The PCAST report: impact and implications for the pharmaceutical industry.

The President's Council of Advisors on Science and Technology (PCAST) report sets out an ambitious goal: to double the output of innovative, new medicines with increased efficacy and safety within the next 10-15 years. If attainable, this could change the face of medicine and bring great benefit to society. Clear leadership, commitment to action, and unprecedented collaboration will be essential if the goal of the report is to be realized.

Long-term (7 to 8-year) experience with finasteride in men with benign prostatic hyperplasia.

OBJECTIVES: To evaluate the effects of finasteride, a specific type II 5-alpha-reductase inhibitor, on symptoms of benign prostatic hyperplasia, prostate volume, and urinary flow during a 7 to 8-year period. METHODS: A total of 190 men with symptomatic benign prostatic hyperplasia and enlarged prostates entered one of two Phase II double-blind 3 to 6-month studies. Of these, 156 patients continued taking open-label finasteride, and more than 70 patients completed 7 to 8 years of treatment. The symptoms were scored using a patient self-administered modified Boyarsky symptom questionnaire. Prostate volume was measured by magnetic resonance imaging or ultrasonography, and the maximal urinary flow rate was assessed noninvasively. RESULTS: Treatment with finasteride for 7 to 8 years led to sustained improvement in symptoms, reduction in prostate volume (28% from baseline), and increased urinary flow (median 2.5 mL/s from baseline). Decreases in dihydrotestosterone (86%) and prostate-specific antigen (54%) levels were also maintained. Long-term finasteride treatment was safe and generally well tolerated. CONCLUSIONS: Long-term treatment with finasteride was well tolerated and resulted in durable symptom relief and improvement in prostate volume and urinary flow.

Effects of statins on biomarkers of bone metabolism: a randomised trial.

BACKGROUND AND AIM: Recently, several studies have indicated there may be differences among statins regarding a possible association between therapy and a reduction in risk of fractures. No data from prospective randomised clinical trials designed to assess either biochemical or clinical effects on bone metabolism are yet available. We assayed levels of biochemical markers of bone formation in stored serum samples from a recently completed randomised clinical trial conducted to compare the effects of simvastatin and atorvastatin on the lipid profile of patients with hypercholesterolaemia. METHODS AND RESULTS: This 12-week, randomised, multicenter, open-label study was designed to compare the safety and lipid-lowering efficacy of simvastatin 40 mg or 80 mg with that of atorvastatin 20 mg or 40 mg in 846 hypercholesterolaemic patients. Stored serum samples from this study were analysed to compare the effects of simvastatin and atorvastatin on 2 biomarkers of bone turnover, bone-specific alkaline phosphatase (BSAP), a marker of bone formation, and C-teleopeptide of type 1 collagen (CTx), a marker of bone resorption. Treatment with simvastatin 40 and 80 mg/day, but not atorvastatin 20 and 40 mg/day, led to significant (p < 0.05) reductions in BSAP in both men (4.1-5.4% reduction) and women (4.2-7.4% reduction). In addition, there appeared to be a dose-dependent effect with greater reductions in BSAP seen with the 80 mg dose of simvastatin. Treatment with either 20 mg or 40 mg of atorvastatin had no significant effect on BSAP levels on the groups as a whole or in the gender-specific subgroups. CTx showed a small, but not statistically significant, decrease with simvastatin, again with an apparent dose-related trend. Atorvastatin treatment generally resulted in small, non significant increases in CTx. CONCLUSIONS: The present serum bone biomarker results show that treatment with simvastatin, but not atorvastatin, decreases BSAP and suggest that simvastatin may have a beneficial effect on bone turnover.

Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia.

