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The entire androgen metabolism of the human prostate is an integral part of the DHT mediated cellular processes, which eventually give rise to the androgen responsiveness of the prostate. Therefore, the potential activities of various androgen metabolizing enzymes were studied. Moreover, the impact of aging on the androgen metabolism and the inhibition of 5 alpha-reductase by finasteride were studied. In epithelium (E) and stroma (S) of normal (NPR) and hyperplastic human prostate (BPH), for each enzyme being involved in the conversion either of testosterone via DHT, 3 alpha- and 3 beta-diol to the C19O3-triols or from testosterone to androstenedione and vice versa, the amount (Vmax) and Michaelis constant (Km) were determined by Lineweaver-Burk plots. Furthermore, Vmax/Km quotients were calculated, which served as an index for the potential enzyme activity. 17 enzymes showed a mean Vmax/Km > or = 0.10. The top four were the 5 alpha-reductases in E and S of NPR and BPH. Among those, the highest activity was found in E of NPR (1.6 +/- 0.2). Moreover, in E a significant age-dependent decrease of 5 alpha-reductase activity occurred, whereas in stroma rather constant activities were found over the whole age range. Similar age-dependent alterations were found for the cellular DHT levels. Finally, the finasteride inhibition of 5 alpha-reductase (IC50;nM) was stronger in E (35 +/- 17) than in S (126 +/- 15). In conclusion, 5 alpha-reductase is: (a) the outstanding androgen metabolizing enzyme in NPR and BPH; (b) dictating the DHT enrichment in the prostate; (c) under the impact of aging; and (d) preferentially inhibited by finasteride in E.

To objectively measure the effects of a 5 alpha-reductase inhibitor on erectile function, we studied 20 sexually active men (aged 41-64 yr) during double blind, randomized administration of 5 mg/day finasteride (F) or placebo (P). Serum testosterone and dihydrotestosterone (DHT) were measured every 4 weeks. Sleep-related erections were assessed with comprehensive polysomnography for 2 nights before randomization (session 1) and at week 12 (session 2). Sexual function questionnaires were administered weekly. Serum DHT levels at week 0 were 1.47 +/- 0.11 and 1.16 +/- 0.27 nmol/L (P > 0.05) in the P and F groups, respectively. F group levels fell to 31% and 28% of control values at week 4 and 12. Penile tip peak tumescence time increased on second nights more in the P than the F group at 12 weeks, producing a session main effect (P < 0.02) and a group X session interaction (P < 0.05). No significant group X session interactions were found for any sleep erection measures in a best night analysis or for self-reported sexual activity. Thus, F did not consistently suppress sleep-related erections compared to P. F primarily inhibits type 2 5 alpha-reductase activity; however, type 1 5 alpha-reductase is the major enzyme in the central nervous system. Therefore, DHT involvement in the maintenance of libido and potency is not excluded. Nonetheless, these data support the feasibility of using a type 2 inhibitor to treat benign prostatic hyperplasia without impairing erectile function.

FCE 27837 is a novel inhibitor of 5 alpha-reductase, the enzyme responsible for the conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). The compound caused inhibition of human and rat prostatic enzymes, with IC50 values of 51 and 60 nM, respectively. The in vivo effect of FCE 27837 on 5 alpha-reductase was evaluated in adult male rats, treated orally at 10 mg/kg/day for 10 days. The compound caused 33 and 42% reductions in ventral prostate and seminal vesicle weights, respectively. The prostatic content of DHT, measured 6 h after the 10th dose of FCE 27837, was reduced by 75%, whereas T content increased by 442%. Similar effects were observed with 10 mg/kg/day of finasteride, whereas epristeride, tested at the same oral dose, was found to be the least effective compound, decreasing prostate weight by 22% and DHT content by 46%. Castration caused > 90% reductions in prostatic weight and prostatic DHT.

The PCPT is a chemoprevention trial of finasteride with a primary endpoint of biopsy-proven presence or absence of prostate cancer. A total of 18,000 healthy men, aged 55 years and older, will be randomized. Half will receive finasteride (5 mg/day) and half will receive placebo (one matching tablet per day) for 7 years. The trial is designed to have 92% power to detect a 25% reduction in period prevalence of biopsy-proven disease using a two-sided test with alpha = 0.05. The trial is complicated by the known impact of finasteride on the major screening test for prostate cancer, prostate specific antigen (PSA). This paper describes the PCPT design with reference to alternatives that were considered. The chosen design depends on five critical assumptions that must be monitored closely throughout the 9-year trial.

Since evidence of 5 alpha-reductase activity in rabbit liver homogenate was discovered in 1954, the presence of this enzyme has been demonstrated in many other organs and tissues of mammalian species. 5 alpha-Reductase selectively transforms a 4-ene-3-oxosteroid (e.g., testosterone) irreversibly to the corresponding 5 alpha-3-oxosteroid (e.g., 5 alpha-dihydrotestosterone) in the presence of NADPH as an essential coenzyme at an optimal pH. However, excessive production of 5 alpha-dihydrotestosterone is the major cause of many androgen-related disorders, such as prostate cancer, benign prostatic hyperplasia, acne, female hirsutism, and male pattern baldness; therefore, inhibition of androgenic action by 5 alpha-reductase inhibitors is a logical treatment. During the past two decades, research has focused on understanding the biological functions and effects of 5 alpha-reductase and its 5 alpha-reduced metabolites: purification of the enzyme, substrates, and metabolites; characterization of their physical, chemical, and biochemical properties; analysis of the amino acid sequence of the enzyme; synthesis of various classes of molecules as potential inhibitors; and examination of the biological activity of the inhibitors in vitro and/or in vivo. This review summarizes the biochemical studies on this enzyme, suggests the mechanisms of action of the enzyme or inhibitors, and discusses the chemistry necessary for the preparation, structure-activity relationships, and in vitro and/or in vivo data obtained from the evaluation of nonsteroidal and steroidal compounds that have been tested as inhibitors of 5 alpha-reductase. In particular, IC50 and Ki values for relevant compounds will be compared according to molecular class. This review could function as a comprehensive working reference of what research has been accomplished so far and what problems remain to be solved in the future for those engaged in this interesting field.

