found in calli and leaves of Solanum using campestenone as substrate. The use of progesterone allowed the detection of both activities in calli. Support for the existence of two 5alphaR isozymes in S. malacoxylon was provided by the differential actions of inhibitors of the human 5alphaR in calli and leaves. The evidence for the presence of two isozymes in different plant tissues extends the analogies between plant and mammalian steroid metabolic pathways.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1983

Binding of a 4-methyl-4-aza-steroid to 5 alpha-reductase of rat liver and prostate microsomes.

A tritium labeled 5 alpha-reductase inhibitor, [1,2-3H] 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one ([3H]4-MA), binds reversibly to a high affinity site (Kd, 6.5 nM) in liver microsomes from male rats. The binding requires a nicotinamide nucleotide coenzyme; NADH is at least 100 times less potent than NADPH, and NADP+, NAD+, flavin adenine dinucleotide, coenzyme A, and ADP are inactive. The relative potencies of 13 steroids as inhibitors of the binding of [3H]4-MA to liver microsomes correlate with their relative potencies as inhibitors of the conversion of [14C]testosterone to [14C]5 alpha-dihydrotestosterone by liver microsomes. Comparison of liver microsomes from mature female rats and microsomes from mature male rat liver, ventral prostate, spleen, kidney, and skeletal muscle shows that their NADPH-dependent [3H]4-MA binding capacities correlate with their levels of 5 alpha-reductase activity. These results suggest that [3H]4-MA binds specifically to 5 alpha-reductase in a NADPH-dependent manner. 5 alpha-Reductase was solubilized from liver microsomes with a detergent, Lubrol-WX, and the solubilized enzyme also binds [3H]4-MA. The relative potencies of 13 steroids as inhibitors of rat ventral prostate and liver 5 alpha-reductase are the same, strongly suggesting that the 5 alpha-reductases in the two tissues are the same.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1983

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

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

5-alpha Reductase Inhibitors↗
PubMed1984

A high affinity inhibitor of pituitary progesterone 5 alpha-reductase.

The capacity of the 5 alpha-dihydroprogesterone analog, 4-aza-4-methyl-5 alpha-pregnane-3,20-dione (AMPD), to inhibit progesterone 5 alpha-reductase and both 5 alpha-dihydroprogesterone 3 alpha-hydroxysteroid oxidoreductase activities (NADPH- and NADH-linked) from the female rat anterior pituitary has been investigated. Dose response studies demonstrate that AMPD is a powerful inhibitor of pituitary progesterone 5 alpha-reduction but is ineffective at inhibiting either of the 3 alpha-hydroxysteroid oxidoreductase activities, even at concentrations up to 10 microM. A kinetic analysis of the interaction of AMPD with progesterone 5 alpha-reductase indicates that it is a competitive inhibitor vs. progesterone [Kislope = 7.2 +/- 0.6 nM; apparent Michaelis-Menten constant (Km) (progesterone) = 193 +/- 18 nM] and an uncompetitive inhibitor vs. NADPH (Kiintercept = 17.9 +/- 1.4 nM). These inhibition patterns are consistent with the view that NADPH binding precedes that of either AMPD or progesterone. Furthermore, AMPD does not appear to be an irreversible inhibitor since preincubation of the enzyme (at 37 C) with AMPD and NADPH, for periods of time up to 60 min, does not lead to a time-dependent loss of activity. The inhibition can also be readily removed by dilution, even after a 60-min preincubation with the inhibitor and NADPH. It is postulated that the selective and potent inhibition of the 5 alpha-reduction of progesterone by AMPD may be due to the steroid functioning as a transition state analog. This inhibitor should prove useful in studying the properties of progesterone 5 alpha-reductase and the function of anterior pituitary progestin metabolism.

3-Hydroxysteroid Dehydrogenases↗
PubMed1986

Nipple differentiation in fetal male rats treated with an inhibitor of the enzyme 5 alpha-reductase: definition of a selective role for dihydrotestosterone.

In the rat, androgens are responsible for sexually dimorphic nipple differentiation. Nipples are expressed in the female, while in the male, the nipple anlage regress prenatally. Mammary gland development is present in both sexes. Treatment of pregnant Sprague-Dawley rats from days 12-21 of gestation with the aza-steroid 17 beta-N,N-diisopropylcarbamoyl-4-aza-5 alpha-androstan-3-one, a competitive inhibitor of the enzyme 5 alpha-reductase, resulted in nipple development in male offspring. Additionally, there was feminization of the external genitalia, with urethral displacement to the base of the phallus. The role of androgens in suppression of nipple anlage in the male rat fetus is known. This study, however, suggests for the first time a selective role for 5 alpha-dihydrotestosterone in regression of the nipple anlage in utero. Thus, 5 alpha-dihydrotestosterone may be critical not only for masculinization of the external genitalia, but also for inhibition of nipple development in the male rat fetus.