OBJECTIVES: To compare the efficacy and safety of finasteride 5 mg in older (65 years old or older) versus younger (45 to younger than 65 years old) men with benign prostatic hyperplasia (BPH). METHODS: The Proscar Long-Term Efficacy and Safety Study (PLESS) was a 4-year, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of finasteride 5 mg in 3040 men 45 to 78 years old with symptomatic BPH, enlarged prostates, and no evidence of prostate cancer. The endpoints included urinary symptoms, prostate volume, occurrence of acute urinary retention and/or BPH-related surgery, and safety. RESULTS: In both age cohorts, finasteride treatment led to a 51% reduction (P <0.001) in the relative risk for acute urinary retention and/or BPH-related surgery, a significant (P <0.001) and durable improvement in symptom score, and a significant (P <0.001) and sustained reduction in prostate volume. Within each age cohort, no significant differences were found between the placebo and finasteride-treated patients in the incidence of cardiovascular adverse events. Significant differences were evident between the placebo and finasteride groups in the incidence of the typical, known, drug-related adverse events, but no specific differences were associated with age. No drug interactions of clinical importance were observed in the finasteride-treated patients. CONCLUSIONS: The present analysis from PLESS demonstrates that in both older (65 years old or older) and younger men with symptomatic BPH and enlarged prostates, finasteride is highly effective in improving symptoms and reducing prostate volume in many men and in reducing the risk of acute urinary retention and BPH-related surgery. In addition, the safety profile of finasteride in both older and younger men is similar and no drug interactions of clinical importance were observed.

Androgen antagonists: Potential role in prostate cancer prevention.

This article summarizes discussions of the importance of androgens and androgen antagonists in the genesis of prostate cancer. These discussions occurred at a recent symposium on prostate cancer chemoprevention sponsored by the National Cancer Institute. Considerable information exists indicating the importance of androgens in the development of prostate cancer. Trials in breast cancer indicate that estrogen antagonists prevent breast cancer-suggesting, by analogy, that the blockade of androgen action might prevent the emergence of prostate cancer. The 5alpha-reductase inhibitors block the intracellular metabolism of testosterone and inhibit the growth of the prostate. Limited data suggest that 5alpha-reductase inhibitors reduces prostate-specific antigen in men with localized and advanced, primary or recurrent prostate cancer. An ongoing national trial of 18,000 men over 50 years of age has completed accrual and will evaluate whether a standard dose of finasteride will prevent the development of prostate cancer. The toxicity profile of finasteride (Proscar, Merck & Co., West Point, PA), the only approved 5alpha-reductase inhibitor, is favorable leading to its evaluation as a potential chemopreventive agent for prostate cancer. Anti-androgens such as bicalutamide (Casodex, AstraZeneca, Wilmington, DE) are active in the treatment of prostate cancer and comparable, in some trials, to testicular androgen suppression. These data suggest that antiandrogens may be active in the prevention of prostate cancer; however, the toxicity of antiandrogens (gynecomastia, gastrointestinal toxicity) poses concerns for application in prevention studies. Opportunities for study of factors predictive or associated with the development of prostate cancer and new agents that may interrupt this process offer numerous leads that may reduce the incidence of prostate cancer.

Prostate volume and serum prostate-specific antigen as predictors of acute urinary retention. Combined experience from three large multinational placebo-controlled trials.

OBJECTIVES: We evaluated prostate volume and prostate-specific antigen (PSA) as predictors of acute urinary retention (AUR) in men with benign prostatic enlargement (BPE). METHODS: Data were pooled from 3 identical 2-year, multinational, multicenter, non-US, placebo-controlled finasteride trials in 4,222 men with BPE and no evidence of prostate cancer. RESULTS: The 2-year incidence of spontaneous AUR was higher in placebo patients with enlarged prostates (4.2% in men with prostate volume > or =40 ml vs. 1.6% in the <40 ml group) and higher PSA levels (3.9% in men with PSA > or =1.4 ng/ml vs. 0.5% in the <1.4 ng/ml group) at baseline. Finasteride reduced AUR incidence by 61% in men with larger prostates, by 63% in men with higher PSA levels, and by 47% in men with smaller prostates, compared with placebo. CONCLUSIONS: BPE patients with larger prostate volumes, higher PSA levels and no evidence of prostate cancer have an increased risk of developing AUR and therefore derive the greatest benefit from the risk reduction seen with finasteride therapy.

Impact of baseline symptom severity on future risk of benign prostatic hyperplasia-related outcomes and long-term response to finasteride. The Pless Study Group.

