Kimio Sugaya md, Department of Urology, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. Email: firstname.lastname@example.org
Aim: To clarify the influence of hypertension on lower urinary tract symptoms (LUTS) we examined the relationship between blood pressure, LUTS, and the effect of terazosin on LUTS in patients with benign prostatic hyperplasia (BPH).
Methods: The subjects were patients who had LUTS and BPH. They were treated with terazosin (1 mg, twice-a-day) for 12 weeks. Calculation of the International Prostate Symptom Score (IPSS), measurement of blood pressure, and uroflowmetry were performed before and after 12 weeks of therapy. Patients were divided into a normotensive (NT) group and a hypertensive (HT) group at the time of first examination.
Results: The IPSS for urinary frequency and nocturia in BPH-HT patients (n = 21; mean age, 71 years) were significantly higher than those in the BPH-NT patients (n = 21; mean age, 69 years) before the administration of terazosin. The total IPSS the BPH-HT patients was also significantly higher than that of the BPH-NT patients. There were no differences of uroflowmetric parameters between the two groups. After 12 weeks of therapy, systolic and diastolic blood pressure decreased in the BPH-HT patients, but not in the BPH-NT patients. However, the systolic pressure of the BPH-HT patients was still significantly higher than that of the BPH-NT patients. The score for each IPSS parameter decreased in both groups, but the difference of the score between the two groups increased.
Conclusion: Hypertension may worsen LUTS and may decrease the improvement of symptoms by terazosin.
Benign prostatic hyperplasia (BPH) induces micturition disorders due to narrowing of the urethra associated with hypertrophy of the prostate gland, and by functional constriction of the prostatic urethra.1 Prostatic urethral constriction is induced by an increase of sympathetic tone. Alpha-1 adrenergic receptor antagonists (alpha-1 antagonists) decrease the prostatic urethral closing pressure.2–6 These antagonists have been used for the treatment of BPH, and can not only improve voiding disorders but also assist in the treatment of collecting disorders.2,5,7 Among non-selective alpha-1 antagonists used for the treatment of BPH, terazosin hydrochloride (terazosin), prazosin hydrochloride, and urapidil have also been employed for the treatment of hypertension.8–10 Our previous study showed that elderly patients with nocturia had a higher blood pressure and higher serum catecholamine levels when compared with healthy elderly controls.11 Therefore, hypertension itself seems to have an adverse influence on lower urinary tract symptoms (LUTS). In our recent study, the effects of terazosin on LUTS, blood pressure, and plasma lipid levels were investigated in patients with BPH, and an excellent influence of the drug on these parameters was shown.12 However, comparison of the severity of LUTS or the effect of terazosin on LUTS between BPH patients with normal blood pressure and patients with hypertension was not investigated. In the present study, to clarify the influence of hypertension on LUTS and the effect of terazosin on LUTS, we examined the relationship between blood pressure, LUTS and the effect of terazosin on BPH using data from our previous study12 and our recent patients.
The subjects were patients with LUTS due to BPH, who were not on any drug or who had not been treated for any other disease in the previous 3 months. The patients consulted our clinics between October 1999 and May 2001. In this period, we decided to prescribe terazosin for new BPH patients if there were no problems. All subjects provided informed consent to the study. At each patient's first examination, measurement of blood pressure in the sitting position, urinalysis, physical examination, digital rectal examination of the prostate, complete blood count, and biochemistry tests (including renal and liver function tests) were performed. The International Prostate Symptom Score (IPSS) was also determined. BPH was diagnosed by digital examination and ultrasonography of the prostate, and the serum level of prostate specific antigen was examined to exclude prostatic cancer. After approximately 2 weeks, uroflowmetry was also performed. Patients who were found to have no obvious diseases, apart from BPH and hypertension by the above examinations, were treated with terazosin. The expected effects and side-effects of terazosin were explained before it was prescribed. The drug was initiated at a dose of 1 mg per day (0.5 mg, twice-a-day), and the dose was increased to 2 mg per day (1 mg, twice-a-day) after 2–4 weeks. Treatment was continued for a total of 12 weeks. During this period, no other alpha-1 antagonists and no antiandrogen agents were administered. The above-mentioned tests, which were performed at the first or second medical examinations, were repeated every 4 weeks (if possible) and were also performed after 12 weeks of treatment. The patients were divided into two groups based on blood pressure at the first medical examination: a normotensive group and a hypertensive group. Hypertension was defined as a systolic blood pressure equal to or higher than 140 mmHg, or a diastolic blood pressure equal to or higher than 90 mmHg. Data were compared before and after administration of terazosin within each group and between the two groups.