We demonstrate that androgens rapidly and specifically increase intracellular calcium in Sertoli cells, investigate the mechanism, and suggest the unifying hypothesis that calcium might be a common intracellular molecular effector to explain the known synergism between FSH and testosterone (T) action on Sertoli cells in support of spermatogenesis. In freshly isolated Sertoli cells, T and its 5 alpha-reduced metabolite dihydrotestosterone increased intracellular calcium from 83 +/- 4 to 147 +/- 8 and 167 +/- 29 nM, respectively, whereas estradiol had minor (117 +/- 9 nM) and progesterone no (80 +/- 6 nM) effect. The effect of T was rapid (20-40 sec) and inhibited by 1) preincubation with either a pure nonsteroidal antiandrogen (hydroxyflutamide) or a 5 alpha-reductase inhibitor (finasteride) or 2) removal of extracellular calcium (47 +/- 4 nM) or pharmacological blockade of voltage-activated (62 +/- 5 nM) or voltage-independent (55 +/- 14 nM) membrane calcium channels. These findings suggest that the T-induced rise in Sertoli cell cytosolic calcium involves sequential 5 alpha-reduction, binding to a classical androgen receptor, and activation of transmembrane influx of extracellular calcium. Immobilization of T by conjugation to a large carrier molecule (BSA) to prevent steroid entry into Sertoli cells also resulted in a rapid increase in cytosolic calcium to a similar magnitude as unconjugated T, consistent with a plasma membrane site of action. This finding together with the rapid cytosolic calcium rise caused by T argues for the possible existence of a short term, nongenomic effects in hormonal regulation of Sertoli cell function in addition to the well known, slower genomic response.

Bone is an androgen-dependent tissue. It is not known whether normal bony growth and mineralization in males is dependent on testosterone alone, or whether its metabolite, dihydrotestosterone (DHT), also is required. To answer this question, we examined the effect of finasteride, an inhibitor of DHT synthesis, on bone in rats. Three-month-old male rats were treated with placebo, finasteride, or orchidectomy. The bone mineral densities (BMD) of the spine and whole body were measured in vivo by dual x-ray absorptiometry at weeks 0 and 11, and the BMD of the femur and tibia were measured ex vivo at week 11. Histomorphometric analysis was performed on the proximal tibia at week 11. The increase in spine and whole body BMD in finasteride-treated rats did not differ from that in controls, whereas these values were significantly lower in orchidectomized rats. Similarly, the BMD of the femur and tibia and the cancellous bone volume of the proximal tibia in finasteride-treated rats did not differ from those in controls, whereas these values were significantly lower in orchidectomized rats. In summary, bone development and density were normal in rats treated with finasteride. We conclude that selective DHT deficiency is not deleterious to the male rat skeleton.

Androgens are essential for the expression of normal libido in the male, but their role in the maintenance of the erectile response in humans is controversial. It has been shown previously in the rat that castration induces 1) loss of penile reflexes; and 2) considerable reduction in the erectile response to electric field stimulation (EFS) of the cavernosal nerve. Both of these effects can be reversed by testosterone replacement. The current study was performed to determine whether these testosterone effects are mediated via its conversion to dihydrotestosterone (DHT), and to what extent the synthesis of the mediator of penile erection, nitric oxide, is affected by castration and androgen replacement. Five-month-old rats were either castrated or left intact. The orchiectomized rats were implanted with SILASTIC brand silicon tubing (Dow Corning) containing testosterone or DHT with or without daily injections of the 5 alpha-reductase inhibitor finasteride. After 7 days, rats were submitted to EFS and the intracavernosal pressure was recorded. Castration reduced the EFS-induced erectile response by 50% in comparison with intact rats and testosterone restored this decrease to normal. When finasteride was given to these testosterone-treated castrate rats, erectile response was not restored. DHT was as effective as testosterone in restoring response to EFS in castrates and this effect was not decreased by finasteride. Nitric oxide synthase activity in the penile cytosol was measured by the arginine-citrulline conversion and was found to correlate with the EFS determinations. These results show that DHT is the active androgen in the prevention of erectile failure seen in castrated rats, and suggest that this effect may be mediated, at least partially, by changes in nitric oxide synthase levels in the penis.

Steroid 5 alpha-reductase is an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT) and is implicated in the pathogenesis of benign prostatic hyperplasia (BPH) in men. We studied in vitro effects of FK143, a nonsteroidal new compound, on 5 alpha-reductase in human and animal prostates. Prostates were obtained from Wistar rats, Beagle dogs, and Cynomolgus monkeys as well as prostatic tissue from BPH patients obtained by the prostatectomy. Nuclear membrane fraction of prostates showed pH dependent 5 alpha-reductase activities, and inhibitory effects of drugs were assayed at pH 6.5. FK143 inhibited human prostatic 5 alpha-reductase in a dose-dependent manner with an IC50 of 1.9 nM and also inhibited animal 5 alpha-reductases with similar IC50 values. FK143 inhibited human and rat 5 alpha-reductases in a noncompetitive fashion while finasteride, a steroidal 5 alpha-reductase inhibitor, showed competitive inhibition. The affinities of FK143 for the human 5 alpha-reductase is constant at pH 5 and 6.5. No inhibitory effects were shown to other oxidoreductases. These results indicate that FK143 is a new type of potent and selective 5 alpha-reductase inhibitor.

Prostatic hyperplasia can be induced in both intact and castrated dogs and in intact cynomolgus monkeys by the administration of androgenic steroids. Estrogenic steroids potentiate this effect in dogs. These changes also can be induced by androstenedione, which increases androgen and estrogen levels. Atamestane (ATA; 1-methyl-3,17-dione-androsta-1,4-diene), a potent aromatase inhibitor, inhibits some of the androstendione-induced effects; however, the nonsteroidal aromatase inhibitor, CGS-16949A, has been reported to decrease serum estradiol levels in adult rats but to have no effect on androgen-dependent organ weights. To examine the mechanisms by which ATA affects the rat prostate, in vivo and in vitro studies were conducted using adult rat ventral prostate (VP). Intact Sprague-Dawley rats were injected daily for 14 days with sesame seed oil, ATA (70 mg/kg/day), finasteride (FIN; 5 mg/kg/day), a 5 alpha-reductase inhibitor, or the combination of FIN plus ATA. A fifth group was castrated (CASTR) on day 1. The mean +/- standard error VP weight of the controls was 350 +/- 19 mg. It was reduced 17% (P < 0.05) by ATA, 29% (P < 0.001) by FIN, 48% (P < 0.001) by FIN plus ATA, and 86% (P < 0.001) by CASTR. The DNA/VP was reduced 22% (not significant) by ATA, 18% by FIN (not significant), 35% (P < 0.01) by FIN plus ATA, and 60% (P < 0.001) by CASTR. More significant changes were observed in RNA and protein. The mRNA for prostatein C3 was reduced by each of the treatments, but only CASTR increased the mRNA for TRPM-2, a marker of apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: To assess the effects of finasteride, a 5-alpha-reductase inhibitor, and of classic antiandrogens on the growth rate of the LnCap human prostate carcinoma cell line, derived from a primary and well-differentiated neoplasm., Methods: Cell proliferation experiments in vitro with and without the antiandrogens cyproterone acetate, hydroxyflutamide, and finasteride in the 0.0001 to 10.0 microM range., Results: The growth rate of the LnCap cell line can be dose-dependently inhibited by 5-alpha-reductase inhibition (finasteride) and by antiandrogens (cyproterone acetate and hydroxyflutamide) in vitro, in defined conditions., Conclusions: Besides other human prostate cell lines derived from metastatic sites (PC3, DU145), also in the LnCap cell line an autonomous androgen-dependent mechanism of growth stimulation can be hypothesized, since testosterone and dihydrotestosterone are unable to stimulate the cell proliferation rate at the same molar concentrations. The clinical implications of these results in prostate cancer therapy and the possible future use of these molecules in the prevention of cancer incidence are discussed.