OBJECTIVES: To evaluate the long-term effects of finasteride on symptoms, acute urinary retention (AUR), and the need for benign prostatic hyperplasia (BPH)-related surgery in relationship to baseline symptom severity. METHODS: A total of 3040 men with BPH were treated for 4 years with finasteride or placebo. The changes from baseline in symptoms and the incidence of BPH-related surgery and AUR were determined in men with mild (less than 8), low-moderate (8 to 12), high-moderate (13 to 19), and severe (greater than 19) baseline quasi-American Urological Association symptoms for all patients and for the subgroup with a baseline prostate-specific antigen (PSA) level of 1.4 ng/mL or greater. RESULTS: In patients who completed the 4-year study, the change in symptom score, stratified by baseline symptom severity, was +1.4 +/- 0.5 (mild), -0.8 +/- 0.3 (low-moderate), -3.6 +/- 0.3 (high-moderate), and -7.7 +/- 0.5 (severe) in finasteride-treated patients and, respectively, +3.4 +/- 0.5, +0.7 +/- 0.3, -1.4 +/- 0.3, and -5.3 +/- 0.6 in placebo-treated patients (between-group P <0.01). The between-group differences were greater in the subgroup of patients with a baseline PSA of 1.4 ng/mL or greater. The risk of BPH-related surgery increased among placebo patients with increasing baseline symptom severity to a greater extent than the risk of AUR. Finasteride reduced the risk of AUR or the need for BPH-related surgery in all subgroups (P <0.001), especially in men with a baseline PSA of 1.4 ng/mL or greater. CONCLUSIONS: Compared with placebo, finasteride had a beneficial effect on symptoms, AUR, and BPH-related surgery in all symptom categories. BPH-related surgery, but not AUR, occurred more commonly in placebo-treated men with more severe baseline symptoms. The greatest absolute benefit of finasteride on symptoms and the reduction in risk of AUR and surgery was in men with higher baseline symptom scores and a baseline PSA level of 1.4 ng/mL or greater.

Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia.

BACKGROUND: Finasteride, an inhibitor of type 2 5alpha-reductase, decreases serum and scalp dihydrotestosterone (DHT) by inhibiting conversion of testosterone to DHT and has been shown to be effective in men with androgenetic alopecia (AGA). The effects of finasteride in women with AGA have not been evaluated. OBJECTIVE: The purpose of this study was to evaluate the efficacy of finasteride in postmenopausal women with AGA. METHODS: In this 1-year, double-blind, placebo-controlled, randomized, multicenter trial, 137 postmenopausal women (41-60 years of age) with AGA received finasteride 1 mg/day or placebo. Efficacy was evaluated by scalp hair counts, patient and investigator assessments, assessment of global photographs by a blinded expert panel, and histologic analysis of scalp biopsy specimens. RESULTS: After 1 year of therapy, there was no significant difference in the change in hair count between the finasteride and placebo groups. Both treatment groups had significant decreases in hair count in the frontal/parietal (anterior/mid) scalp during the 1-year study period. Similarly, patient, investigator, and photographic assessments as well as scalp biopsy analysis did not demonstrate any improvement in slowing hair thinning, increasing hair growth, or improving the appearance of the hair in finasteride-treated subjects compared with the placebo group. Finasteride was generally well tolerated. CONCLUSION: In postmenopausal women with AGA, finasteride 1 mg/day taken for 12 months did not not increase hair growth or slow the progression of hair thinning.

Urinary retention in patients with BPH treated with finasteride or placebo over 4 years. Characterization of patients and ultimate outcomes. The PLESS Study Group.

