John D. McConnell

The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia

Background Finasteride is known to improve urinary symptoms in men with benign prostatic hyperplasia, but the extent to which the benefit is sustained and whether finasteride reduces the incidence of related events, including the need for surgery and the development of acute urinary retention, are not known. Methods In this double-blind, randomized, placebo-controlled trial, we studied 3040 men with moderate-to-severe urinary symptoms and enlarged prostate glands who were treated daily with 5 mg of finasteride or placebo for four years. Symptom scores (on a scale of 1 to 34), urinary flow rates, and the occurrence of outcome events were assessed every four months in 3016 men. Prostate volume was measured in a subgroup of the men. Complete data on outcomes were available for 2760 men. Results During the four-year study period, 152 of the 1503 men in the placebo group (10 percent) and 69 of the 1513 men in the finasteride group (5 percent) underwent surgery for benign prostatic hyperplasia (reduction in risk with finasteride, 55 percent; 95 percent confidence interval, 41 to 65 percent). Acute urinary retention developed in 99 men (7 percent) in the placebo group and 42 men (3 percent) in the finasteride group (reduction in risk with finasteride, 57 percent; 95 percent confidence interval, 40 to 69 percent). Among the men who completed the study, the mean decreases in the symptom score were 3.3 in the finasteride group and 1.3 in the placebo group (P<0.001). Treatment with finasteride also significantly improved urinary flow rates and reduced prostate volume (P<0.001). Conclusions Among men with symptoms of urinary obstruction and prostatic enlargement, treatment with finasteride for four years reduces symptoms and prostate volume, increases the urinary flow rate, and reduces the probability of surgery and acute urinary retention.

Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression.

The synthesis of dihydrotestosterone is catalyzed by steroid 5 alpha-reductase isozymes, designated types 1 and 2. Mutation of type 2 results in male pseudohermaphroditism, in which the external genitalia are phenotypically female at birth. Two striking and unexplained features of this disorder are that external genitalia of affected males undergo virilization during puberty and that these individuals have less temporal hair regression. The tissue-specific and developmental expression patterns of the 5 alpha-reductase isozymes were investigated by immunoblotting. The type 1 isozyme is not detectable in the fetus, is transiently expressed in newborn skin and scalp, and permanently expressed in skin from the time of puberty. There was no qualitative difference in 5 alpha-reductase type 1 expression between adult balding vs. nonbalding scalp. The type 2 isozyme is transiently expressed in skin and scalp of newborns. Type 2 is the predominant isozyme detectable in fetal genital skin, male accessory sex glands, and in the prostate, including benign prostatic hyperplasia and prostate adenocarcinoma tissues. Both isozymes are expressed in the liver, but only after birth. These results are consistent with 5 alpha-reductase type 1 being responsible for virilization in type 2-deficient subjects during puberty, and suggest that the type 2 isozyme may be an initiating factor in development of male pattern baldness.

Relationship of Symptoms of Prostatism to Commonly Used Physiological and Anatomical Measures of the Severity of Benign Prostatic Hyperplasia

In previous studies the severity of symptoms of prostatism in men with benign prostatic hyperplasia have not correlated well with prostate size, degree of bladder trabeculation, uroflowmetry or post-void residual volume. As part of a prospective cohort study of benign prostatic hyperplasia treatment effectiveness in 4 university-based urology practices, we correlated symptom severity and these commonly used measures of disease severity. Symptom severity was quantified using the American Urological Association symptom index. Analyses were based on 198 outpatients completing a standardized evaluation (84 of these men have completed 6 months of followup after treatment with prostatectomy, balloon dilation, terazosin or watchful waiting). At baseline, symptom severity was not correlated with uroflowmetry, post-void residual, prostate size and degree of bladder trabeculation. However, symptom severity was much more strongly related to overall health status than the other measures. Reduction in symptoms with treatment did correlate with improvements in uroflowmetry. This poor baseline correlation with symptoms may reflect unreliability in measurement of the physiological/anatomical variables. Alternatively, these parameters may be measuring different pathophysiological phenomena.

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

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 IS A STRONG PREDICTOR OF FUTURE PROSTATE GROWTH IN MEN WITH BENIGN PROSTATIC HYPERPLASIA

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.

The Effect of Finasteride in Men with Benign Prostatic Hyperplasia

BACKGROUND Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5 alpha-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. METHODS In a double-blind study, we evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period. RESULTS As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. CONCLUSIONS The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.

Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo.

PURPOSE We analyzed data from the placebo arm of the MTOPS trial to determine clinical predictors of BPH progression. MATERIALS AND METHODS A total of 3,047 patients with LUTS were randomized to either placebo, doxazosin (4 to 8 mg), finasteride (5 mg), or a combination of doxazosin and finasteride. Average length of followup was 4.5 years. The primary outcome was time to overall clinical progression of BPH, defined as either a confirmed 4-point or greater increase in AUA SS, acute urinary retention, incontinence, renal insufficiency, or recurrent urinary tract infection. We analyzed BPH progression event data from the 737 men who were randomized to placebo. RESULTS The rate of overall clinical progression of BPH events in the placebo group was 4.5 per 100 person-years, for a cumulative incidence (among men who had at least 4 years of followup data) of 17%. The risk of BPH progression was significantly greater in patients on placebo with a baseline TPV of 31 ml or greater vs less than 31 ml (p <0.0001), a baseline PSA of 1.6 ng/dl or greater vs PSA less than 1.6 ng/dl (p = 0.0009), a baseline Qmax of less than 10.6 ml per second vs 10.6 ml per second or greater (p = 0.011), a baseline PVR of 39 ml or greater vs less than 39 ml (p = 0.0008) and baseline age 62 years or older vs younger than 62 years (p = 0.0002). CONCLUSIONS Among men in the placebo arm, baseline TPV, PSA, Qmax, PVR and age were important predictors of the risk of clinical progression of BPH.

