Joanne Waldstreicher’s research while affiliated with Pennsylvania State University and other places

We determined the effect of long-term treatment with finasteride on the incidence of acute urinary retention (AUR) and benign prostatic hyperplasia (BPH) related surgery in men with BPH. The Proscar (Merck and Co., Inc., Whitehouse Station, New Jersey) Long-Term Efficacy and Safety Study (PLESS) was comprised of 3040 men with enlarged prostates, moderate to severe symptomatic BPH and no clinical evidence of prostate cancer. Patients were randomized to placebo or 5 mg finasteride daily for 4 years. Of the 3016 randomized patients with available efficacy data 62% completed the original 4-year study (1006 on finasteride and 891 on placebo) and 89% of these (908 from the original finasteride arm and 785 from the placebo arm) continued in a 2-year open extension on finasteride. Followup was attempted in discontinued patients. Complete 6-year outcomes data, including 6-year followup in 770 men who had discontinued treatment during years 1 to 6, were available for 2463 (82%) of the 3016 originally randomized patients. For patients on continuous finasteride treatment the decrease in incidence of AUR and/or BPH related surgery in the 4-year base study was sustained during the open extension. In patients who were switched from placebo to finasteride in the extension, the incidence of AUR and/or BPH related surgery was similar to that in the continuous finasteride arm. The 6-year data from PLESS confirmed and further extended the findings from the original 4-year trial, demonstrating that finasteride treatment led to a sustained decrease in the incidence of AUR and/or BPH related surgery in men with BPH and enlarged prostates.

Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.

To examine the effect of finasteride on serum testosterone in men with benign prostatic hyperplasia (BPH). The Proscar Long-Term Efficacy and Safety Study (PLESS) was a 4-year trial comparing the safety and efficacy of finasteride 5 mg with placebo in 3040 men with moderate to severe symptomatic BPH and enlarged prostates. PLESS included the prospective measurement of annual serum testosterone in a randomly selected subset of patients comprising approximately 10% of the randomized population (n = 301). Finasteride treatment led to a modest, but significant (P <0.001), increase relative to placebo in serum testosterone, with this increase greatest in patients who had low baseline testosterone levels. The larger testosterone increases seen in finasteride-treated patients in the lower baseline testosterone tertiles were associated with significant mean reductions relative to placebo at year 4 in body mass index (BMI), ranging from 0.6 to 0.8 kg/m2. No statistically significant between-group difference was found in BMI in the upper testosterone tertile. The sexual adverse experience profiles for finasteride and placebo were similar across the baseline testosterone cohorts examined. Finasteride treatment led to a generally modest increase relative to placebo in serum testosterone, with the greatest increases occurring in men with low baseline testosterone levels. The physiologic significance of these changes in men with low baseline testosterone levels is unclear, but the associated reduction in BMI is intriguing and may be related, because BMI is known to be negatively correlated with serum testosterone levels in men.

To summarize the 6-year clinical trial data with finasteride. Benign prostatic hyperplasia is a chronic and progressive disease and therefore assessment of long-term safety and efficacy is important. The North American and International Phase III Finasteride trials enrolled symptomatic men with enlarged prostate glands. The initial 1-year placebo-controlled study was followed by a 5-year open-label extension. In total, 6-year finasteride data were available in 487 patients originally randomized to finasteride, and 5-year data were available on 238 patients originally randomized to placebo. After 6 years of treatment with finasteride 5 mg, the mean quasi-American Urological Association Symptom Score improved by 4.0 points, the median prostate volume decreased by 24%, and the mean maximal urinary flow rate increased by 2.9 mL/s (P <0.001 for all parameters). Long-term finasteride treatment was well tolerated, with a low incidence of drug-related sexual adverse events occurring during the first year and even fewer occurrences during the 5-year open extension. Treatment with finasteride leads to durable improvement in urinary tract symptoms, flow rate, and prostate volume, with no increase in the prevalence of drug-related adverse events over time.

To evaluate the incidence and resolution of sexual adverse experiences (AEs) in men with benign prostatic hyperplasia treated with finasteride 5 mg compared with placebo. 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, aged 45 to 78 years, with symptomatic benign prostatic hyperplasia, enlarged prostates, and no evidence of prostate cancer. Patients completed a questionnaire at screening regarding their history of sexual dysfunction. During treatment, spontaneously self-reported sexual AEs were recorded. At screening, 46% of patients in each treatment group reported some history of sexual dysfunction. During year 1 of the study, 15% of finasteride-treated patients and 7% of placebo-treated patients had sexual AEs that were considered drug related by the investigator (P <0.001). During years 2 to 4, no between-group difference was noted in the incidence of new sexual AEs (7% in each group). The drug-related sexual AE profile for finasteride was similar for men with or without a history of sexual dysfunction. Sexual AEs resolved while continuing therapy in 12% of finasteride patients and 19% of placebo patients. Only 4% of finasteride and 2% of placebo patients discontinued the study because of sexual AEs. In men who discontinued with a sexual AE, 50% and 41% experienced resolution of their sexual AE after discontinuing finasteride or placebo therapy, respectively. Compared with placebo, men treated with finasteride experienced new drug-related sexual AEs with an increased incidence only during the first year of therapy.