OBJECTIVES: Knowledge regarding the incidence and prevalence of acute urinary retention and the ultimate outcome is very limited. The purpose of the present analysis was to document the natural history and outcomes of acute urinary retention (AUR) further specified as being either precipitated or spontaneous, and to evaluate the potential benefit of finasteride therapy. MATERIALS AND METHODS: Three thousand and forty men with moderate to severe symptoms of BPH and enlarged prostate glands by digital rectal examination were enrolled into the 4-year placebo-controlled PLESS trial and were evaluated for occurrences of AUR and BPH-related surgery. Men in the study were seen every 4 months; discontinued patients were followed up 6 months after discontinuation and again at the end of the 4-year trial. Complete 4-year data on outcomes (occurrence of AUR or BPH-related surgery) was available for 92% of the enrolled subjects in each treatment group. An endpoint committee, blinded to treatment group and center, reviewed and categorized all study-related documentation relating to retention and surgery. RESULTS: Over the 4-year period, 99 of 1,503 placebo-treated patients (6.6%) experienced one or more episodes of AUR in comparison with 42 or 1,513 finasteride-treated patients (2.8%; p<0. 001). Approximately half of the episodes of retention were spontaneous and clearly BPH-related, while the other episodes were precipitated by another factor (PAUR). After spontaneous AUR, subsequent surgery was performed in 39 of 52 (75%) placebo-treated patients versus 8 of 20 (40%) finasteride-treated patients (p = 0. 01). BPH-related surgery was less common in men who had a prior episode of PAUR (26% in the placebo group and 14% in the finasteride group). CONCLUSION: There is a continual risk of spontaneous and precipitated acute urinary retention in men with moderate to severe lower urinary tract symptoms and an enlarged prostate gland. Fewer patients who developed precipitated AUR than spontaneous AUR go on to need subsequent BPH-related surgery. Significantly fewer finasteride-than placebo-treated patients developed AUR, and among those men, fewer ultimately needed BPH-related surgery.

Development of a health-related quality of life questionnaire for women with androgenetic alopecia.

Despite the negative effects of androgenetic alopecia (AGA), no standardized health-related quality of life (HRQOL) questionnaire which is both specific to women and suitable for use in clinical trials currently exists. A questionnaire to assess HRQOL in women with AGA, the Women's Androgenetic Alopecia Quality of Life Questionnaire (WAA-QOL), was recently developed. Aspects of life affected by AGA were generated from literature review, discussion with experts, and a focus group. The number of issues identified was reduced based on importance and relevance to women with AGA. A questionnaire was then constructed and pilot-tested for comprehension. The resulting 25-item instrument was later included in a double-blind, placebo-controlled clinical trial of finasteride 1 mg for the treatment of hair thinning in postmenopausal women (n = 137). Based on test characteristics, several questions were eliminated, resulting in a 16-item questionnaire. The WAA-QOL exhibited excellent test-retest reliability overall (intraclass correlation coefficient = 0.89), and for individual items (kappa = 0.66-0.85), as well as high internal consistency (Crohnbach's alpha = 0.98). Responsiveness of the questionnaire could not be assessed. The WAA-QOL is self-completed in about 10 min, exhibits good content validity, internal consistency, and test-retest reliability, and may be useful in assessing the impact of female AGA on HRQOL or in evaluating therapeutic effects in clinical trials.

Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR long-term efficacy and safety study.

PURPOSE: We analyze patterns of prostate growth in men diagnosed with benign prostatic hyperplasia (BPH) and treated with placebo during 4 years, and determine which baseline parameters were the strongest predictors of growth. MATERIALS AND METHODS: A total of 3,040 men were enrolled in the 4-year randomized, placebo controlled Proscar Long-Term Efficacy and Safety study. Of these men a subgroup of 10% underwent pelvic magnetic resonance imaging prostate volume measurement at baseline and yearly thereafter. Absolute and percent volume changes during 4 years were calculated in the 164 placebo treated men in the subgroup. The ability of age, baseline prostate volume and prostate specific antigen (PSA) to predict prostate growth in placebo treated patients was assessed by multiple linear regression analyses, receiver operator characteristics curves, and evaluations of growth stratified by tertiles of baseline serum PSA and decades of life. RESULTS: In placebo treated patients a steady increase in mean plus or minus standard deviation prostate volume from year to year was noted (2.5+/-6.1, 4.9+/-6.8, 6.4+/-8.5 and 7.2+/-8.8 ml. at years 1, 2, 3 and 4, respectively). Mean volume changes at 4 years ranged from -9 to +30 ml. Mean percent change from baseline ranged from 12.5% to 16.6% for men 50 to 59 years old to those 70 to 79 years old. Baseline serum PSA was a strong predictor of growth with 7.4% to 22.0% change at 4 years from the lowest to highest PSA tertiles. Annualized growth rates from baseline were 0.7 ml. per year for PSA 0.2 to 1.3, 2.1 for PSA 1.4 to 3.2 and 3.3 for PSA 3.3 to 9.9 ng./ml. Multiple linear regression analysis showed that serum PSA was a stronger predictor of prostate growth than age or baseline prostate volume. All but 1 man with baseline serum PSA greater than 2.0 ng./ml. had prostate growth during 4 years, and 32.6% of men with serum PSA less than 2.0 exhibited a decrease in volume. CONCLUSIONS: Serum PSA is a stronger predictor of growth of the prostate in placebo treated patients than age or baseline prostate volume. Since prostate volume is a risk factor for acute urinary retention and the need for BPH related surgery, the ability of PSA to predict prostate growth may be an important factor when considering individual treatment options for BPH. Such use of PSA represents a shift in paradigm away from focusing solely on symptoms of BPH toward a more comprehensive approach with consideration of predicting and preventing risk factors of BPH related outcomes.