Four new azasteroid inhibitors of steroid 5 alpha-reductase were compared to the benchmark compound finasteride, each at a dose level of 1 mg/kg/day, as well to placebo and to castration, in seven groups of mature male beagle dogs with enlarged prostates. Prostate volumes were measured repetitively by a volume MRI method over 15 weeks of treatment. The study probed the obverse of the familiar relation between DHT and prostate growth, and provides the first documentation of a tight negative correlation between prostate regression and the prostatic concentration of DHT across a range of treatment regimens (r = -0.982). In this first direct comparison study of structure vs. in vivo activity for several azasteroids in the dog model of BPH, relative efficacy for induction of shrinkage of the dog prostate did not correlate at all with the inhibitor's relative activity against the dog 5 alpha-reductase in vitro. On the basis of the relative IC50 values it would not have been predicted that, at the dose tested, the analogue MK-434 (17 beta-benzoyl-4-aza-5 alpha-androst-1-en-3-one) was distinguished from the other inhibitors with respect to the induction of faster and more complete regression (69%) as well as greater reduction in prostatic DHT (95%), both of which approached the castrated dog levels of 75% prostatic shrinkage and > 98% reduction in DHT. Treatment with any one of the five azasteroids induced two- to five-fold increases in prostatic testosterone. However, total androgen was conserved at the placebo control level. Despite the differences noted, each azasteroid tested induced a highly significant decrease in prostatic volume that correlated tightly with a decreased prostatic DHT level in canine spontaneous BPH.

Castration causes cell loss in the rat ventral prostate through a process called apoptosis. Although 5 alpha-reductase inhibition also causes prostate cell loss, the mechanisms involved have been debated. To investigate this question further, we have evaluated the histological responses of the rat ventral prostate to both castration and 5 alpha-reductase inhibition. Rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride. After 4, 9, 14, and 21 days the prostates were excised, the androgen and DNA content determined, and the tissue was subjected to histological and histomorphometric analysis. Finasteride and castration decreased prostate weight at day 21 by 65% and 93%, respectively. Castration decreased DNA content (micrograms per prostate) by a maximum of 88% at 14 days. Finasteride had no significant effect on DNA content after 4 days and decreased DNA content by a maximum of 52% at 14 days. When castrate prostate sections were stained for tissue transglutaminase, a marker of apoptotic cell death, a maximum of 23% of epithelial cells were stained by day 14 with a return to control levels by day 21. Finasteride caused a less intense increase in staining in which 16% of epithelial cells stained for tissue transglutaminase on day 9 with a return to baseline by day 14. When prostate sections were stained for DNA breaks, another marker of cell death, castration, caused a peak of staining on day 4 with 6% of epithelial cells staining and a return to near control levels by day 21. Finasteride-induced staining was less intense with peak staining at day 4 (0.7% of epithelial cells) and a return to control values by day 9. Morphometrics were used to assess the effect of castration and finasteride on prostate duct size and epithelial cell mass. After 4 days of finasteride treatment, the mean ductal mass decreased by 47%, with no significant change thereafter. The mean epithelial cell mass decreased by 15% on day 4 and 60% on day 9, with no further decrease thereafter. Castration caused a more rapid and greater decrease in both morphometric parameters with a 95% reduction in the mass of prostate ducts and a 93% decrease in epithelial cell mass by day 9. We conclude that castration induces a more profound involution of the rat ventral prostate than does 5 alpha-reductase inhibition. Cell loss occurs in both groups, but the degree of cell loss is less with finasteride.(ABSTRACT TRUNCATED AT 400 WORDS)

The transforming growth factor beta (TGF-beta) superfamily includes several closely related peptides including the activins and inhibins. Since we recently reported that TGF-beta 1 and beta 2 are potent inducers of steroid 5 alpha-reductase (5 alpha R), we have now studied the effects of these other peptides using primary cultures of human scrotal skin fibroblasts. Recombinant human activin A or inhibin A were added to cultured cells (2 x 10(5) cells) for 2 days in a serum free media and 5 alpha R activity was measured by the %-conversion of tracer [3H]-testosterone to dihydrotestosterone (DHT) over a 4-h period. Activin significantly stimulated 5 alpha R activity in a dose related manner (control 3.0 +/- 0.4%, activin (1.2 x 10(-9) M) 6 +/- 0.7%, P < 0.01, (2.4 x 10(-9) M) 8.5 +/- 0.6%, P < 0.001). In comparison, androgen (DHT 10(-7) M) induction of 5 alpha R was 4.7 +/- 0.2%, P < 0.05. Combined exposure of fibroblasts to activin (1.2 x 10(-9) M) and androgen (10(-7) M) did not result in additive or synergistic effect on 5 alpha R activity. In contrast, exposure of cells to an androgen (10(-7) M) and TGF-beta (2 x 10(-10) M) led to synergistic effects on 5 alpha R activity (control 1.5 +/- 0.1%, DHT 2.6 +/- 0.2% TGF-beta 1 4.8 +/- 0.5, TGF-beta 1 + DHT 9.2 +/- 1.2%).(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to determine the efficacy of the 5 alpha-reductase inhibitor finasteride (Proscar, MK-906) in men with reduced urinary flow rates and symptoms of urinary outflow obstruction secondary to benign prostatic hyperplasia. Forty-five men were randomized to one of three groups receiving either placebo, 1 mg/day or 5 mg/day finasteride for the first 12 months of the study period. At the end of this period all men received 5 mg/day finasteride for a further 2 years. Efficacy was determined by measurement of prostate volume, maximum urinary flow rate, and symptom score using a modified Boyarsky assessment. Prostate volume reduced by 20 and 27%, respectively, for those on 1 and 5 mg after the first year. At 3 years the volume had reduced by 43%. This reduction in prostate volume was associated with an improvement in maximum urinary flow rate by 50% (1 mg), and 35% (5 mg) at 1 year, and 36% at 3 years. The total, obstructive and non-obstructive symptom scores decreased (improved) for patients on 1 and 5 mg finasteride, with the total score reducing by 33% from baseline at year 3. The results demonstrate that finasteride causes a modest but significant clinical improvement in men with urinary outflow obstruction secondary to benign prostatic hyperplasia.

