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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↗
PubMed1996

5alpha-reductase inhibitors/finasteride.

Benign prostatic hyperplasia (BPH) is a disease diagnosed by the presence of prostatic enlargement and lower-tract urinary obstruction. Finasteride (Proscar), is a potent and specific inhibitor of 5alpha-reductase, which inhibits the conversion of testosterone (T) to dihydrotestosterone (DHT) an important promoter of prostatic growth. It has provided a new therapeutic alternative for the treatment of BPH. The safety and efficacy of finasteride in the treatment of symptomatic BPH have been demonstrated by two multi-center placebo-controlled studies. After 12 months of treatment with 5 mg finasteride daily, prostate volume, DHT and prostate-specific antigen (PSA) levels were reduced and maximum urinary flow rates and symptom scores were improved. Finasteride was well-tolerated. Upon completion of the controlled studies, patients were eligible to enter an open-label extension study in which all patients received 5 mg finasteride. Approximately half of the 543 patients randomized to the 5 mg finasteride group in the controlled studies have now been treated with 5 mg finasteride continuously for 3 years. The data provided by this group of patients on the long-term safety and efficacy of finasteride in the treatment of symptomatic BPH are reviewed.

Cholestenone 5 alpha-Reductase↗
PubMed2005

Monotherapy versus combination drug therapy for the treatment of benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a medical condition occurring in older men (ie, those aged >60 years) resulting from enlargement of the prostate gland. Consequently, affected men may experience bother-some urinary tract symptoms and diminished quality of life. The risk of lower urinary tract symptoms and complications such as acute urinary retention (AUR) may increase if BPH is untreated. Currently, 2 classes of drugs-alpha-adrenergic blockers (alpha-blockers) and 5alpha-reductase inhibitors-are indicated for the treatment of BPH. Although the 2 classes are commonly used in combination, the evidence has frequently not been supportive of this practice. Results from the Medical Therapy of Prostatic Symptoms (MTOPS) trial, the largest and longest clinical trial on this topic to date, revisited the role of combination therapy in the treatment of BPH. OBJECTIVE: This review presents published trials evaluating alpha-blockers or 5alpha-reductase inhibitors used alone or in combination for the treatment of BPH. METHODS: A MEDLINE search was conducted (December 1974 to November 2004) using the MeSH term prostatic hyperplasia limited to the subheading of drug therapy. These results were cross-referenced with the MeSH term combination drug therapy. An additional search was conducted using the MeSH terms finasteride and adrenergic alpha-antagonists limited to adverse effects and therapeutic uses. These results were cross-referenced with prostatic hyperplasia and combination drug therapy. Review articles and meta-analyses were also used. RESULTS: The Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group and the Prospective European Doxazosin and Combination Therapy studies were well-designed trials that failed to support the theory that combination therapy is preferred over alpha-blockers alone. Finasteride was also shown to be no better than placebo for the outcomes of symptom score and peak urinary flow rates. Other trials suggested that combination therapy (which included finasteride) was more effective at reducing symptom scores in men with enlarged prostates at 1 year and that alpha-blockers may be successfully discontinued once patients are stabilized on finasteride. Although it was a prespecified secondary end point, the incidence of surgery or AUR was reduced by 51% using finasteride over placebo. The additive benefit finasteride provides in reducing symptoms, risk of AUR, and invasive surgery was observed within the first year of treatment and correlated with larger prostate sizes (mean [SD], approximately 55 [26] mL). The MTOPS trial further demonstrated a relative risk reduction of 66% in clinical progression rates for the combination-therapy group versus 39% for the doxazosin group compared with placebo (P < 0.001); the doxazosin group was not statistically different from the finasteride monotherapy group. Improvements in symptom scores were greater in the combination-therapy group versus the doxazosin (P = 0.006) and finasteride monotherapy (P < 0.001) groups. CONCLUSION: Based on the literature, combination therapy has been proven to relieve symptoms and delay progression of BPH in men with moderate to severe symptoms and moderately enlarged prostate glands.

5-alpha Reductase Inhibitors↗
PubMed2004

Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line.

