Do baseline estrogen and testosterone affect lower urinary tract symptoms (LUTS) prior to or after pharmacologic treatment with tadalafil?

Little is known about how total testosterone and estradiol-17ß influence lower urinary tract symptoms (LUTS) in men with benign prostatic hypertrophy (BPH). We analyzed data from a subset of men aged ≥18 years randomized to tadalafil 5 mg once-daily or placebo who had ≥6 month history of LUTS and an International Prostate Symptom Score (IPSS)≥13 enrolled in one of three randomized, placebo-controlled tadalafil clinical trials (N = 958). Three specific aims were addressed, as follows: (i) To characterize enrolled men by treatment randomization and testosterone level; (ii) to assess cross-sectional associations of estradiol-17ß, testosterone, and LUTS prior to treatment with tadalafil; and, (iii) to assess longitudinal associations between baseline estradiol-17ß and testosterone and improvements or worsening of LUTS during a 12-week period of tadalafil or placebo administration. LUTS were assessed by total IPSS, IPSS voiding sub-score (IPSS-V) and IPSS storage sub-score (IPSS-S) for cross-sectional analyses, and change in total IPSS (ΔIPSS), ΔIPSS-V, and ΔIPSS-S between baseline and 12-week visit for longitudinal analyses. Correlation analyses and linear regression examined associations. Baseline testosterone was not significantly associated with IPSS. In contrast, estradiol-17ß was inversely correlated with IPSS (r = -0.08; p < 0.05) and IPSS-S (r = -0.14; p < 0.05). Tadalafil treatment resulted in greater IPSS improvements in men with lower baseline estradiol-17ß versus those with higher baseline estradiol-17ß. Lower baseline estradiol-17ß was significantly associated with modestly improved ΔIPSS-V (p = 0.04) and Δtotal IPSS (p = 0.05) but not with ΔIPSS-S, following treatment which may substantiate the role of bladder dysfunction because of nerve and smooth muscle changes in the bladder in addition to benign prostatic enlargement in LUTS. Circulating baseline testosterone did not predict ΔIPSS. Men with lower baseline estradiol-17ß levels showed greater responsiveness to tadalafil 5 mg treatment than those with higher baseline estradiol-17ß levels when responsiveness was measured using total IPSS and IPSS-V.

Rural vs. urban disparities in association with lower urinary tract symptoms and benign prostatic hyperplasia in ageing men, NHANES 2001-2008.

OBJECTIVE: The objective of this study was to investigate rural/urban and socio-demographic disparities in lower urinary tract symptoms and benign prostatic hyperplasia (LUTS/BPH) in a nationally representative population of men. METHODS: Data on men age ≥40 years (N = 4,492) in the 2001-2008 National Health and Nutrition Examination Surveys were analysed. Self-report of physician-diagnosed enlarged prostate and/or BPH medication use defined recognised LUTS/BPH. Urinary symptoms without BPH diagnosis/medications defined unrecognised LUTS/BPH. Rural-Urban Commuting Area Codes assessed urbanisation. Unadjusted and multivariable associations (odds ratios (OR)) between LUTS/BPH and covariates were calculated using logistic regression. RESULTS: Recognised and unrecognised LUTS/BPH weighted-prevalence estimates were 16.5% and 9.6%. There were no significant associations between LUTS/BPH and rural/urban status. Significant predisposing factors for increased adjusted odds of recognised and unrecognised LUTS/BPH included age, hypertension (OR=1.4;1.4), analgesic use (OR=1.4;1.4) and PSA level >4 ng/mL (OR=2.3;1.9) when adjusted for rural/urban status, race, education, income, alcohol, health insurance, health care and proton pump inhibitor (PPI) use (all p ≤ 0.1). Restricting to urban men only (N = 3,371), healthcare use (≥4visits/year) and PPI's increased adjusted odds of recognised LUTS/BPH (OR=2.0;1.6); no health insurance and

Tadalafil - a therapeutic option in the management of BPH-LUTS.