Patient-perceived importance of negative effects of androgenetic alopecia in women.

Despite the prevalence of androgenetic alopecia (AGA) and the acceptance of its associated psychological factors in women, few studies have directly queried women about which specific aspects of their lives are affected by hair thinning and the relative importance of such effects. Perceptions of such negative effects can influence patient satisfaction, health-related quality of life (HRQL) and the impetus to seek medical attention for hair loss. Women (n = 120) aged 22-66 years with at least mild (Ludwig I) AGA were recruited from two dermatology clinics and from a large worksite and asked to complete a questionnaire. The questionnaire solicited information about specific aspects of their lives potentially affected by AGA and the relative importance of those aspects. Inability to style their hair, dissatisfaction with their appearance, concern about hair loss continuing, and concern about others noticing their hair loss were most important to women. Emotional aspects also ranked high, including self-consciousness, jealousy, embarrassment, and feeling powerless to stop their hair loss. In summary, women with AGA report numerous ways in which their hair thinning affects their lives. Knowledge of these effects may be beneficial in counseling such patients and in designing clinical trials or epidemiological studies to evaluate hair loss in women.

Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group.

OBJECTIVES: To determine whether baseline prostate-specific antigen (PSA), in addition to prostate volume, is associated with long-term changes in symptoms and urinary flow rate. METHODS: Three thousand forty men with benign prostatic hyperplasia enrolled in the PLESS trial were randomly assigned to finasteride 5 mg or placebo for 4 years. Symptoms and flow rate were assessed every 4 months, and data were analyzed by dividing the patients into three groups by baseline PSA tertiles (0 to 1.3, 1.4 to 3.2, and 3.3 ng/mL or greater) and baseline prostate volume tertiles (14 to 41, 42 to 57, and 58 to 1 50 mL). RESULTS: After the initial placebo effect, a slow deterioration in symptoms over time was observed in the placebo-treated men with a baseline PSA 1.4 ng/mL or greater. However, placebo-treated men in the lowest PSA tertile (less than 1.4 ng/mL) had sustained symptomatic improvement that was not seen in placebo-treated men in the higher tertiles (P<0.001). In all finasteride-treated groups, there was initial improvement followed by maintenance or continued symptom improvement over time (approximately 3 to 3.5 points by the end of 4 years). The differences in symptom score improvement between placebo and finasteride were marginal for men with baseline PSA levels less than 1.4 ng/mL (P = 0.128) but were highly significant for men with PSA levels 1.4 ng/mL or greater (P<0.001). Urinary flow rate results were similar to those observed for symptoms. Analysis of symptom and flow rate data by prostate volume tertiles in a 10% subset of men yielded similar results, namely a deterioration of symptoms and flow rate in the two higher tertiles treated with placebo (greater than 41 mL) and a sustained improvement in all three groups of finasteride-treated patients. CONCLUSIONS: Baseline PSA and prostate volume are good predictors of long-term symptomatic and flow rate changes. Baseline PSA levels of 1.4 ng/mL or greater and enlarged prostate glands predict the best long-term response to finasteride compared with placebo.

Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia. PLESS Study Group. Proscar Long-term Efficacy and Safety Study.