The action of testosterone (T) on the sex accessory organs, such as ventral prostate (VP) and seminal vesicles (SV) is amplified by its 5 alpha-reduction to dihydrotestosterone (DHT). This does not happen in the case of muscle (levator ani, LA) which contains little or no 5 alpha-reductase activity. It has been suggested that the regulation of gonadotropins by T may also be mediated by its 5 alpha-reduced metabolites. We investigated this question by utilizing two types of androgens: (1) T and 17 alpha-methyl-testosterone (17MT), whose potency increases following 5 alpha-reduction; and (2) 19-nortestosterone (NT) and 17 alpha-methyl-19-nortestosterone (17MNT) whose potency decreases following 5 alpha-reduction. Castrated rats were used to investigate the ability of these androgens to stimulate VP, and SV (androgenic action) and LA growth (anabolic action) and to suppress the post-castration rise in LH levels. In addition, modification of these actions by a 5 alpha-reductase inhibitor (5 alpha-RI) was studied. Compared to T, NT was approximately 5 times less potent in stimulating VP and SV. By contrast, it was twice as potent as T in stimulating LA growth. Similarly, 17MNT was 5 times less androgenic but twice as anabolic as 17MT. The antigonadotropic potency of both the 19-nor compounds was 2-3 times greater than that of their respective 19-methylated parent compounds. The similarity in their anabolic and antigonadotropic potency suggested that 5 alpha-reduction is not a factor in their antigonadotropic action. This was confirmed by the use of the 5 alpha-RI. Treatment of rats receiving the androgens with 5 alpha-RI showed that it decreases the androgenic activity of T and 17MT while it increases the androgenic activity of NT and 17 MNT. In all cases the anabolic activity and the antigonadotropic potency remained unchanged. It is concluded that the regulation of pituitary gonadotropin secretion by T does not depend upon its 5 alpha-reduction to DHT.

In 18 of 55 original patients who completed 5 years of treatment with finasteride, significant reductions in prostate size were noted at 1 year and sustained thereafter. Symptom scores in these same patients were significantly improved or stable over the 5 years while maximal urinary flow rates were unchanged. Data from 15 of 18 other patients who dropped out of the study before 5 years showed changes in prostate size, symptom score and flow rates that were similar to those noted in patients treated for 5 years. No side effects were noted in this study except for sexual dysfunction, which occurred in less than 5% of the patients. With few exceptions, finasteride appears to arrest the process of BPH over a 5 year period as indicated by sustained reductions in prostate size accompanied by either symptomatic improvement or stability in all other patients.

A reflection is made, on the one hand, on the lack of correlation between the intensity of micturition problems and the volume of the prostate and, on the other hand, on the different therapeutic approaches of irritative or obstructive voiding problems, and finally on the insufficiently convincing activity of Finasteride.

Finasteride (MK-0906), a drug used for the treatment of benign prostatic hyperplasia, is a highly specific inhibitor of steroid 5 alpha-reductase, an enzyme that converts testosterone (T) to dihydrotestosterone (DHT) in animals and humans. In a study to evaluate the effect of finasteride on the growth of green alga, Selenastrum capricornutum, the parent drug was not detected by HPLC in the posttreatment (14 day) samples, suggesting complete biotransformation. Thermospray LC/MS, followed by NMR analysis, indicated that the major algal metabolite was 11 alpha-hydroxy-finasteride. This metabolite has negligible in vitro bioactivity against human prostatic 5 alpha-reductase; its potency is only 2% that of finasteride. The primary metabolite of finasteride produced by the green alga involved a biotransformation not previously observed in mammalian and human studies. The green alga effectively deactivates the drug, thereby mitigating any potential environmental impact.

Finasteride is a specific 5 alpha-reductase inhibitor that has been shown to reduce the size of human benign prostatic hyperplasia (BPH) by inhibiting the intraprostatic conversion of testosterone to 5 alpha-dihydrotestosterone. The aim of the present in vitro study was to describe in more detail the inhibitory effect of finasteride on 5 alpha-reductase in epithelium and stroma of human BPH. 5 alpha-Reductase activity in epithelium and stroma was inhibited dose-dependently by finasteride. The mean IC50 (50% inhibitory concentration) values, determined in the presence of various testosterone concentrations, were generally 2- to 4-fold lower in epithelium than in stroma. With finasteride concentrations greater than 5 nM, competitive inhibition of 5 alpha-reductase occurred both in epithelium and stroma. The mean inhibition constant Ki[nM +/- SEM] was 7 +/- 3 and 31 +/- 3 in epithelium and stroma, respectively. In the presence of finasteride concentrations < or = 5 nM, the epithelial 5 alpha-reductase seems to be inhibited in an uncompetitive manner, whereas such low finasteride concentrations cause either no inhibition (1-2 nM) or competitive inhibition (5 nM) in stroma. Our present study provides evidence that the inhibitory effect of finasteride on 5 alpha-reductase is much stronger in epithelium than in stroma. Therefore, it is conceivable that the global size-reduction of BPH under finasteride treatment is primarily due to the regression of BPH epithelium.