BACKGROUND/AIMS: Men with signs of benign prostatic hyperplasia (BPH) may experience lower urinary tract symptoms (LUTS) such as urinary frequency, urgency, intermittence, nocturia, straining, incomplete emptying or a weak urinary stream. The effective management of LUTS suggestive of BPH (BPH-LUTS) requires careful consideration of several factors, including the severity of a patient's symptoms, concurrent or other coexisting medical conditions, the ability to improve symptoms and impact quality of life (QOL), as well as the potential side effects of available treatment options. Several clinical studies have assessed phosphodiesterase type 5 (PDE5) inhibitors in reducing LUTS; however, tadalafil is the only PDE5 inhibitor approved for the treatment of signs and symptoms of BPH, as well as in men with both erectile dysfunction (ED) and the signs and symptoms of BPH. This review examined articles that assessed tadalafil in patients with signs and symptoms of BPH, with or without erectile dysfunction (ED), which led to regulatory approval in the United States and Europe. RESULTS: In dose-ranging and confirmatory studies, results demonstrate that tadalafil significantly improved total International Prostate Symptom Score (IPSS) following 12 weeks of treatment with once daily tadalafil 5 mg. Statistically significant improvements in Benign Prostatic Hyperplasia Impact Index (BII), IPSS subscores, IPSS QOL and International Index of Erectile Function (IIEF) were also observed. Improvement in urinary symptoms occurred regardless of age, previous treatment with an α1 -adrenergic blocker, BPH-LUTS severity at baseline or ED status. CONCLUSIONS: While tadalafil is most frequently recognised as a standard treatment option for men with ED, it also represents a well-tolerated and effective treatment option in men with moderate to severe BPH-LUTS.

Reliability of efficacy in men with erectile dysfunction treated with tadalafil once daily after initial success.

The reliability of response to treatment is an important component of erectile dysfunction (ED) treatment. This study examined the reliability of tadalafil once daily (that is, successful attempts/total attempts) following initial successful intercourse. Data pooled from two randomized, double-blind, placebo-controlled trials of men with ED who received tadalafil 2.5 mg (N=96), tadalafil 5 mg (N=206) or placebo (N=148) once daily were analyzed to determine the first-attempt success rate and subsequent reliability of response. The first-attempt success rate (Sexual Encounter Profile question 3 (SEP3)) was significantly higher among men taking tadalafil 2.5 mg (45.7%) and 5 mg (55.2%) compared to placebo (28.5%; P<0.05 and P<0.001, respectively). Furthermore, following initial success, men taking tadalafil 5 mg had a significantly greater proportion of successful intercourse (SEP3) on subsequent attempts (85.9%, P<0.001) compared to men taking placebo (70.2%). Overall, men with ED taking tadalafil once daily experienced a high rate of reliability of efficacy.

Daily patterns of sexual intercourse attempts by men with erectile dysfunction treated with tadalafil: influence of age and marital status.

This retrospective analysis examined the daily/weekly patterns of sexual activity, by age and marital status, of men with erectile dysfunction (ED) participating in a 12-week, multicenter, open-label study of tadalafil (20 mg) as needed. The timing of intercourse attempts post dose and satisfaction were assessed using the Sexual Encounter Profile diary. Patients' behaviors regarding sexual self-confidence, spontaneity and time concerns were assessed with the Psychological and Interpersonal Relationship Scale. Overall, the timing of sexual intercourse attempts varied among patients, regardless of age or marital status; at least 46% of intercourse attempts occurred within the 4-36-h post-dose time interval. Across age groups and marital status, men treated with tadalafil reported greater satisfaction compared with baseline; they also reported fewer time concerns, improved self-confidence and improved spontaneity. Information regarding sexual behavioral patterns of men with ED is important to consider when discussing patient expectations.

Improvements in confidence, sexual relationship and satisfaction measures: results of a randomized trial of tadalafil 5 mg taken once daily.