OBJECTIVES: To investigate the long-term effects of finasteride on bother and health-related quality of life (HRQOL) in men with symptomatic benign prostatic hyperplasia. METHODS: A large prospective 4-year placebo-controlled trial (PLESS) of 3040 men with moderate to severe lower urinary tract symptoms and an enlarged prostate was performed that included self-administered questionnaires assessing HRQOL. RESULTS: Significantly greater reductions in bother score were seen for finasteride compared with placebo at every time point after 4 months. Analysis of bother scores by baseline serum prostate-specific antigen (PSA), as it is highly correlated with prostate volume, suggested greater differences from placebo for men with PSA 1.4 ng/mL or greater, primarily due to worsening after the first-year improvement in the placebo group. An activity interference domain score was significantly improved for finasteride over placebo at each time point (P<0.01), with greater treatment differences in men with higher baseline PSA levels. Comparable results were seen for worry at each time point and embarrassment due to urinary symptoms in the last 2 years of the trial. Mean changes in sexual interest and satisfaction were somewhat better for the placebo group overall, as has been previously reported, but little difference between treatments was found in sexual satisfaction measures for men with PSA 1.4 ng/mL or greater. CONCLUSIONS: Compared with placebo, men receiving finasteride had significantly less bother, activity interference, and worry due to urinary symptoms, with more pronounced differences for men with baseline PSA 1.4 ng/mL or greater. As expected, sexual satisfaction and sexual drive were slightly worse for finasteride overall, but little difference in sexual satisfaction measures was found for men with a higher baseline PSA. Thus, HRQOL was improved for finasteride compared with placebo, especially for men with a baseline PSA 1.4 ng/mL or greater.

The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia.

BACKGROUND: Data suggest that androgenetic alopecia is a process dependent on dihydrotestosterone (DHT) and type 2 5alpha-reductase. Finasteride is a type 2 5alpha-reductase inhibitor that has been shown to slow further hair loss and improve hair growth in men with androgenetic alopecia. OBJECTIVE: We attempted to determine the effect of finasteride on scalp skin and serum androgens. METHODS: Men with androgenetic alopecia (N = 249) underwent scalp biopsies before and after receiving 0.01, 0.05, 0.2, 1, or 5 mg daily of finasteride or placebo for 42 days. RESULTS: Scalp skin DHT levels declined significantly by 13.0% with placebo and by 14.9%, 61.6%, 56. 5%, 64.1%, and 69.4% with 0.01, 0.05, 0.2, 1, and 5 mg doses of finasteride, respectively. Serum DHT levels declined significantly (P <.001) by 49.5%, 68.6%, 71.4%, and 72.2% in the 0.05, 0.2, 1, and 5 mg finasteride treatment groups, respectively. CONCLUSION: In this study, doses of finasteride as low as 0.2 mg per day maximally decreased both scalp skin and serum DHT levels. These data support the rationale used to conduct clinical trials in men with male pattern hair loss at doses of finasteride between 0.2 and 5 mg.

Finasteride in the treatment of men with frontal male pattern hair loss.

BACKGROUND: Finasteride, a specific inhibitor of type II 5alpha-reductase, decreases serum and scalp dihydrotestosterone and has been shown to be effective in men with vertex male pattern hair loss. OBJECTIVE: This study evaluated the efficacy of finasteride 1 mg/day in men with frontal (anterior/mid) scalp hair thinning. METHODS: This was a 1-year, double-blind, placebo-controlled study followed by a 1-year open extension. Efficacy was assessed by hair counts (1 cm2 circular area), patient and investigator assessments, and global photographic review. RESULTS: There was a significant increase in hair count in the frontal scalp of finasteride-treated patients (P < .001), as well as significant improvements in patient, investigator, and global photographic assessments. Efficacy was maintained or improved throughout the second year of the study. Finasteride was generally well tolerated. CONCLUSION: In men with hair loss in the anterior/mid area of the scalp, finasteride 1 mg/day slowed hair loss and increased hair growth.

Does long-term finasteride therapy affect the histologic features of benign prostatic tissue and prostate cancer on needle biopsy? PLESS Study Group. Proscar Long-Term Efficacy and Safety Study.