BACKGROUND: Reduction of T to DHT by 5alphaR in the prostate enhances androgenic activity for most targets. Inhibition of 5alphaR activity with finasteride attenuates androgen action in men and animal models. The objective of this study was to compare and contrast the effects of a potent new 5alphaR inhibitor, dutasteride, with finasteride in the LNCaP prostate cancer cell line. METHODS: LNCaP cells were incubated for varying times with T or DHT in steroid-free medium in the absence or presence of increasing doses of dutasteride or finasteride and the effects on 5alphaR activity, PSA accumulation in the medium, and on cell proliferation were determined. Drug effects on apoptosis were investigated using Annexin V staining and a cell death ELISA assay. Effects of the drugs on AR ligand-binding activity and on AR protein levels were determined. RESULTS: Dutasteride inhibited (3)H-T conversion to (3)H-DHT and, as anticipated, inhibited T-induced secretion of PSA and proliferation. However the drug also inhibited DHT-induced PSA secretion and cell proliferation (IC(50) approximately 1 microM). Finasteride also inhibited DHT action but was less potent than dutasteride. Dutasteride competed for binding the LNCaP cell AR with an IC(50) approximately 1.5 microM. High concentrations of dutasteride (10-50 microM), but not finasteride, in steroid-free medium, resulted in enhanced cell death, possibly by apoptosis. This was accompanied by loss of AR protein and decreased AR ligand-binding activity. Occupation of AR by R1881 partly protected against cell death and loss of AR protein. PC-3 prostate cancer cells, which do not contain AR, also were killed by high concentrations of dutasteride, as well as by 50 microM finasteride. CONCLUSIONS: Dutasteride exhibited some inhibitory actions in LNCaP cells possibly related to 5alphaR inhibition but also had antiandrogenic effects at relatively low concentrations and cell death-promoting effects at higher concentrations. Finasteride also was antiandrogenic, but less than dutasteride. The antiandrogenic effects may be mediated by the mutant LNCaP cell AR. Promotion of cell death by dutasteride can be blocked, but only in part, by androgens.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2000

New topical antiandrogenic formulations can stimulate hair growth in human bald scalp grafted onto mice.

The purpose of this study was to test the ability of topical formulations of finasteride and flutamide to re-enlarge hair follicles in male-pattern baldness. This was evaluated by an experimental model of human scalp skin graft transplanted onto SCID mice. A comparison was made between formulations containing finasteride and flutamide, and a vehicle formulation in terms of the mean hairs per graft, length, diameter of the shafts, and structures of the growth stages of the hair. Flutamide and finasteride had a significantly higher effect (P<0.05) than the placebo in all the tested parameters, but flutamide demonstrated more hair per graft and longer hair shafts than finasteride (P<0.05). The number of hairs per graft for flutamide and finasteride groups were 1.22+/-0. 47 and 0.88+/-0.95 hairs/0.5 mm2 graft, respectively, versus 0. 35+/-0.6 hairs/graft for vehicle-treated graft. Similarly, hair lengths for flutamide and finasteride were 5.82+/-0.50 and 4.50+/-0. 32 mm, respectively, versus 2.83+/-0.18 mm for the vehicle-treated grafts. An in vitro diffusion study of flutamide gel using hairless mouse skin demonstrated the beneficial effect of the vehicle composition in comparison with a hydroalcoholic solution or a gel containing no penetration enhancer. It is therefore suggested that this topical composition containing flutamide or finasteride may effectively result in regression of male-pattern baldness.

Administration, Topical↗
PubMed1997

Promoting effects and mechanisms of action of androgen in bladder carcinogenesis in male rats.