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. 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. 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. Long-term treatment with finasteride was well tolerated and resulted in durable symptom relief and improvement in prostate volume and urinary flow.

To assess the utility of voiding and filling symptom subscores in predicting features of benign prostatic hyperplasia (BPH) progression, including acute urinary retention (AUR) and prostate surgery. The Proscar Long-term Efficacy and Safety Study (PLESS) was a 4-year study designed to evaluate the effects of finasteride versus placebo in men with lower urinary tract symptoms (LUTS), clinical evidence of BPH, and no evidence of prostate cancer. A self-administered questionnaire was employed to quantify LUTS at baseline. Receiver operating characteristics (ROC) curves were used to assess baseline characteristics from patients treated with placebo as predictors of outcomes. The characteristics assessed included the overall symptom score (Quasi-AUA SI), separate voiding and filling subscores, prostate volume (PV) and serum prostate-specific antigen (PSA) levels. PV and PSA were superior to the symptom scores at predicting episodes of spontaneous AUR and all types of AUR. The Quasi-AUA SI and the filling and voiding subscores were effective at predicting progression to surgery; however, PSA was more effective at predicting this outcome. To better evaluate symptoms as predictors of surgery, patients who experienced a preceding episode of AUR were excluded from the surgery analysis. In the absence of preceding AUR, the best predictors of future surgery were the Quasi-AUA SI and the filling subscore. Among men with LUTS, clinical BPH and no history of AUR, the overall symptom score and storage subscore are useful parameters to aid clinicians in identifying patients at risk for future prostate surgery. PV and PSA were the best predictors of AUR, while PSA was the best predictor of prostate surgery (for all indications).

In this double-blind, randomized, placebo-controlled study, normally cycling women (n = 86) with elevated low density lipoprotein cholesterol (LDL-C) levels were studied over six menstrual cycles. At the end of the screening phase, participants received placebo for the second menstrual cycle and subsequently were randomized to receive either placebo or simvastatin (40 mg/d) for the next four cycles. The second and sixth menstrual cycles were considered baseline and treatment cycles, respectively. Participants kept a menstrual diary throughout the study and provided daily first-void urine samples during cycles 2 and 6. Urine samples were assayed for LH and pregnanediol glucuronide (PdG). The primary end point was change in luteal phase duration as defined by the day of the urinary LH peak to the day preceding the onset of menstruation. Treatment with simvastatin (40 mg/d) effectively lowered LDL-C by 34.3% (P < 0.001). Simvastatin was generally well tolerated, and no meaningful difference in adverse event profile was observed between treatment groups. Compared with the placebo group, simvastatin did not have clinically relevant effects on luteal phase duration, peak PdG concentration, or integrated luteal phase PdG concentration. The results of this study demonstrate that treatment of healthy premenopausal women for approximately 4 months with simvastatin (40 mg/d) lowers LDL-C without adversely affecting reproductive gonadal function. Simvastatin should not be used during pregnancy or by nursing mothers.

We determine the effect of long-term suppression of dihydrotestosterone with finasteride, a specific type II 5alpha-reductase inhibitor, on bone mineral density. As part of a large (3,040 cases) 4-year, double-blind, placebo controlled trial designed to assess the long-term effects of finasteride in men with benign prostatic hyperplasia, 157 men 46 to 76 years old who were randomized to receive either 5 mg. finasteride or placebo underwent dual energy x-ray absorptiometry of the lumbar spine at baseline and at years 2, 3 and 4. Of 117 patients who had a baseline measurement and at least 1 additional measurement during the study baseline mean plus or minus standard deviation bone mineral density values were 1.12 +/- 0.17 gm./cm.2 in the finasteride group (63) and 1.10 +/- 0.17 gm./cm.2 in the placebo group (54). After 4 years bone mineral density was not different between treatment groups (finasteride 1.14 +/- 0.17 gm./cm.2 and placebo 1.13 +/- 0.18 gm./cm.2). Similar results were obtained for the 33 finasteride and 25 placebo treated patients who completed the study with year 4 bone mineral density measurements. These data demonstrate that long-term inhibition of type II 5alpha-reductase with finasteride does not adversely affect bone mineral density.