OBJECTIVES: Finasteride, a common agent used to treat benign prostatic hyperplasia (BPH), inhibits 5-alpha-reductase. Testosterone is converted by 5-alpha-reductase to the more potent dihydrotestosterone, which is the primary androgen in the prostate. Leuprolide is a stronger antiandrogen that is used to downstage prostate cancer before radical prostatectomy. Leuprolide induces marked atrophy of prostate carcinoma cells, which sometimes makes pathologic diagnosis of cancer difficult, although evaluation at radical prostatectomy is easier than at biopsy. It is unknown whether finasteride produces similar changes, which would result in greater diagnostic difficulty because such changes would be seen on biopsy to rule out cancer in men with suspicious clinical findings treated for BPH. The current study investigated the histologic effects of finasteride therapy on human prostate cancer and benign prostatic tissue on needle biopsy. METHODS: In blinded manner, we reviewed 53 needle biopsy specimens showing prostate carcinoma (35 treated with finasteride, 18 with placebo). Also reviewed in blinded manner were 50 benign needle biopsy specimens (25 treated with finasteride, 25 with placebo). The Gleason score, number of cores involved, percentage cancer involvement in a core, percentage of atrophic changes in cancer cells, presence of mitoses, blue-tinged mucinous secretions, prominent nucleoli, and high-grade prostatic intraepithelial neoplasia were documented for each case in the cancer group. The percentage of atrophy, basal cell hyperplasia, transitional metaplasia, chronic inflammation, and stromal proliferation was documented for each case in the benign group. RESULTS: No significant histologic differences were present in either the benign or cancer group between cases treated with finasteride and placebo. CONCLUSIONS: We conclude that finasteride treatment for BPH does not cause difficulty in the diagnosis of cancer in prostate needle specimens. It is possible that there are severely atrophic areas resulting from finasteride treatment that are undersampled. However, the conclusion that cancer seen on needle biopsy in men treated with finasteride is unaltered and readily identified as cancer remains valid.

Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group.

OBJECTIVES: Prostate-specific antigen (PSA) is produced exclusively in the prostate gland and is currently the most useful clinical marker for the detection of prostate cancer. In this report, we examine whether serum PSA is also a predictor of important benign prostatic hyperplasia (BPH)-related outcomes, acute urinary retention (AUR), and the need for BPH-related surgery. METHODS: Three thousand forty men were treated with either placebo or finasteride in a double-blind, randomized study of 4-year duration. Serum PSA was measured at baseline, and baseline prostate volume was measured in a 10% subset of 312 men. Probabilities and cumulative incidences of AUR and BPH-related surgery, as well as reduction in risk of events with finasteride, were calculated for the entire patient population, stratified by treatment assignment, baseline serum PSA, and prostate volume. RESULTS: The risk of either needing BPH-related surgery or developing AUR ranged from 8.9% to 22.0% during the 4 years in placebo-treated patients stratified by increasing prostate volume and from 7.8% to 19.9% when stratified by increasing serum PSA. In comparison with symptom scores, flow rates, and residual urine volume, receiver operating characteristic curve analyses showed that serum PSA and prostate volume were the most powerful predictors of spontaneous AUR in placebo-treated patients (area under the curve 0.70 and 0.81, respectively). Finasteride treatment reduced the relative risk of needing surgery or developing AUR by 50% to 74% and by 43% to 60% when stratified by increasing prostate volume and serum PSA, respectively. CONCLUSIONS: Serum PSA and prostate volume are powerful predictors of the risk of AUR and the need for BPH-related surgery in men with BPH. Knowledge of baseline serum PSA and/or prostate volume are useful tools to aid physicians and decision makers in predicting the risk of BPH-related outcomes and choosing therapy for BPH.

Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia.