OBJECTIVE: It has been reported that blocking of testosterone production inhibits bladder carcinogenesis in various animal models. We investigated how testosterone acts on rat bladder carcinogenesis using an antiandrogen, flutamide, and a 5 alpha-reductase inhibitor, finasteride. METHODS: Experiment 1: we administered 0.05% BBN [N-butyl-N-(4-hydroxybutyl)nitrosamine] orally to 117 Wistar rats for 10 weeks, divided them into seven groups-control, surgical castration, finasteride (2 mg/kg), luteinizing hormone releasing hormone (LH-RH) agonist (1 mg/kg) flutamide (50 mg/kg), LH-RH agonist plus finasteride, and LH-RH agonist plus flutamide-, and then cystectomized them to investigate the incidence of bladder cancer on week 21; experiment 2: we administered 0.05% BBN to 154 Wistar rats for 7 weeks, divided them into seven groups-control, finasteride 2, 4, and 8 mg/kg, and flutamide 50, 100, and 200 mg/kg-, and then we cystectomized them to investigate the dose-dependent influence on bladder carcinogenesis of these drugs on week 20, and experiment 3: we investigated the presence of androgen receptors in rat and mouse normal bladder mucosa using a monoclonal antibody. RESULTS AND CONCLUSIONS: Experiment 1: Surgical castration and LH-RH agonist treatment significantly reduced the occurrence of carcinomas. There was no significant additive effect of coadministered finasteride or flutamide with LH-RH agonist. Finasteride or flutamide monotherapy showed no statistically significant effects on the results of experiment 1 at the doses used. Experiment 2: Flutamide showed a dose-dependent effect on reducing the number of rats with bladder cancer, and at a dosis of 200 mg/kg twice a week, the difference was statistically significant when compared with the control group, whereas finasteride had no statistically significant suppressing effect at any dose. Experiment 3: Mouse and rat bladder urothelium expressed the androgen receptor. Our results indicate that testosterone itself might have a more potent action on bladder carcinogenesis rather than its converting form, 5 alpha-dihydrotestosterone.

Administration, Oral↗
PubMed1995

Proscar: five-year experience.

We assessed the long-term safety and efficacy of finasteride, an orally active 5 alpha-reductase inhibitor, in 2 previously reported groups of patients with symptomatic benign prostatic hyperplasia (BPH). Prostate volume was measured by magnetic resonance imaging, and the maximum urinary flow rate was assessed noninvasively. Symptoms were scored utilizing a patient self-administered symptom score questionnaire. Total symptom scores ranged from 0 (or asymptomatic) to 35 (severely symptomatic). After an initial double-blind period, the patients in study 1 were treated with 10 mg finasteride for 1 year and then switched to 5 mg finasteride for an additional 4 years, whereas patients in study 2 were treated with 5 mg finasteride for the entire 5 years. A total of 190 patients were randomized in the double-blind studies, 156 entered year 1 of the open extension and 70 patients completed 5 years of finasteride therapy. In both studies prostate volume was reduced from baseline by 30%, dihydrotestosterone was reduced by 72%, and the maximum urinary flow rate improved by approximately 1.5 ml/s. Prostate-specific antigen was decreased by approximately 50%. Finasteride was well tolerated; approximately 10% of patients reported sexual adverse experiences during the 5-year study period, which were considered drug related by the investigators. The incidence in reporting sexual adverse experiences did not increase with the increased duration of treatment: findings consistent with previous reports. In summary treatment of BPH with finasteride for 5 years inhibits the progression of the disease with an excellent safety profile and represents a low-risk medical option for the treatment of symptomatic BPH.

Aged↗
PubMed2005

Assessing benefit and risk in the prevention of prostate cancer: the prostate cancer prevention trial revisited.

PURPOSE: The Prostate Cancer Prevention Trial demonstrated a 25% reduction in period prevalence of prostate cancer in men randomly assigned to 5 mg/d of finasteride. However, widespread use of finasteride for prevention is inhibited by the observed increased risk of high-grade disease. We present a model of risk and benefit that estimates the potential effects of histologic artifact in the assignment of excess risk for high-grade disease and the possible effect of overdetection bias introduced by finasteride-induced volume reduction. METHODS: The absolute benefit/absolute risk ratio of finasteride use was estimated by calculating the ratio of absolute risk reduction in the finasteride arm to the absolute risk of excess high-grade cancers. This ratio was recalculated for assumptions that 10%, 25%, or 50% of the excess high-grade cancers were due to histologic artifact, and that there was a 25% overdetection bias in the finasteride arm. RESULTS: For all cancers the absolute benefit/absolute risk ratio increased from 4.6:1 to 5.1:1, 6.2:1, and 9.2:1 for assumptions of 10%, 25%, or 50% histologic artifact, respectively. The ratio increased from 4.6:1 to 8.2:1 for the assumption of 25% overdetection bias, and to 9.1:1, 10.9:1, and 16.3:1 for combined assumptions of 25% overdetection bias and 10%, 25%, or 50% histologic artifact, respectively. CONCLUSION: The adoption of a prevention strategy hinges on potential benefits weighed against potential risks. This model demonstrates the magnitude of effect for a hypothesized range of histologic artifact and overdetection bias on the assessment of risk versus benefit for finasteride.