Association of the Circulating Levels of the Urokinase System of Plasminogen Activation With the Presence of Prostate Cancer and Invasion, Progression, and Metastasis

PURPOSE To assess whether preoperative plasma levels of urokinase-type plasminogen activator (uPA) and its soluble receptor (uPAR) would predict cancer of the prostate (CaP) presence, stage, and prognosis. PATIENTS AND METHODS Plasma levels of uPA and uPAR were measured in patients who underwent radical prostatectomy for clinically localized CaP (preoperative, n = 429; postoperative, n = 76), 44 healthy men, 19 patients with metastases to regional lymph nodes, and 10 patients with bone metastases. RESULTS uPA and uPAR levels were significantly elevated in patients with CaP compared with healthy men and significantly declined after prostate removal. In CaP patients, uPA and uPAR levels both increased significantly from patients with nonmetastatic CaP to patients with lymph node metastases to patients with skeletal metastases. On univariate analysis, preoperative uPA and uPAR levels were significantly elevated in patients with extracapsular extension, seminal vesicle involvement, higher prostatectomy Gleason sum, lymph node invasion, lymphovascular invasion, perineural invasion, and higher tumor volume. Higher preoperative uPAR was associated with biochemical progression in univariate analysis. Conversely, higher preoperative uPA was independently associated with biochemical progression in preoperative or postoperative multivariate models. In patients with biochemical progression, preoperative uPA and uPAR were both significantly associated with shorter postprogression total serum prostate-specific antigen doubling times, failure to respond to salvage local radiation therapy, and/or development of distant metastasis. CONCLUSION Elevation of plasma uPA and uPAR levels in CaP patients seems to be partly caused by local release from the prostate. Plasma levels of uPA and uPAR are associated with features of biologically aggressive CaP, disease progression after radical prostatectomy, and metastasis.

Combination Therapy With Doxazosin and Finasteride for Benign Prostatic Hyperplasia in Patients With Lower Urinary Tract Symptoms and a Baseline Total Prostate Volume of 25 Ml or Greater

Purpose: We examined data from the Medical Therapy of Prostatic Symptoms trial to determine the relationship between baseline TPV and the effect of medical therapy in men with LUTS secondary to BPH.Materials and Methods: A total of 3,047 patients with LUTS were randomized to placebo, 4 to 8 mg doxazosin, 5 mg finasteride or the combination of doxazosin and finasteride. Average treatment duration was 4.5 years The primary outcome was time to overall clinical progression of BPH, defined as a confirmed 4 point or greater increase in AUA SS, acute urinary retention, incontinence, renal insufficiency or recurrent urinary tract infection. Secondary outcomes were the need for invasive therapy for BPH, and changes in AUA SS and the maximum urinary flow rate with time. TPV was measured by transrectal ultrasound at baseline and study end.Results: In patients with a small prostate (baseline TPV less than 25 ml) combination therapy was no better than doxazosin alone for decreasing the risk of clinical progression of ...

Analysis of Factors Contributing to Success or Failure of 1-Stage Urethroplasty for Urethral Stricture Disease

We reviewed charts with adequate documentation and followup (mean 24.6 months) between 1970 and 1987 of 110 patients who had undergone 1-stage urethroplasty for urethral stricture disease at our institutions. Two age peaks were observed, 1 in the younger population (21 to 30 years old) with traumatic strictures (50% of all strictures) and 1 in elderly men (61 to 70 years old) with mainly post-inflammatory strictures (28.2% of all strictures). The majority of all strictures (63.6%) were in the bulbous urethra. Only strictures induced by trauma were located in the membranous urethra (total 28.2%). A patch graft repair was used in 49.1% of all cases, an end-to-end technique in 29.1% and a transpubic repair in 21.8%. Overall, a 57% rate of excellent results was observed with 24% failures. The results were best for patch graft repairs (65% excellent), followed by end-to-end repairs (56% excellent) and transpubic repairs (42% excellent). The choice of the surgical approach in urethral stricture surgery is dictated by the location of the stricture. The location in turn is dependent on the etiology of the stricture. Consequently, the cause of the stricture affects the location and character of the stricture and, therefore, has an immediate impact on the choice of the surgical approach and, thus, the outcome of the patient. The failure rate doubled overall when the patients had a previous manipulation for the stricture disease or if the urine was infected preoperatively despite antibiotic coverage. While our patient population may not be representative for other institutions, some general conclusions regarding proper management and treatment selection can be drawn from our experience.