OBJECTIVES: To assess the utility of prostate-specific antigen (PSA) as a predictor of prostate volume by characterizing the relationship between prostate volume and serum PSA in men with symptomatic benign prostatic hyperplasia (BPH) and no evidence of prostate cancer, stratified by decade of life. METHODS: Placebo-controlled multicenter trials in patients with BPH and a safety study in normal young men provided baseline measurements of serum PSA and prostate volume. The analyses included patients with a baseline prostate volume measured by either transrectal ultrasound (TRUS) or magnetic resonance imaging and baseline serum PSA. A common central laboratory was used for all but one of the individual studies; both laboratories used the Hybritech method. Patients 80 years of age or older were excluded. Patients with a baseline serum PSA greater than 10 ng/mL were excluded to reduce the likelihood of including occult prostate cancer cases. The patients in the BPH trials were screened at baseline by digital rectal examination (DRE) and serum PSA. Those with suspicious findings underwent TRUS-guided biopsy; only patients with negative biopsies are included in these analyses. RESULTS: The analyses included 4627 patients, 4448 from the BPH trials and 179 from the safety study. The men in the BPH trials were older (mean age+SE, 63.7+0.10 years) than the men in the safety study (mean age + SE, 30.8+/-0.43), had larger prostates (mean volume+/-SE, 43.7+/-0.38 mL versus 26.3+/-0.49 mL in the safety study), and had higher serum PSA values (mean+/-SE, 2.6+/-0.03 ng/mL versus 0.7+/-0.39 ng/mL in the safety study). The relationship between prostate volume and serum PSA was evaluated using only the BPH trial data. Prostate volume and serum PSA have an age-dependent log-linear relationship (ie, their logarithms are linearly related, and the parameters of the relationship depend on age). Older men tend to have a steeper rate of increase in prostate volume with increasing serum PSA (P < 0.00 for differences between slopes), and there was a slight tendency for PSA density to increase with age. Receiver operating characteristic (ROC) curves were constructed to evaluate the ability of serum PSA to predict threshold prostate sizes in men with BPH. The ROC curve analyses revealed that PSA had good predictive value for assessing prostate volume, with areas under the curve ranging from 0.76 to 0.78 for various prostate volume cutoff points (30, 40, and 50 mL). Conclusions. Prostate volume is strongly related to serum PSA in men with BPH and no evidence of prostate cancer, and the relationship depends on age. Since treatment outcome or risk of long-term complications depend on baseline prostate volume, serum PSA can estimate the degree of prostate enlargement sufficiently accurately to be useful for therapeutic decision making. To achieve a specificity of 70% while maintaining a sensitivity between 65% and 70%, approximate age-specific criteria for detecting men with prostate glands exceeding 40 mL are PSA > 1.6 ng/mL, >2.0 ng/mL, and >2.3 ng/mL for men with BPH in their 50s, 60s, and 70s, respectively.

Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizontal sections of serial scalp biopsies: results of finasteride 1 mg treatment of men and postmenopausal women.

Hair regrowth was evaluated by histologic analysis in men and women treated for androgenetic alopecia, by counting follicles in horizontal sections of scalp biopsies. Serial 4mm punch biopsies were taken at baseline and after 12mo of treatment from the transitional area of hair thinning between normal hair and vertex balding in men, and in an area of frontal/parietal thinning in women. Horizontal sections of reticular and papillary dermis were read by one observer, blinded to patient, treatment, and time. All terminal hair bulbs, terminal anagen and telogen hairs, and vellus and vellus-like miniaturized hairs were counted. Twenty-six men aged 18-41y, comprising 14 on finasteride 1 mg daily and 12 on placebo, and 94 postmenopausal women, aged 41-60y, comprising 44 on finasteride 1 mg daily and 50 on placebo, were evaluated. In the male study, the terminal hairs increased from a mean baseline count of 15.5-20.9 after 12mo of finasteride, versus 17.3-18.3 in the placebo patients. The miniaturized hairs decreased from 26.7 to 23.6 with finasteride versus 21.3-20.3 with placebo. The terminal-to-vellus ratio increased more in the finasteride than in the placebo patients, suggesting some reversal of the miniaturization process with finasteride. In the female study, no significant differences in follicular counts were found between the finasteride and placebo groups after 12mo of treatment. Follicular counts in horizontal sections provide an informative adjunct to noninvasive measures used in hair growth studies. Finasteride appears to be capable of reversing hair miniaturization in androgenetic alopecia in young to middle-aged men, but not in postmenopausal women.