Adenocarcinoma↗
PubMed1997

MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen.

Two isozymes (types 1 and 2) of 5alpha-reductase (5alphaR; EC 1.3.99.5), with differential tissue distribution, catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT) in humans. This study examined sequentially increasing oral doses of MK-386 (4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one), an azasteroid that specifically inhibits the human 5alphaR1 isozyme in vitro. Finasteride, a selective inhibitor of 5alphaR2, was included for comparison. One hundred men were evaluated in a double blind, randomized, placebo-controlled, sequential, increasing dose, parallel group trial. Ten to 20 subjects received MK-386, and 2 to 5 received placebo in each of 6 panels. In 1 panel, 10 subjects received finasteride (5 mg), and 5 received placebo. Treatments were given once daily for 14 days, except in 1 panel in which MK-386 was administered 10 mg twice daily for comparison to 20 mg daily. Serum, sebum, and semen DHT concentrations and serum and sebum T concentrations were measured before and after treatment. The mean changes from baseline on day 14 for serum DHT after placebo and 0.1, 0.5, 5, 20, and 50 mg MK-386 were 6.9%, 4.6%, -2.7%, -1.2%, -14.1% (P < 0.05 vs. placebo), and -22.2% (P < 0.05 vs. placebo), respectively. No significant alterations in serum T were observed after any dose of MK-386. Serum DHT fell 65.8% from the baseline 14 days after finasteride treatment (P < 0.05 vs. placebo). The mean changes from baseline on day 14 in sebum DHT were 5.0%, 3.0%, -25.4% (P < 0.05 vs. placebo), -30.1% (P < 0.05 vs. placebo), and -49.1% (P < 0.05 vs. placebo) for the placebo and 0.5, 5, 20, and 50 mg MK-386 groups, respectively. Finasteride also reduced sebum DHT, but to a lesser extent (- 14.9%; P < 0.05 vs. placebo). Reciprocal increases in sebum T concentration were noted at doses of 5 mg or more of MK-386, but not with finasteride. The mean reduction in semen DHT with 5 mg finasteride was approximately 88% (P < 0.01 vs. placebo); no significant change in semen DHT was noted with 20 or 50 mg MK-386. Serum 3alpha-androstanediol glucuronide values were also reduced after the 20- and 50-mg MK-386 treatments in parallel with the changes in serum DHT. No meaningful changes were observed in serum LH after MK-386 treatment. MK-386 was generally well tolerated by all subjects; reversible aspartate aminotransferase/alanine aminotransferase elevations were observed in two subjects at the 50-mg dose. The differential responses in serum, sebum, and semen DHT concentrations associated with MK-386 and finasteride treatments are consistent with those changes anticipated for selective inhibitors of the human 5alphaR isozymes. Dose-dependent suppression of sebum DHT by a 5alphaR1 inhibitor suggests the potential utility of such compounds in the treatment of acne.

5-alpha Reductase Inhibitors↗
PubMed2001

Inhibiting progesterone metabolism in the hippocampus of rats in behavioral estrus decreases anxiolytic behaviors and enhances exploratory and antinociceptive behaviors.

Blocking progesterone's metabolism to 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP) with finasteride, a 5 alpha-reductase inhibitor, and effects on anxiolytic, exploratory, and antinociceptive behaviors of rats in behavioral estrus were examined. Rats in behavioral estrus received finasteride systemically (SC), to the hippocampus, or to control implant sites, the nucleus accumbens (NA) or ventral tegmental area (VTA), and were tested in horizontal crossing, open-field, elevated plus-maze, emergence, holeboard, social interaction, tailflick, pawlick, and defensive freezing tasks. Finasteride, SC or intrahippocampally, reduced 3 alpha,5 alpha-THP in the hippocampus relative to vehicle implants or finasteride to the NA or VTA. Systemic or intrahippocampal finasteride decreased central entries in the open field and open-arm time on the elevated plus-maze and increased freezing in response to shock relative to vehicle. Finasteride to the hippocampus decreased emergence latencies and increased social interaction, pawlick, and tailflick latencies relative to all other groups. Finasteride to the hippocampus of rats in behavioral estrous decreased anxiolysis and enhanced exploration and analgesia. In summary, these data demonstrate that decreases in anxiolytic behavior of behavioral estrous rats can be produced by reductions in 3 alpha,5 alpha-THP in the hippocampus, which suggest that elevations in 3 alpha,5 alpha-THP in the hippocampus may give rise to anxiolysis seen during behavioral estrus.