An efficacy study of tadalafil (5 mg once daily) for treating erectile dysfunction included sexual satisfaction and psychosocial outcome measures such as Treatment satisfaction (THX) domain of Sexual Life Quality Questionnaire, Self-Esteem And Relationship (SEAR) questionnaire, Sexual Encounter Profile questions 4 (SEP4; hardness satisfaction) and 5 (SEP5; overall satisfaction), intercourse satisfaction (IS) and overall satisfaction (OS) domains of International Index of Erectile Function (IIEF), and partner SEP question 3 (pSEP3). After a 4-week run-in phase, participants were randomized to receive either tadalafil (N=264) or placebo (N=78) for 12 weeks. Participants and partners were more satisfied (THX) with tadalafil (75 and 73, respectively) than with placebo (51 and 55, respectively, P<0.001). Statistically significant improvements in sexual relationship, confidence, self-esteem and overall relationship (SEAR), in addition to IS, OS, SEP5 and pSEP3 for tadalafil compared with placebo (P<0.001) correlated with erectile function (EF) improvement (assessed by change from baseline in IIEF-EF score). Tadalafil significantly improved treatment and sexual satisfaction, while improving multiple outcomes measured by SEAR.

Response to treatment with tadalafil in men with erectile dysfunction who reported no successful intercourse attempts at baseline.

The purpose of this post hoc analysis was to evaluate response to tadalafil in patients with erectile dysfunction (ED) who reported failures in all sexual intercourse attempts before treatment. In a multicenter, open-label study, 1911 men received tadalafil 20 mg dosed as needed (up to once daily), for 12 weeks following a 4-week treatment-free run-in period. Efficacy measures included the sexual encounter profile (SEP) and the erectile function (EF) domain of the International Index of Erectile Function (IIEF-EF). Approximately, one-half (n=952, 49.9%) of the patients reported no successful intercourse attempts during the 4-week run-in period. Of these, 771 patients (81.0%) had at least one successful intercourse attempt during the treatment period. Furthermore, among responders, mean IIEF-EF scores at study end were similar regardless of success or no success at baseline. Patients who are unable to have successful intercourse should be encouraged to try oral phosphodiesterase type 5 inhibitor treatment for ED.

Effect of an exercise program on the perception of exertion in males at retirement.

To describe the association between perception of exertion and exercise, 138 men at retirement, mean age 62.7 years, were studied before and after a one-year program of exercise. VO2max and ratings of perceived exertion (RPE) using the Borg psychophysical scale were determined by a continuous exercise treadmill protocol to fatigue. The men were randomly assigned to an exercise program (n = 69) or control (n = 69). The program consisted of walking or jogging for 30 min, 3 times per week for one year. After training, the activity group showed a significant improvement in VO2max (12%). Linear regression analysis was used to relate RPE to selected physiological measurements for control and activity groups. The equations for the before and after training relationships were compared. Changes in the relationship of RPE vs VO2 and Ve, after training, were not significant for the activity group. However, the control group showed significant changes in these relationships at one year post retirement. For VO2 and Ve, ratings were 1-2 units higher than at time of retirement. Results indicate that perception of a physical task normally changes at retirement such that a given amount of exertion may seem subjectively greater. Results also suggest that a structured exercise program is successful at maintaining perception of task at pre-retirement levels. This maintenance of a low rating of perception may retard a reluctance to be physically active which often accompanies ageing.

Amiloride with or without salbutamol versus placebo: effects on lipoproteins in hypertensive patients treated with timolol-hydrochlorothiazide.

Because thiazides and beta-blockers have adverse effects on lipoproteins, while magnesium repletion (shown to occur with amiloride) and beta 2 agonists improve lipids, we studied the effects of 3 months each of amiloride with and without salbutamol with and without placebo in a 2 X 2 factorial crossover study in which all patients took timolol-hydrochlorothiazide twice daily for 1 year. A total of 118 subjects entered, and 97 patients completed all four crossovers of amiloride + salbutamol, amiloride + placebo, salbutamol + placebo and placebo + placebo. No significant differences were seen among the four study regimens with respect to blood pressure, total cholesterol, triglycerides or high-density lipoproteins (HDL). The study power was 99% for total cholesterol, 46% for triglycerides and 93% for HDL. Timolol-hydrochlorothiazide had no significant effect, suggesting that the use of such drugs to offset the adverse effects of antihypertensive drugs on lipoproteins is not effective; the selection of alternative antihypertensive agents appears to be a preferable strategy.

Effect of non-steroidal anti-inflammatory drugs on control of hypertension by beta-blockers and diuretics.