Results are reported as the mean ± SD. Student's t-test for paired or unpaired data was used for statistical analysis, and P < 0.05 was considered to indicate statistical significance.
The number of BPH patients registered in this study was 58. However, another alpha-1 antagonist was administered to one patient, and the measurement of blood pressure and investigation of IPSS before and after treatment was not performed in 14 patients. One patient complained of vertigo 3 days after starting treatment with terazosin, so the drug was stopped. The remaining 42 patients (72%) were suitable for analysis. Their hematology, biochemistry, and urinalysis data before and after treatment were normal.
There were 21 BHP patients (69 ± 8 years old) in the normotensive (NT) group and 21 BPH patients (71 ± 11 years old) in the hypertensive (HT) group, and there was a significant difference of systolic pressure (129 ± 8 mmHg vs. 151 ± 16 mmHg, P < 0.0001) and diastolic pressure (74 ± 9 mmHg vs. 85 ± 8 mmHg, P = 0.0048) between the two groups before administration of terazosin (Fig. 1). After administration of terazosin, the blood pressure (systolic pressure, 139 ± 13 mmHg, P = 0.0046; and diastolic pressure, 80 ± 9 mmHg, P = 0.0206) was significantly decreased in BPH-HT patients, but not in BPH-NT patients (systolic pressure, 129 ± 10 mmHg; and diastolic pressure, 75 ± 9 mmHg). However, there was still a significant difference (P = 0.0110) of systolic pressure between the two groups after administration of terazosin.
Among the seven parameters of the IPSS, the scores of the BHP-HT patients for urinary frequency (3.3 ± 1.3) and nocturia (3.7 ± 1.2) were significantly higher (P = 0.0124 and P = 0.0410, respectively) before administration of terazosin than those of the BPH-NT patients (2.0 ± 1.1 and 2.6 ± 1.2, respectively) (Table 1 and Fig. 2). Although there were no significant differences in the remaining IPSS parameters between the two groups, the scores for the remaining parameters were also higher in the BPH-HT patients. The total IPSS of the BPH-HT patients (21.1 ± 7.2) was also significantly higher (P = 0.0262) than that of the BPH-NT patients (15.3 ± 5.4) before administration of terazosin.
Table 1. International Prostate Symptom Score (IPSS) before and after administration of terazosin for 12 weeks in patients with benign prostatic hyperplasia and normal blood pressure (BPH-NT) and patients with benign prostatic hyperplasia and hypertension (BPH-HT).†
Values are the mean ± SD. Significant differences between before and after administration of terazosin for 12 weeks in each group or between the two groups are indicated by
P < 0.05,
P < 0.01 and
P < 0.001.
2.9 ± 1.6
1.8 ± 1.2
1.2 ± 1.0
0.5 ± 0.8
2.0 ± 1.1
1.3 ± 0.9
4.0 ± 0.8
2.3 ± 0.9
0.9 ± 1.0
0.3 ± 0.5
1.6 ± 1.0
0.6 ± 0.5
2.6 ± 1.2
1.8 ± 0.9
15.3 ± 5.4
8.2 ± 4.1
3.3 ± 1.6
2.3 ± 1.4
2.3 ± 1.8
1.6 ± 1.2
3.3 ± 1.3
2.3 ± 1.0
4.5 ± 0.7
3.1 ± 1.2
2.0 ± 2.0
1.3 ± 1.4
2.1 ± 1.6
1.5 ± 1.5
3.7 ± 1.2
2.9 ± 1.1
21.1 ± 7.2
15.0 ± 5.1
After administration of terazosin, the scores for each parameter decreased in both groups (Fig. 2). However, the decrease of the urgency score in both groups and the decrease of the intermittency and hesitancy scores in the BPH-HT patients were not significant. After administration of terazosin, there were significant differences in the scores for urgency, frequency, intermittency and nocturia between the two groups. There were four IPSS parameters showing a significant difference between the two groups after administration of terazosin compared with two parameters before administration of terazosin. The total IPSS score of the BPH-HT patients (15.0 ± 5.1) was also significantly higher (P = 0.0021) than that of the BPH-NT patients (8.2 ± 4.1) after administration of terazosin.