5-alpha Reductase Inhibitors↗
PubMed1989

The effect of a 5 alpha-reductase inhibitor on androgen physiology in the immature male rat.

To provide insight into the role of 5 alpha-dihydrotestosterone (DHT) in postnatal androgen physiology, we administered the 5 alpha-reductase inhibitor finasteride to male rats from birth through the onset of puberty. In 4-week-old control rats serum testosterone levels averaged 0.21 ng/ml, and DHT levels averaged 0.64 ng/ml. By 7 weeks of age, testosterone levels increased more than 7-fold to 1.57 ng/ml, while the circulating DHT level declined to 0.26 ng/ml. In both the 4- and 7-week-old inhibitor-treated animals, circulating DHT levels were 25-50% of control values, and circulating testosterone levels were higher than control values. In 7-week-old inhibitor-treated rats, the weights of prostate, penis, seminal vesicles, and epididymal tissues were only 30-50% those of the controls. However, DHT formation is apparently not critical for postnatal development of the preputial glands or the androgen-dependent perineal muscles, since the weights of these tissues were not affected by treatment with inhibitor. Treatment with the 5 alpha-reductase inhibitor had no apparent effect on testicular histology or daily sperm production despite the fact that testicular DHT content was lower (70%) and testosterone content was higher (250%) than those in controls. We conclude that DHT formation is important for the normal postnatal growth of the prostate, seminal vesicles, epididymis, and penis and may be important for normal feedback control of testosterone production in rats, but that its formation is not critical for the onset of spermatogenesis or the development of the preputial glands or the androgen-dependent perineal muscles.

5-alpha Reductase Inhibitors↗
PubMed1990

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

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

5-alpha Reductase Inhibitors↗
PubMed1991

Effects of flutamide and finasteride on rat testicular descent.

The endocrine control of descent of the testis in mammalian species is poorly understood. The androgen dependency of testicular descent was studied in the rat using an antiandrogen (flutamide) and an inhibitor of the enzyme 5 alpha-reductase (finasteride). Androgen receptor blockade inhibited testicular descent more effectively than inhibition of 5 alpha-reductase activity. Moreover, its inhibitory effect was limited to the outgrowth phase of the gubernaculum testis, particularly the earliest stages of outgrowth. Gubernacular size was also significantly reduced in fetuses exposed to flutamide during the outgrowth period. In contrast, androgen receptor blockade or 5 alpha-reductase inhibition applied after the initiation of gubernacular outgrowth or during the regression phase did not affect testicular descent. Successful inhibition of the development of epididymis and vas by prenatal flutamide did not correlate with ipsilateral testicular maldescent, suggesting that an intact epididymis is not required for descent of the testis. Plasma androgen assays confirmed significant inhibition of dihydrotestosterone formation in finasteride-treated rats. These data suggest that androgens, primarily testosterone, are required during the early phases of gubernacular outgrowth for subsequent successful completion of testicular descent.

5-alpha Reductase Inhibitors↗
PubMed1991

Time-specific androgen blockade with flutamide inhibits testicular descent in the rat.

Inhibition of androgen action by flutamide, a nonsteroidal antiandrogen, blocked testicular descent in 40% of the testes exposed to this agent continuously from gestational day 13 through postpartal day 28. By contrast, only 11% of the testes failed to descend when blocked by 5 alpha-reductase inhibitors during the same period. Flutamide administration over narrower time intervals (gestational day 13-15, 16-17, or 18-19) revealed maximal interference with testicular descent after androgen inhibition during gestational days 16-17. No significant differences in testicular or epididymal weights were evident between descended and undescended testes; furthermore, no correlation was detected between the presence of epididymal abnormalities and testicular descent. These findings indicate that androgen inhibition during a brief period of embryonic development can block testicular descent. The mechanism through which this inhibition occurs remains to be elucidated.

5-alpha Reductase Inhibitors↗
PubMed1992

Comparison of the effects of the 5 alpha-reductase inhibitor finasteride and the antiandrogen flutamide on prostate and genital differentiation: dose-response studies.