In many turtles the temperature during the middle of incubation determines the gonadal sex of the hatchling. In the red-eared slider turtle (Trachemys scripta), an incubation temperature of 26 degrees C results in all male offspring, whereas an incubation temperature of 31 degrees C results in all female offspring; at temperatures intermediate to these (e.g. 29, 29.2, 29.4 degrees C) a mixed sex ratio is obtained. Administration of exogenous oestrogens will overcome the effects of an all-male producing incubation temperature to cause female sex determination, whereas administration of exogenous dihydrotestosterone (DHT) or testosterone to eggs incubating at an all-female temperature will have no discernible effect. Administration of DHT will cause male sex determination only if administered at intermediate incubation temperatures whereas administration of testosterone to eggs incubating at all male-producing and male-biased intermediate temperatures results in a significant number of female offspring, an effect presumably due to aromatization of testosterone to oestradiol (OE2). Since testosterone serves as the precursor to both DHT and OE2, being metabolized by reductase and aromatase respectively, three experiments were conducted to determine whether various putative reductase and aromatase inhibitors would overcome the effect of incubation temperature. First, while administration of testosterone to eggs incubating at all male-producing and male-biased intermediate temperatures produced females in a dose- and temperature-dependent manner, significant numbers of intersex individuals resulted from high dosage testosterone treatment to eggs incubating at a female-biased intermediate temperature. The reductase inhibitors 4MA and MK906 were capable of producing female offspring if administered at intermediate temperatures, but not in a dose-dependent fashion. Administration of the aromatase inhibitors CGS16949A and CGS20267 resulted in male offspring at both female-biased intermediate and at all female-producing temperatures in a dose-dependent fashion. Second, similar findings were obtained with combined doses of testosterone and reductase or aromatase inhibitors. Combined treatment of eggs at male-biased intermediate incubation temperatures with testosterone and reductase inhibitor resulted in female hatchlings, whereas combined treatment of testosterone and aromatase inhibitor at both female-biased intermediate and at all female-producing temperatures resulted in male hatchlings.(ABSTRACT TRUNCATED AT 400 WORDS)

Finasteride, a 5 alpha-reductase inhibitor, was administered orally (1 mg/kg.day) for 6 months to six male and five female stumptail macaques. Vehicle was given to five male and five female animals over the same period of time. Hair weights in a defined 1-in.2 area of frontal scalp were measured periodically every 1-2 months, and serum was collected for measurement of testosterone and dihydrotestosterone. In addition, scalp biopsies were taken before and 6 months after treatment to evaluate the micromorphometry of hair follicles. Results showed that both male and female serum dihydrotestosterone levels were significantly reduced (60-70%) by finasteride treatment. Both males and females showed statistically significant increases in mean hair weight over the treatment period compared to controls (P = 0.034). In addition, there was a statistically significant increase in mean follicle length (measured histologically in scalp biopsies) compared to baseline in the finasteride-treated animals (P = 0.028). These data show that an inhibition of 5 alpha-reductase in the stumptail macaque can reverse the balding seen with age in both the male and female animals.

The effects of the 5 alpha-reductase inhibitor, finasteride, on scalp skin testosterone (T) and dihydrotestosterone (DHT) levels were studied in patients with male pattern baldness. In a double blind study, male patients undergoing hair transplantation were treated with oral finasteride (5 mg/day) or placebo for 28 days. Scalp skin biopsies were obtained before and after treatment for measurement of T and DHT by high pressure liquid chromatography-RIA. In 10 male subjects studied at baseline, mean (+/- SEM) DHT levels were significantly higher in bald (7.37 +/- 1.24 pmol/g) compared to hair-containing (4.20 +/- 0.65 pmol/g) scalp, whereas there was no difference in mean T levels at baseline. In bald scalp from 8 patients treated with finasteride, the mean DHT concentration decreased from 6.40 +/- 1.07 pmol/g at baseline to 3.62 +/- 0.38 pmol/g on day 28. Scalp T levels increased in 6 of 8 subjects treated with finasteride. Finasteride decreased the mean serum DHT concentration from 1.36 +/- 0.18 nmol/L (n = 8) at baseline to 0.46 +/- 0.10 nmol/L on day 28 and had no effect on serum T. There were no significant changes in scalp or serum T or DHT in placebo-treated patients. In this study, male subjects treated with 5 mg/day finasteride for 4 weeks had significantly decreased concentrations of DHT in bald scalp, resulting in a mean level similar to the baseline levels found in hair-containing scalp.

Finasteride, a 5 alpha-reductase inhibitor, does not bind to the androgen receptor and has no other known hormonal activity. To determine what effect, if any, it has on adrenal steroidogenesis, 10 healthy men received 5 mg finasteride daily for 28 days. Adrenocorticotropic hormone (ACTH) stimulation tests were performed before and after 4 weeks of finasteride administration (5 mg daily). Serum levels of 17-hydroxypregnenolone, 17-hydroxyprogesterone, deoxycorticosterone, corticosterone, aldosterone, cortisol, dehydroepiandrosterone, and androstenedione were measured before and 60 minutes after i.v. ACTH. Finasteride decreased serum dihydrotestosterone levels from 31 +/- 5 to 4.4 +/- 1.2 ng/dl (P < 0.001). There were no significant changes in basal or ACTH-stimulated serum levels of adrenal steroids. There was also no significant decrease in the product to precursor ratio for the seven adrenal enzymes tested. Finasteride increased mean serum androstenedione levels by 17% (P = 0.10) and significantly increased the androstenedione to 17-hydroxyprogesterone ratio (P = 0.02 before ACTH and 0.05 after ACTH). These changes are most likely due to inhibition of androstenedione metabolism by 5 alpha-reductase. In conclusion, finasteride has no detectable effect on adrenal steroidogenesis, other than that which can be explained by inhibition of the 5 alpha-reductase enzyme.

Inhibitors of aromatase and 5 alpha-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, respectively. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compound was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation (t1/2 4.5 vs 15.1 min) and a similar Ki(inact) (56 vs 66 nM). The compound was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17 beta-amidic side chains, three compounds, namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5 alpha-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, respectively. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compounds were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, respectively.

Objective: To determine any potential direct and/or indirect effects of elevated intraprostatic T levels on the prostates of rats chronically (1-2 years) exposed to high doses (160 mg/kg/day) of finasteride, a selective inhibitor of 5-alpha reductase., Methods: Sprague-Dawley male rats were administered daily finasteride by oral gavage. Prostates from all rats were weighed, fixed in 10% neutral buffered formalin, and processed for light microscopic examination. The volume fractions of the prostatic glandular and stromal compartments were quantitated by morphometric analysis., Results: Administration of finasteride at doses of 20, 40, and 80 mg/kg/day for one year resulted in a significant (P < or = 0.05) decrease in prostatic weight; prostatic atrophy was evident by light microscopy. Morphometric analysis of the prostate showed that chronic finasteride administration resulted in a significant (P < or = 0.001) decrease in the absolute volume of both glandular (-65.2%) and stromal (-57.1%) compartments of the prostate. Furthermore, the total number of epithelial and stromal cells per gland were significantly (P < or = 0.002) decreased in finasteride-treated rats compared with vehicle controls; the magnitude of mean decrease was 69.8 percent and 50.6 percent of controls in epithelial and stromal cells, respectively. In addition, prostates from all two hundred fifty rats in a two-year study were qualitatively evaluated by light microscopy. Administration of finasteride at doses ranging from 2.5 mg/kg/day to 160 mg/kg/day for two years did not result in an increase over the background incidence of prostatic focal hyperplasia or adenoma. No malignant tumors of the prostate were seen in any of the groups., Conclusions: These studies have demonstrated that the expected pharmacologic effects of finasteride on the prostate are maintained following chronic treatment and that there was no evidence of a direct and/or an indirect effect of elevated intraprostatic T on prostatic morphology in rats.