Uroflowmetry showed that there were no significant differences of the maximum urine flow rate (BPH-NT and BPH-HT groups: 10.5 ± 4.4 mL/s vs. 10.2 ± 4.2 mL/s, respectively), average urine flow rate (5.3 ± 2.3 mL/s vs. 5.4 ± 2.0 mL/s, respectively), voided urine volume (205 ± 100 mL/s vs. 177 ± 124 mL, respectively), and residual urine volume (59 ± 55 mL vs. 115 ± 130 mL, respectively) between the two groups before administration of terazosin. After administration of terazosin, the residual urine volume of the BPH-HT patients (31 ± 28 mL) was significantly decreased (P = 0.0061), but not that of the BHP-NT patients (39 ± 55 mL). The maximum urine flow rate (BPH-NT and BPH-HT patients: 12.7 ± 5.1 mL/s vs. 12.7 ± 4.1 mL/s, respectively), average urine flow rate (6.3 ± 2.9 mL/s vs. 6.8 ± 2.6 mL/s, respectively), and voided urine volume (202 ± 108 mL/s vs. 219 ± 103 mL, respectively) were unchanged or slightly improved in each group, and there were no significant differences before and after administration of terazosin. There were also no significant differences of uroflowmetric parameters between the two groups after administration of terazosin.
The study presented here showed that the BPH-HT patients had more severe LUTS than the BPH-NT patients. In particular, collecting disorders, such as frequency and nocturia were more severe in the BPH-HT patients before administration of terazosin. Therefore, hypertension may influence bladder sensation or nocturnal urine volume. However, although the severity of voiding disorders and the uroflowmetric parameters showed no significant differences between the two groups before administration of terazosin, each IPSS parameter showed a higher score in the BPH-HT patients than in the BPH-NT patients, suggesting that hypertension not only worsens collecting disorders but also voiding disorders.
In our previous study, intrathecal injection of tamsulosin or naftopidil (alpha-1a or -1d adrenergic receptor antagonists, respectively) at the lumbosacral level of the spinal cord prolonged the interval between isovolumetric bladder contractions in rats.13 This effect of naftopidil has also been recognized in rats with chronic spinal cord injury (SCI).14 Since there are noradrenergic projections to the spinal cord from the brainstem,15 the effect of naftopidil in SCI rats suggests that circulating catecholamines may act on the lumbosacral cord to influence urinary frequency. Since circulating catecholamine levels are high in patients with hypertension,16,17 increased serum catecholamine levels may influence the lumbosacral cord and induce urinary frequency, including nocturia in hypertensive BPH patients. Moreover, increased serum catecholamine levels may also influence prostatic smooth muscle tone, and worsen catecholamine-related bladder outlet obstruction.
It has been reported that renal arterial resistance is high in patients with hypertension,18,19 and an increase of renal arterial resistance leads to lower urine output. Serum catecholamine levels have a diurnal rhythm, increasing in the daytime and decreasing at night.11 Therefore, in patients with hypertension, there may be little urine production during the daytime, leading to fluid retention. At night-time, urine volume may increase, because the nocturnal decrease of serum catecholamine levels may induce an increase of renal blood flow. Thus, the nocturnal frequency of urination may be increased in patients with hypertension.
In the present study, the IPSS improved in both groups after administration of terazosin, but the difference in score between the two groups became more prominent. Blood pressure decreased in the BPH-HT patients and did not change in the BPH-NT patients, but there was a significant difference of systolic pressure between the two groups even after administration of terazosin. Therefore, the dose of terazosin (2 mg per day) might have been too low for the BPH-HT patients. In Japan, the permitted terazosin dose is only 2 mg per day for the treatment of BPH, while 4 mg per day is allowed for the treatment of hypertension. If the dose of terazosin was increased for BPH-HT patients, daytime renal blood flow might increase, so that the daytime urine output might also increase and nocturnal output might decrease. Since it has been reported that terazosin acts on the central nervous system,20,21 an increased dose of the drug might also block more alpha-1 receptors in the lumbosacral cord, increase the threshold of bladder sensation, and thus improve collecting disorders. Moreover, an increased dose of terazosin might also block more alpha-1 receptors in the prostate and thus improve voiding disorders.
In summary, LUTS, especially collecting disorders, were more severe in BPH-HT patients when compared with BPH-NT patients. Terazosin significantly improved hypertension and the IPSS in both groups. However, there was still a significant difference of systolic pressure between both groups after administration of terazosin at 2 mg daily. The differences of the IPSS parameters between the two groups became larger after the administration of terazosin. Therefore, hypertension seems to worsen LUTS and it may also decrease the effect of terazosin on LUTS.