Animals↗
PubMed1998

Combination medical therapy for symptomatic benign prostatic hyperplasia.

PURPOSE: The purpose of this study was to evaluate treatment response to terazosin, finasteride, or a combination of both in men with symptomatic benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Patients with BPH were consecutively enrolled from a clinical urology practice. International Prostate Symptom Score (IPSS), peak urinary flow rate, and prostate volume were assessed at baseline and every 2 months for 12 months. Detrusor pressure at maximum flow was assessed at baseline, 4 and 12 months. Patients were randomized into 1 of 3 treatment groups - terazosin alone, finasteride alone, or combination therapy. RESULTS: At 12 months, symptom scores had decreased significantly in all 3 treatment groups (p<0.05). Combination therapy resulted in significantly greater reductions in IPSS than terazosin or finasteride (6.4, 4.9, 4.1 points, respectively, p<0.05) There were significant increases in peak urinary flow rate within each treatment group, although there were no significant changes between groups. Detrusor pressure also significantly decreased from baseline within each treatment group. Patients treated with combination therapy had a significantly greater mean decrease in detrusor pressure after 12 months when compared with finasteride-treated patients (16.7 versus 10.5 cm H20, p<0.03). There were no significant differences between terazosin and combination therapy or between terazosin and finasteride despite the relatively greater decrease in detrusor pressure seen in the terazosin group when compared with the finasteride group. CONCLUSIONS: Combination medical therapy with finasteride and terazosin provides greater symptom relief than monotherapy in men with BPH.

Journal Article↗
PubMedDate not supplied

The person-years saved model and other methodologies for assessing the population impact of cancer-prevention strategies.

The results of the Prostate Cancer Prevention Trial spurred debate because finasteride was found to reduce the period prevalence of prostate cancer by about 25% while also increasing the rate of high-grade prostate cancers. Assessing how finasteride would impact mortality at the population level is key to evaluating the public health implications of these results. Any model for evaluating the impact of chemoprevention at the population level will involve methods for assigning weights to competing outcomes of the chemoprevention. The person-years saved model, which uses survival to weigh outcomes, assesses the impact on population mortality and has particular strengths. The person-years saved model shows that more than 300,000 person-years would be saved during a period of 10 years with the widespread use of finasteride, assuming no change in the rate of high-grade prostate cancers. The rate of high-grade prostate cancers in the population, about 20% in any given year, would have to nearly triple to 60% for the net positive impact of finasteride to be zero. The person-years saved model shows that the administration of finasteride is likely to result in a net positive impact of finasteride on population mortality, even with an increase in the rate of high-grade prostate cancers. Future models may use other outcomes to assess population impact, including economic, quality-of-life, or various combinations of outcomes.

Chemoprevention↗
PubMed2005

The effects of 5alpha-reductase inhibitors on the natural history, detection and grading of prostate cancer: current state of knowledge.

PURPOSE: The Prostate Cancer Prevention Trial (PCPT) showed that the 5alpha-reductase inhibitor (5ARI) finasteride significantly decreased the 7-year period prevalence of prostate cancer vs placebo. However, Gleason score 7-10 tumors were significantly more common in the finasteride vs the placebo group. We considered data on the effects of 5ARIs on prostate cancer natural history and detection. MATERIALS AND METHODS: A detailed review was performed of the literature identified from the MEDLINE database examining the effects of 5ARIs on prostate cancer prevalence and tumor histopathology. RESULTS: In PCPT there were fewer biopsies performed for cause in the finasteride vs the placebo group and the proportion of high grade tumors in the treatment groups did not diverge with time. Given that finasteride has an effect on prostate specific antigen and prostate volume, which are key factors in triggering prostate biopsies, they may be significant confounders of Gleason score results. Prostate shrinkage in the finasteride treated group may minimize biopsy sampling error. Furthermore, histological studies have shown that 5ARIs have a significant effect on prostate architecture, which can make the interpretation of prostate specimens in men treated with 5ARIs difficult. Further evaluation of PCPT findings will help determine the true nature of these observations. CONCLUSIONS: 5ARIs decrease the risk of prostate cancer but also alter the detection of disease through effects on prostate specific antigen, and prostate volume and histology. The weight of evidence suggests an artifactual effect of finasteride on Gleason grading in the PCPT. The role of 5ARIs for prostate cancer chemoprevention needs further examination before it can be considered for wide recommendation.