TRPM-2, not normally expressed in the rat ventral prostate, has been identified as an important genetic marker of castration-induced apoptotic cell death. It is not known whether other agents capable of causing growth inhibition of the rat ventral prostate also induce TRPM-2 expression. To investigate this further, 270 mature Sprague-Dawley rats were randomized into one of six groups: control, castration, diethylstilbestrol (DES), flutamide, MK-906 (finasteride), or coumarin. Five rats per group were sacrificed on days 1, 3, 5, 7, 10, and 21. Serum testosterone, body weights, and prostate weights were determined at each time point. The ventral prostate was removed and cellular RNA extracted. Northern blot analysis using cDNA probes for TRPM-2 and gamma-actin were performed at each time point. Only DES significantly decreased rat weights. DES and castration reduced serum testosterone to undetectable levels by the next day. Flutamide caused a 3.0- to 4.5-fold increase in serum testosterone above control. Coumarin and MK-906 did not affect serum testosterone levels. DES and castration reduced prostate weights to 20% and 6% of control, respectively, while inducing TRPM-2 expression to a maximum on day 5 of the experiment. DES induced TRPM-2 expression over a longer duration than did castration, suggesting that more than just the decrease of serum testosterone to castrate levels plays a role in the expression of TRPM-2. MK-906, coumarin, and flutamide reduced prostatic weights to a lesser extent (50%, 63%, 71% of control, respectively), but these agents did not induce TRPM-2 expression at any time during the experiment. TRPM-2 expression in the rat ventral prostate does not correlate simply with catabolic effects on the prostate.

The purpose of this study was 2-fold: (1) to identify the 5 alpha-reductase (5 alpha-R) isozyme(s) present in DU 145 cells, a human cell-line of low androgen sensitivity derived from a cerebral metastasis of an epithelial prostate cancer; and (2) to compare the inhibitory potencies of three compounds on the 'basic' 5 alpha-R isozyme expressed in a baculovirus-directed insect cell system. Conversion of testosterone (T) into 5 alpha-dihydrotestosterone (DHT) in DU 145 cells was measured by HPLC coupled to a Flo-one HP radioactivity detector. DU 145 cells exhibited 5 alpha-R activity (21 pmol DHT/min/mg protein) at pH 7.4 which disappeared at pH 5.5 suggesting that, of the two genomically distinct human isozymes identified so far, type 1 5 alpha-R is expressed in DU 145 cells. This was confirmed by at least two observations: first, 5 alpha-R activity in DU 145 cells was inhibited with much higher potency by 4-MA than by finasteride which is known to be a very poor competitor of the 'basic' enzyme (IC50s = 2.8 +/- 0.2 and 264 +/- 55 nM, respectively). Second, only the type 1 5 alpha-R cDNA and not type 2 5 alpha-R cDNA hybridized with DU 145 RNA. A high potency differential was also recorded for the inhibition of 'basic' type 1 5 alpha-R expressed in a baculovirus-directed-insect cell system by these two compounds, 4-MA being considerably more active than finasteride (Ki = 8.4 +/- 2.3 and 330 +/- 9 nM, respectively). This inhibition was competitive. On the other hand, inhibition by an n-hexane lipid/sterol extract of Serenoa repens (LSESr) was non-competitive and, when expressed in terms of recommended therapeutic doses, was 3-fold greater for LSESr than for finasteride. These studies suggest that LSESr might exert a regulatory inhibitory activity due to its specific lipid/sterol composition.

17 beta-(N-tert-butylcarbamoyl)-4-aza-5 alpha-androstan-1-en-3-one (finasteride), which has been approved for treatment of benign prostatic hyperplasia, is shown here to be a slow time-dependent inhibitor of human steroid 5 alpha-reductase isozyme 1. This inhibition is characterized by an initial, fast step where the inhibitor binds to the enzyme followed by a slow step that leads to a final enzyme-inhibitor complex (EI*). No recovery of activity from this EI* complex was observed after dialysis for 3 days. The formation of EI* is diminished in the presence of a competitive, reversible inhibitor, indicating that the inhibition is active site-directed. At 37 degrees C and pH 7.0, the rate constant for the second, slow inhibition step, k3, is (1.40 +/- 0.04) x 10(-3) s-1 and the pseudo-bimolecular rate constant, k3/Ki, is (4.0 +/- 0.3) x 10(3) M-1 s-1. This latter rate constant is less than the value of 2.7 x 10(5) M-1 s-1 determined for the inhibition of 5 alpha-reductase 2 by finasteride [Faller, B., Farley, D., & Nick, H. (1993) Biochemistry 32, 5705-5710].(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To assess the long-term safety and efficacy of finasteride in the treatment of symptomatic benign prostatic hyperplasia in patients treated with finasteride 5 mg for thirty-six months., Methods: Two large multicenter studies were used. Patients were randomly assigned to treatment with finasteride, 1 or 5 mg, or placebo for twelve months. After completing twelve months of therapy, patients were invited to enter an open extension to the study in which all patients received finasteride 5 mg. Urinary symptoms, urinary flow rate, prostate volume, and serum concentrations of prostate-specific antigen and dihydrotestosterone were measured periodically during the study., Results: After thirty-six months of treatment with finasteride 5 mg, prostate volume was reduced from baseline by approximately 27 percent, maximum urinary flow rate improved by approximately 2.3 mL/second, and symptom scores improved by 3.6 points. Forty-two percent of patients had a 30 percent or greater decrease in prostate volume, 40 percent of patients showed an increase of 3 mL/second or more in maximum urinary flow rate, and 48 percent of patients experienced a 50 percent or greater improvement in symptom scores. Finasteride was well tolerated and there was no evidence of increased adverse experiences with increased duration of treatment., Conclusions: The excellent safety profile and sustained clinical efficacy, over thirty-six months, of daily treatment with finasteride 5 mg recommend finasteride as a low-risk medical option for the treatment of symptomatic benign prostatic hyperplasia.