Studies were performed to compare the effects of 5 alpha-reductase inhibition and antiandrogen receptor blockade on differentiation of male internal and external genital structures and prostate in the rat. Dose-response studies were performed on male rats treated in utero during the period of sexual differentiation with either the potent 5 alpha-reductase inhibitor finasteride or the antiandrogen flutamide. The treated animals were raised to adulthood and killed, and genital structures were evaluated. Treatment with the 5 alpha-reductase inhibitor finasteride at a dose of 25 mg/kg.day resulted in significant feminization of the external genitalia. There was no further feminization of the genitalia at doses up to 300 mg/kg.day. Wolffian ductal differentiation occurred at all doses evaluated. Seminal vesicle weight, however, significantly decreased at 25 mg/kg.day, but without a further decrease at higher doses of the 5 alpha-reductase inhibitor. Vas deferens and epididymal weights were unchanged at all doses evaluated. There was a significant decrease in prostate size at 25 and 50 mg/kg.day, with no further decrease at higher doses. In flutamide-treated animals, complete feminization of the genitalia occurred at 24 mg/kg.day in all animals. At 18 mg/kg.day, Wolffian ductal differentiation occurred, but seminal vesicle weight was decreased. At dosages of 100, 200, and 300 mg/kg.day flutamide, the vas deferens was absent unilaterally or bilaterally, with small remnants of epididymal head and tail present. At dosages of 24 mg/kg.day and above, the prostate was absent. Studies with the 5 alpha-reductase inhibitor finasteride demonstrate the dependency of prostate and male external genital differentiation on dihydrotestosterone (DHT). However, unlike androgen receptor blockade with flutamide, finasteride did not totally abolish prostate differentiation or completely feminize the external genitalia, despite increasingly higher doses. Since there is no evidence of multiple 5 alpha-reductase isoenzymes to date in the rat, these results suggest that testosterone (T) can compensate for DHT to some degree at the level of the androgen receptor. Wolffian differentiation, however, was not affected by inhibition of DHT, demonstrating its T dependency, but seminal vesicle growth was impaired. Thus, inhibition of 5 alpha-reductase activity limits seminal growth potential in adulthood. Studies with the antiandrogen flutamide show that at doses significantly above that required to completely block prostate differentiation and cause genital feminization, Wolffian ductal differentiation is significantly impaired. Thus, higher doses of flutamide are needed to block the paracrine effect of T on the Wolffian ducts.

5-alpha Reductase Inhibitors↗
PubMed1993

Effect of combination treatment with zanoterone (WIN 49596), a steroidal androgen receptor antagonist, and finasteride (MK-906), a steroidal 5 alpha-reductase inhibitor, on the prostate and testes of beagle dogs.

The effects of the steroidal androgen receptor antagonist zanoterone (WIN 49596) and the steroidal 5 alpha-reductase inhibitor finasteride (MK-906) either alone or in combination on prostatic size, histomorphology, and biochemistry were determined in the intact male dog. Additionally, the effects of treatment with zanoterone and/or finasteride on testicular size, serum testosterone and LH levels, and spermatogenesis were determined in the same dogs. Daily oral treatment for 16 weeks with either zanoterone alone at 10 mg/kg.day or finasteride alone at 1.0 mg/kg.day reduced (P < 0.05) the size of the prostate, resulted in mild to moderate diffuse glandular atrophy of the prostate, and decreased prostatic DNA and prostatic arginine esterase (the primary canine prostatic protein) levels compared to those in intact controls. These changes occurred with no effect on testicular weight, testicular histomorphology, daily sperm production, or serum LH levels. Serum testosterone concentrations were increased (P < 0.05) approximately 3-fold in the 10 mg/kg.day zanoterone treatment group compared to those in intact controls. Combination treatment of male dogs for 16 weeks with zanoterone (10 mg/kg.day) plus finasteride (1.0 mg/kg.day) orally also reduced (P < 0.05) prostate size, resulted in moderate to marked diffuse prostatic glandular atrophy, and decreased prostatic DNA and arginine esterase levels more than either drug alone, without affecting testicular size, testicular histomorphology, serum LH concentrations, or serum testosterone concentrations compared to those in intact controls. The effects of combination treatment with zanoterone and finasteride on prostatic size; histomorphology; and DNA, arginine esterase protein, and arginine esterase mRNA levels were similar to those observed in castrate controls. In addition, in situ estimates of prostatic size using transrectal ultrasonography indicated that the median time to 70% prostatic regression in dogs administered combination zanoterone plus finasteride was similar to that in castrate controls (9.6 and 9.3 weeks, respectively), indicating that the combination was more effective in causing prostatic regression than either drug alone. Finally, at the dosages used, no adverse effects of combination treatment with zanoterone plus finasteride on testicular or other major body organ weights were observed. Based on these results, combination therapy using zanoterone and finasteride for the treatment of human androgen-dependent disorders such as benign prostatic hyperplasia and prostate cancer has potential utility.

Androstenes↗
PubMed2004

Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor.

Dihydrotestosterone (DHT) is the primary metabolite of testosterone in the prostate and skin. Testosterone is converted to DHT by 5alpha-reductase, which exists in two isoenzyme forms (types 1 and 2). DHT is associated with development of benign prostatic hyperplasia (BPH), and reduction in its level with 5alpha-reductase inhibitors improves the symptoms associated with BPH and reduces the risk of acute urinary retention and prostate surgery. A selective inhibitor of the type 2 isoenzyme (finasteride) has been shown to decrease serum DHT by about 70%. We hypothesized that inhibition of both isoenzymes with the dual inhibitor dutasteride would more effectively suppress serum DHT levels than selective inhibition of only the type 2 isoenzyme. A total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 +/- 1.2% with 5.0 mg dutasteride and 94.7 +/- 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 +/- 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo.

Androgen Antagonists↗