Antineoplastic Agents↗
PubMed2002

Comparative efficacy of various treatment regimens for androgenetic alopecia in men.

Our understanding of the aetiology of androgenetic alopecia (AGA) has substantially increased in recent years. As a result, several treatment modalities have been tried with promising results especially in early stages of AGA. However, as far as has been ascertained, there is no comprehensive study comparing the efficacy of these agents alone and in combination with each other. One hundered male patients with AGA of Hamilton grades II to IV were enrolled in an open, randomized, parallel-group study, designed to evaluate and compare the efficacy of oral finasteride (1 mg per day), topical 2% minoxidil solution and topical 2% ketoconazole shampoo alone and in combination. They were randomized into four groups. Group I (30 patients) was administered oral finasteride, Group II (36 patients) was given a combination of finasteride and topical minoxidil, Group III (24 patients) applied minoxidil alone and Group IV (10 patients) was administered finasteride with topical ketoconazole. Treatment efficacy was assessed on the basis of patient and physician assessment scores and global photographic review during the study period of one year. At the end of one year, hair growth was observed in all the groups with best results recorded with a combination of finasteride and minoxidil (Group II) followed by groups IV, I and III. Subjects receiving finasteride alone or in combination with minoxidil or ketoconazole showed statistically significant improvement (p<0.05) over minoxidil only recipients. No signifcant side-effects related to the drugs were observed. In conclusion, it is inferred that the therapeutic efficacy is enhanced by combining the two drugs acting on different aetiological aspects of AGA.

5-alpha Reductase Inhibitors↗
PubMed2005

Inhibiting biosynthesis and/or metabolism of progestins in the ventral tegmental area attenuates lordosis of rats in behavioural oestrus.

In the ventral tegmental area (VTA), lordosis of rats is facilitated by 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). Central 3alpha,5alpha-THP results from metabolism of peripheral progesterone, from the ovaries and/or adrenals, by sequential enzymatic activity of 5alpha-reductase and 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR). In addition, in glial cells, cholesterol is converted into pregnenolone by the P450 side-chain cleavage enzyme (P450scc), which is then metabolized to progesterone by 3beta-hydroxysteroid dehydrogenase, and subsequently reduced to 3alpha,5alpha-THP. We hypothesize that, in the VTA, formation of 3alpha,5alpha-THP by both metabolism and biosynthesis is necessary for facilitation of lordosis of female rats. In Experiment 1, naturally-receptive rats received bilateral VTA infusions of a P450scc inhibitor, digitoxin (1 microg/side); a 5alpha-reductase inhibitor, finasteride (10 microg/side); digitoxin (1 microg/side)+finasteride (10 microg/side); or vehicle and were tested 3 h later for lordosis. In Experiment 2, the effects of VTA infusions of digitoxin, finasteride, digitoxin+finasteride, or vehicle on lordosis and midbrain and plasma 3alpha,5alpha-THP levels were examined. In Experiment 3, we investigated whether infusions of 3alpha,5alpha-THP to the VTA reinstated lordosis and midbrain 3alpha,5alpha-THP levels following administration of inhibitors. VTA infusions of digitoxin, finasteride, or digitoxin+finasteride, significantly and similarly reduced lordosis and midbrain, but not plasma 3alpha,5alpha-THP levels, compared to vehicle. Following receipt of inhibitor infusions, 3alpha,5alpha-THP to the VTA restored lordosis and midbrain 3alpha,5alpha-THP levels. These data suggest that, in the VTA, both central biosynthesis of progesterone and metabolism of progesterone (from central and/or peripheral sources) to 3alpha,5alpha-THP are important for mediating lordosis of rats.

Animals↗
PubMed1995

Differential suppression of serum prostatic acid phosphatase and prostate-specific antigen by 5-alpha-reductase inhibitor.