Turosteride was tested in a series of studies for its effect on 5 alpha-reductase and for its possible influence on other steroidogenic enzymes and on steroid receptors. The compound was found to inhibit human and rat prostatic 5 alpha-reductases with IC50 values of 55 and 53 nM, respectively, whereas it caused a less marked inhibition of the dog enzyme (IC50 2.2 microM). Turosteride showed no relevant effect on rat adrenal C20,22-desmolase (IC50 254 microM) and human placental aromatase (IC50 > 100 microM), and only at relatively high concentrations it caused inhibition of human placental 5-ene-3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) (IC50 2.5 microM). Turosteride was found to be a selective 5 alpha-reductase inhibitor showing no noteworthy binding to receptors for androgens (relative binding affinity, RBA, 0.004%), estrogens (< or = 0.005%), progesterone (< 0.005%), glucocorticoids (< 0.01%) and mineralocorticoids (< 0.03%). Its biochemical profile was similar to that of finasteride, whereas 4-MA (17 beta-N,N-diethyl-carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) was confirmed to be a non-selective 5 alpha-reductase inhibitor, showing a degree of binding affinity to the androgen receptor (RBA 0.1%) and a marked inhibition of 3 beta-HSD-I (IC50 32 nM). When given orally in immature castrated rats together with subcutaneous testosterone propionate (TP) for 7 consecutive days, turosteride reduced the ventral prostate and seminal vesicle growth promoting effect of TP, with IC50 values of approximately 5 and 6.7 mg/kg/day, whereas levator ani weight was unchanged. In comparison, 4-MA was approx. 3-fold less potent than turosteride in reducing the prostate and seminal vesicle weights and caused a marked reduction of levator ani weight, thus showing its unselectivity.

A four-period, two-panel, single-rising-dose study (0.1-100 mg) was conducted in healthy males to investigate the pharmacodynamics, tolerability and pharmacokinetics of MK-0434, a steroid 5 alpha-reductase inhibitor. MK-0434 was associated with a significant reduction in dihydrotestosterone, which was maximal at 24 h and maintained through 48 h post treatment. The maximum reduction was approximately 50% and occurred at all doses above 5 mg (10, 25, 50 and 100 mg). MK-0434 appeared to have no effect on serum testosterone at these single doses. Rising single doses of MK-0434 were associated with an increase in Cmax and AUC but the changes were less than proportional to dose, most likely due to nonlinear absorption. MK-0434 given in single doses up to 100 mg was without significant adverse effects in healthy male volunteers. In summary, MK-0434 is a well-tolerated, potent, orally active 5 alpha-reductase inhibitor in man.

Objective: Prostate-specific antigen density (PSAD) has been proposed as a diagnostic marker for prostate cancer. Because treatment with finasteride may affect PSAD differently in men with BPH compared with men with BPH plus prostate cancer, we evaluated the diagnostic utility of PSAD in men treated with finasteride for twelve months., Methods: Data for this analysis were obtained from 895 men with BPH enrolled in a twelve-month placebo-controlled North American study. Prostate volume was measured by magnetic resonance imaging and PSA was measured by the Hybritech immunoradiometric assay., Results: Treatment with finasteride for twelve months increased the positive predictive value of PSAD for identifying the presence of prostate cancer from 14 percent to 30 percent. Using PSA values alone with a cutoff of 10 ng/mL at baseline and 5 ng/mL after twelve months of treatment, similar specificity and sensitivity could be achieved., Conclusion: The data suggest that adjustment of PSA values during treatment with finasteride can be used to maintain the diagnostic accuracy for prostate cancer while PSAD can be used to provide additional reassurance without requiring adjustment for treatment.

A total of 32 healthy male volunteers (age range 20-30 years) were enrolled in a 1-week open, randomized, placebo-controlled study comparing finasteride (Proscar), a 5 alpha-reductase inhibitor, with Permixon, the plant extract of Serenoa repens. The objective of the study was to evaluate the effect of single and multiple doses of the drugs on the inhibition of 5 alpha-reductase as assessed by serum dihydrotestosterone level determination. Following baseline measurements on day 1, the subjects were randomized to finasteride 5 mg once a day (n = 10), Permixon 80 mg x 2 twice a day (n = 11), or to placebo once a day (n = 11) for 7 days. Serum testosterone and dihydrotestosterone levels, were determined on day 1 (baseline and 12 h) and on days 2 (24 h), 3 (48 h), 4 (72 h), 6 (120 h), and 8 (168 h). After 12 h, a single dose of finasteride 5 mg reduced the serum dihydrotestosterone level by 65% (p < or = 0.01). The decreases ranged from -52 to -60% with multiple doses of finasteride 5 mg once a day (p < or = 0.01). As in the placebo group, there was no effect of Permixon on the serum dihydrotestosterone level. No significant difference was detected between finasteride and Permixon or between finasteride and placebo with respect to serum testosterone, except on days 3 and 6, respectively (p < or = 0.05). However, the corresponding serum testosterone levels remained within the normal ranges. These data confirm the efficacy of finasteride as inhibitor of 5 alpha-reductase.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study we examined the possibility that chronic reduction in serum dihydrotestosterone (DHT) attained by pharmacologic inhibition of 5 alpha-reductase modulates serum sex-hormone-binding globulin (SHBG) levels in elderly men. Twenty-one men, ages 58-79 years (mean 66) with benign prostatic hypertrophy were treated with the 5 alpha-reductase inhibitor finasteride (5 mg daily) for 12 months. Serum DHT declined by 80% (p < 0.001) and total testosterone rose by 14% (p < 0.05). Serum SHBG concentration remained unchanged (44.1 +/- 4.5 vs 45.2 +/- 5.7 nmol/l for pre- and post-therapy levels, respectively). Thus, the conversion of testosterone to DHT is not required to maintain the androgenic effect on serum SHBG concentration in elderly men.

Young mature dogs received finasteride, a selective 5 alpha-reductase inhibitor, orally at 0, 5, 15, and 45 mg/kg/day for 27 or 53 weeks. The effect of finasteride administration on prostatic size and morphology was evaluated macroscopically and microscopically. Changes in glandular and fibromuscular compartments were quantitated by a point counting method on trichrome-stained sections. Finasteride administration induced a decrease of mean prostatic weights and epithelial atrophy in all treated groups. No changes in testicular weights and morphology were observed. The greatest prostatic shrinkage was obtained in the group receiving 45 mg/kg/day for 53 weeks; compared to placebo controls, the percent decreases in absolute volumes occupied by epithelium, lumens, fibrovascular stroma, and smooth muscle were 88, 97, 51 and 72, respectively. These results clearly demonstrate that prostatic shrinkage following finasteride administration results from a decrease in both glandular and fibromuscular compartments.