The effect of sulindac on renal function and blood pressure was compared with those of placebo, piroxicam, and naproxen in 20 patients with primary hypertension being treated with a diuretic and a beta-blocker. Although the three non-steroidal anti-inflammatory drugs (NSAIDs) did not differ in their effect on renal function (weight, glomerular filtration rate, creatinine clearance) or on serum thromboxane and plasma 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), blood pressure was significantly lower with sulindac than with placebo, piroxicam, or naproxen. These differences were associated with less renal cyclooxygenase inhibition by sulindac (reflected by urinary thromboxane B2 and 6-keto PGF1 alpha) than by other NSAIDs. The findings suggest that the blood pressure differences reflect vasodilation due to differences in the balance between systemic and renal effects of the NSAIDs.

Effects of triamterene and amiloride on urinary sediment in hypertensive patients taking hydrochlorothiazide.

In a crossover study of 26 hypertensive patients, the effects of triamterene (50 mg/day) and amiloride (5 mg/day) on urinary sediment were compared. Each drug was given for one month and all patients also received hydrochlorothiazide (50 mg/day). An abnormal urinary sediment--evident grossly as a reddish-brown precipitate after routine staining procedures and microscopically as characteristic reddish-brown crystals and casts, as previously described--was identified in 14 of 26 (54%) triamterene urine samples but in none of the amiloride samples. Results of renal function tests were similar for both drugs. In a clinic population of more than 1000 hypertensive patients over 4 years, interstitial nephritis was diagnosed in 4, all of whom were taking a triamterene-containing combination diuretic. It is possible that triamterene is a factor in the aetiology of interstitial nephritis.

Blood pressure measurement in the elderly: correlation of arterial stiffness with difference between intra-arterial and cuff pressures.

Intra-arterial (radial) blood pressure (BP) measurement was compared with the indirect cuff method in 55 healthy volunteers aged from 59-80 years (mean 68.6 +/- 5.2 s.d.). On average, the cuff method underestimated systolic BP by 5 mmHg and overestimated diastolic BP by 8 mmHg. Cuff measurement underestimated systolic BP by greater than 10 mmHg in 17 cases, and by greater than 20 mmHg in three cases. The cuff method overestimated diastolic BP by greater than 10 mmHg in nine cases (one greater than 20 mmHg) and in two cases the cuff overestimated diastolic BP by greater than 30 mmHg, compared with intra-arterial pressures. The differences correlated with pulse wave velocity, an index of arterial stiffness. A pulse wave velocity index reflecting the entire length from the aortic root to the posterior tibial artery (PWVI/ao-pt) gave a correlation (r) of 0.48 (P less than 0.0005) with systolic arterial/cuff (A/C) difference, a correlation of 0.43 (P less than 0.001) with diastolic A/C difference, and a correlation of 0.57 (P less than 0.00001) with the A/C difference in measurement of mean arterial pressure. A positive but weaker correlation was observed between A/C difference and PWVI aorta-femoral. Although the pressure differences were not as great in these healthy elderly subjects as in previous studies of patients suspected of having pseudo-hypertension, caution still appears to be indicated in the interpretation of cuff blood pressure measurement in the elderly.

Increased prevalence of mitral valve prolapse in patients with migraine.

Patients with classic migraine (69 women and 31 men) selected randomly from a practice list of over 1000 were matched for age, sex and neighbourhood with 100 people who did not have headache problems, and both groups underwent M-mode and two-dimensional echocardiography and clinical examination by cardiologists blinded to the subjects' clinical status. The mean ages were 34.9 +/- 11.3 years for the migraine group and 33.1 +/- 9.9 years for the control group. Definite and possible mitral valve prolapse (MVP), diagnosed according to predefined echocardiographic criteria, were found about twice as often in the migraine group as in the control group (in 15 v. 7 and 16 v. 8 patients respectively); the echocardiograms were definitely normal in 69 migraine patients and 85 controls (chi 2 = 8.39, p less than 0.025). Altogether 25% of the migraine group and 11% of the control group had evidence of MVP from a combination of the echocardiographic and auscultatory findings (chi 2 = 5.72, p less than 0.025). The odds ratio was 2.7, with 95% confidence limits of 1.17 and 6.29. The association between migraine and MVP has implications for the understanding of platelet abnormalities and episodes of cerebral ischemia occurring in both these conditions.