OBJECTIVE: To evaluate the effect of finasteride (Proscar) on the serum levels of prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) in patients with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Thirty patients on finasteride therapy for BPH formed the study group. Serum PSA and PAP levels were monitored for 2 years while the patients were receiving finasteride. RESULTS: During 12 months of finasteride therapy the serum PSA was suppressed but serum PAP was unaffected. The baseline mean PAP value was 1.303 ng/mL prior to finasteride therapy; this changed to 1.510 ng/mL (P = 0.195) at 6 months and 1.166 ng/mL (P = 0.383) at 12 months. The serum PSA was 2.630 ng/mL at baseline, 1.757 ng/mL (P < 0.001) at 6 months and 1.545 ng/mL (P = 0.001) at 12 months. CONCLUSIONS: Further studies are warranted to determine if PAP has a role as a tumour marker in patients whose PSA is suppressed as a result of finasteride therapy.

Acid Phosphatase↗
PubMed2006

The cost of prostate cancer chemoprevention: a decision analysis model.

BACKGROUND: The Prostate Cancer Prevention Trial found reduced prostate cancer prevalence for men treated with finasteride. The public health cost of wide-scale chemoprevention is unclear. We developed a model to help clarify the cost effectiveness of public use of prostate cancer-preventive agents. METHODS: A Markov decision analysis model was designed to determine the lifetime prostate health-related costs, beginning at the age of 50 years, for men treated with finasteride compared with placebo. Model assumptions were based on data from the Prostate Cancer Prevention Trial, a literature review of survival and progression rates for patients treated with radical prostatectomy, and costs associated with prostate cancer disease states. RESULTS: Chemoprevention with finasteride resulted in a gain of 8.7 [corrected] life years per 1,000 men at a cost of $1.107 million [corrected] per life year saved (LYS). However, if finasteride is assumed to not increase the incidence of high-grade tumors, it renders a gain of 16.9 [corrected] life years per 1,000 men at a cost of $578,400 [corrected] per LYS; finasteride must cost $160 per year [corrected] to reach $100,000 [corrected] per LYS. When applied to a population at higher risk (lifetime prevalence >or=40%) [corrected]for developing prostate cancer, the cost of finasteride must be reduced from its current cost ($62/month) to <$15/month [corrected]for the cost effectiveness to fall below $50,000 [corrected] per LYS. CONCLUSIONS: Given the natural history of treated prostate cancer, implementation of chemoprevention would require an inexpensive medication with substantial cancer risk reduction to be cost effective. Targeting populations at higher risk for developing prostate cancer, however, allows for considerable flexibility in the medication cost to make prostate cancer chemoprevention a more attainable goal.

Aged↗
PubMed2000

Medical treatment modalities for lower urinary tract symptoms: what are the relevant differences in randomised controlled trials?

OBJECTIVES: Relevant differences in efficacy and tolerability will be reviewed among medical treatment modalities for lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO). Available data on the long-term effectiveness of these treatments will be also discussed. METHODS: Information reviewed here comes mainly from published scientific articles and abstracts describing direct comparative trials among alpha1-adrenoceptor antagonists, finasteride, and/or phytotherapy. RESULTS: Direct comparative trials demonstrated alpha1-adrenoceptor antagonists to be more effective than finasteride in improving symptoms and increasing urinary flow. Moreover, finasteride did not perform better than placebo in those studies that included a placebo arm. While finasteride treatment appears more beneficial in patients with an enlarged prostate volume (>50 ml), the efficacy of alpha1-adrenoceptor antagonists is not related to prostate size. To study the efficacy of plant extracts, adequately performed placebo-controlled and direct comparative trials are needed. Medical treatment modalities generally have a low incidence of adverse events. Regarding long-term effectiveness of medical treatment, the few available data show that finasteride can reduce the risk of acute urinary retention (AUR) and surgery. Short-term, direct comparative studies suggest that, like finasteride, alpha1-adrenoceptor antagonists have a comparable positive effect on disease progression. CONCLUSION: More comparative information is needed on the long-term efficacy, tolerability, and effectiveness of medical treatments for LUTS. Information on disease progression (i.e., long-term complications related to BPO) and treatment outcomes (i.e., switch to other therapy or surgery) is necessary because such information directly effects a treatment's cost-effectiveness.

Finasteride↗