1. The authors investigated the administration of finasteride, a 5 alpha-reductase inhibitor; flutamide, an androgen receptor blocker and; exogenous dihydrotestosterone (DHT) during intervals covering different portions of the "critical period" of neural development (i.e. prenatal, perinatal or pre- and postnatal development) to determine the long-term effects of these agents on altering androgen metabolism in hypothalamic and pituitary tissue of juvenile (30 day-old) male rats. 2. The efficacy of the treatments and hypothalamic-pituitary axis function was monitored by measuring luteinizing hormone levels by radioimmunoassay. 5 alpha-Reductase and aromatase activity was determined in hypothalamic and pituitary tissue. 3. Significant alterations in pituitary 5 alpha-reductase activity was detected in DHT-treated animals, whereas, hypothalamic 5 alpha-reductase activity was significantly decreased by finasteride treatment and significantly increased by DHT treatment. Hypothalamic aromatase activity was significantly decreased in flutamide-treated animals. 4. These results suggest that: a) prenatal exposure to exogenous DHT stimulates hypothalamic (but inhibits pituitary) 5 alpha-reductase activity long-term and b) basal 5 alpha-reductase activity levels can be inhibited by finasteride treatment in hypothalamic but not in pituitary tissue, suggesting that a different regulatory mechanism exists for 5 alpha-reductase in hypothalamic versus pituitary tissue.

Finasteride, a 5-alpha reductase inhibitor recently introduced for the treatment of symptomatic benign prostatic hyperplasia, reduces prostate size and decreases serum PSA concentration. To interpret PSA in men treated with finasteride, it is necessary to take the reduction into account. This article describes the effect of finasteride on the serum PSA concentration in the North American Phase III clinical trial and discusses implications of these findings for the interpretation of serum PSA in men treated with finasteride.

Turosteride [FCE 26073; 1-(4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carbonyl)-1,3- diisopropylurea] is a novel inhibitor of 5 alpha-reductase, the enzyme responsible for the conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 55 and 53 nM, respectively. In addition, turosteride did not show any relevant binding affinity to the rat prostate androgen receptor (IC50 84 microM; relative binding affinity 0.004% of DHT). The endocrine effects of turosteride were evaluated in adult male rats, treated orally at daily doses of 3, 10 and 30 mg/kg for 20 days. At these doses, the compound reduced the ventral prostate weight by 10, 33 and 42% and the intraprostatic total DHT content by 61, 74 and 78%, respectively, whereas no change in the intraprostatic content of T was observed. Turosteride caused a 40% reduction of serum DHT levels which, however, did not reach statistical significance, whereas serum T levels were similar to control animals. No effect on serum luteinizing hormone or prolactin was observed. These results indicate that the antiprostatic effect of turosteride in the adult rat is related to inhibition of the conversion of T to DHT. However, at variance with other 5 alpha-reductase inhibitors (e.g. finasteride), turosteride caused a decrease in prostatic DHT not associated with a secondary increase in T content. This peculiarity of turosteride may represent an improvement of the compound over other inhibitors.

A single-blind study was conducted to investigate the effect of multiple doses of finasteride, a 5 alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia, on the single-dose pharmacokinetics of antipyrine. Twelve patients with benign prostatic hyperplasia received a total of four single oral doses of 18 mg/kg antipyrine before, during, and after treatment with 10 mg/day of finasteride for 28 days. Finasteride had no effect on antipyrine concentration profiles. There were also no changes in urinary excretion of three principal antipyrine metabolites. A slight increase in renal clearance of antipyrine was observed; however, this is not considered relevant because excretion of unchanged antipyrine represents a minor fraction of total elimination and is not directly related to oxidative metabolism. These results imply that significant interactions between finasteride and drugs metabolized by these cytochrome P-450 enzymes are unlikely.

The 5 alpha-reductase inhibitor, finasteride, inhibits progesterone synthesis in the MA-10 Leydig tumor cells. Inhibition is dose-dependent with half maximal inhibition occurring at 10 ng/ml, a concentration significantly less than serum concentrations detected in finasteride-treated patients. Experiments to localize the site of inhibition by this compound revealed that the 3 beta-hydroxysteroid dehydrogenase delta 5-->delta 4 isomerase enzyme was not blocked by finasteride, but that cholesterol side-chain cleavage was inhibited. Thus, both dibutyryl-cAMP-stimulated and 22-hydroxycholesterol-stimulated steroidogenesis were inhibited by finasteride. This effect of finasteride to block cholesterol side-chain cleavage may be species-specific. Inhibition is readily detected in the mouse-derived MA-10 cells; however, human granulosa cell steroidogenesis is finasteride-insensitive while rat Leydig cell steroidogenesis is only minimally effected by finasteride.

Finasteride is a novel therapeutic agent that selectively inhibits the enzyme 5 alpha-reductase, thereby reducing prostatic dihydrotestosterone (DHT) levels and prostate size. In men with symptomatic benign prostatic hyperplasia (BPH), these effects have been associated with improvements in peak urinary flow rate and urological symptoms; withdrawal from therapy, however, results in regrowth of the adenoma and long term therapy is therefore necessary. Although the magnitude of clinical improvement seen with finasteride has been perceived to be modest [especially when compared with that associated with transurethral resection of the prostate (TURP)], it has been maintained in the medium term (up to 2 years) and thus may represent significant reversal of disease progression. Such beneficial effects, however, may not become apparent until completion of at least 6 months of therapy. Furthermore, since clinical studies have been unable to proactively identify a responsive subgroup, a trial period of 6 or possibly 12 months is necessary to assess patient responsiveness. Despite these potential shortcomings, the benefits of therapy appear to outweigh the risks. Indeed, finasteride is well tolerated; most adverse events have been related to sexual dysfunction (decreased libido, ejaculation disorders and impotence) and occurred in only a small proportion (about 2 to 3%) of patients. Moreover, although there has been concern that finasteride might mask the detection of prostate cancer through its decremental effects on serum prostate specific antigen (PSA) levels, careful monitoring in clinical trials appears to have avoided this problem. Thorough pretreatment assessment and periodic follow-up examinations for malignancy are therefore required in clinical practice. The role of finasteride in the treatment of patients with BPH is still emerging and will no doubt gain in clarity with further planned investigations. TURP (or other invasive procedures such as the insertion of prostatic stents in patients unsuitable for resection), continues to be the mainstay of therapy for those patients with severe symptomatic BPH. However, available data support a first line role for finasteride in the treatment of patients with uncomplicated symptomatic BPH. Within this setting, finasteride appears to offer a needed additional treatment option for those patients in whom surgery is not indicated, and may be of special benefit to the considerable proportion of patients who opt not to undergo prostatectomy.