Nocturia Potentially Influences Maintenance of Sexual Function in Elderly Men with Benign Prostatic Hyperplasia

Authors


Osamu Ishizuka, MD, PhD, Department of Urology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. Tel: +81-263-37-2661; Fax: +81-263-37-3082. Email: ishizuk@shinshu-u.ac.jp

Abstract

Objective: This study examined the relationship between bothersome symptoms of nocturia and erectile function.

Methods: Subjects comprised patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Patients were prospectively followed on treatment with the alpha-1 blocker naftopidil for 8 weeks. Patient backgrounds and efficacy of naftopidil associated with LUTS and sexual activity were evaluated.

Results: The percentage of patients who identified nocturia as the most bothersome symptom was 30.2% (n = 135), representing the highest percentage among International Prostate Symptom Score (IPSS) items. The number of patients with nocturia as the most bothersome symptom plateaued at an IPSS for nocturia of two or three points. In contrast, the number of patients with slow stream as the most bothersome symptom increased with symptom severity according to IPSS for slow stream. Logistic regression analysis on association between nocturia and erectile function confirmed that the odds ratio was 1.41 (P < 0.05). Naftopidil showed excellent efficacy related to male LUTS, but International Index of Erectile Function 5 (IIEF5) total score was almost unchanged. Among patients with nocturia improved by naftopidil, IIEF5 total score was significantly changed in the group with IPSS nocturia score ≤1 as compared to the group with IPSS nocturia score ≥2 per night (P = 0.038).

Conclusion: Nocturia the most bothersome symptom correlated with aging. Nocturia could associate erectile dysfunction, and keeping the frequency of nocturia at ≤1 episode might be meaningful for maintaining quality of life in elderly men.

1. INTRODUCTION

Lower urinary symptoms (LUTS) are common in daily life among elderly men and women. Benign prostatic hyperplasia (BPH) is the primary cause of LUTS in men ≥50 years old.1,2 Nocturia, defined as waking at night to void,3 is a bothersome urological symptom among older individuals.4–6 Previous studies have reported nocturia as a bothersome symptom that reduces quality of life (QOL).7 Nocturia was identified as one of the most serious symptoms of BPH, having a significant impact on daily life8,9 and representing the most frequently cited cause of nocturnal awakening resulting in sleep loss, daytime fatigue, mood disturbance, and increased risk of fracture and mortality.10–13

Erectile dysfunction (ED), defined as the inability to develop and maintain an erection for satisfactory sexual intercourse or activity,14 is a common physiological change among aging men. LUTS and sexual dysfunction are highly prevalent in aging men and LUTS is a known risk factor for ED.15–17 Although the mechanisms underlying this association are unknown, leading theories include overactivity of the autonomic nervous system and changes in endothelial function by way of the nitric oxide-cyclic guanosine monophosphate pathway.16,18 Male LUTS has generally been managed using alpha 1-adrenoceptor blockers (α1-blockers) as the first-line therapy. However, evidence as to whether α1-blockers improve ED has been inconsistent.19–21 In addition, whether individual LUTS are associated with sexual function has hardly been investigated, particularly in terms of relationships between nocturia and ED. Naftopidil, a popular α1-blocker approved for use in Japan, Korea, India and China, has beneficial effects on storage symptoms22–24 when compared to tamsulosin and has the unique effects of increasing nocturnal voided volume and decreasing nocturnal urine volume, thus helping to decrease the frequency of nocturic episodes.25 This study analyzed the relationship between bothersome LUTS, particularly nocturia, and erectile function.

2. METHODS

2.1. Subjects and study design

This investigation was performed from February until October 2010 at 62 urology hospitals and clinics in Japan. The protocol was ethically approved and carried out conforming to the provisions of the Declaration of Helsinki. Patients who visited a urological hospital or clinic and were able to take naftopidil for suggestive of BPH were enrolled in this study to collect data for analysis and to investigate the circumstances under real clinical practice conditions. Patients who had received some pharmacotherapy for LUTS, but not surgery, were also included along with newly suggestive as BPH. Patients commonly completed 8 weeks of naftopidil treatment. Patients showing any one of total IPSS <8, QOL index <2, Qmax ≥15 mL/sec, or prostate volume <20 mL at baseline were excluded before conducting any analyses. Enrolled patients were prospectively followed for 8 weeks after initiation of naftopidil administration. The dosage of naftopidil was increased or decreased within a range of 25–75 mg/day, depending on the decisions of the treating doctor to address LUTS. Background characteristics of patients were analyzed, including age, International Prostate Symptom Score (IPSS), most bothersome symptoms according to IPSS, prostate volume and sexual activity. To determine the efficacy of naftopidil, IPSS, QOL index, uroflowmetry, residual urine volume and International Index of Erectile Function 5 (IIEF5) were evaluated.

2.2. Statistical analysis

Data are expressed as mean ± standard deviation, number of patients or percentage. Data at baseline and end-point were compared using the Wilcoxon signed-ranks test or paired t-test. Each correlation was analyzed by Spearman's rank correlation method. Logistic regression analysis on the impacts of age, IPSS on each item and comorbidities (e.g. cardiovascular disease, hypertension and diabetes) for erectile function was undertaken with the subjects divided into two groups: IIEF5 ≤16 (more severe than mild ED) and IIEF5 ≥17 (mild or no ED). Values of P < 0.05 were considered significant.

3. RESULTS

3.1. Patient characteristics

A total of 701 patients were enrolled, and 500 patients were defined as showing moderate BPH without IPSS <8, QOL index <2, Qmax ≥15 mL/sec and prostate volume <20 mL at baseline for analyses. Mean age of patients was 71.1 ± 8.3 years (range, 47–93 years; Table 1). The most bothersome symptom was identified as nocturia in 135 patients (30.2%), slow stream in 88 patients (19.7%), frequency in 53 patients (11.9%), urgency in 50 patients (11.2%), feeling of incomplete emptying in 45 patients (10.1%), straining in 33 patients (7.4%) and intermittent stream in 24 patients (5.4%) (Table 2). The percentage of patients with no bothersome symptoms was 4.3% (n = 19). The proportion of patients who showed a storage symptom as the most bothersome symptom was 53.2%, and 32.4% and 10.1% of patients showed voiding and post-micturition symptoms as a bothersome symptom, respectively. Nocturia was the only most bothersome symptom that increased with age (Fig. 1). In generation analysis of the most bothersome symptom, frequency and slow stream were the most frequent (27.8% each) in patients ≤59 years old (Table 2). The percentage of patients with nocturia as the most bothersome symptom increased in an age-dependent manner, and almost half of patients ≥80 years old reported this as the most bothersome symptom (42.9%).

Table 1.  Baseline characteristics of patients
ItemsMean ± SDnItemsMean ± SDn
  1. IIEF, International Index of Erectile Function; IPSS, International Prostate Symptom Score; PRV, post-void residual urine volume; PV, prostate volume; Qmax, maximum flow rate; QOL, quality of life; SD, standard deviation.

Age, years71.1 ± 8.3500Qmax, mL/sec9.8 ± 4.9166
IPSS  PRV, mL57.0 ± 85.9254
 Total17.4 ± 6.6499PV, mL38.2 ± 19.6261
 Voiding symptoms7.6 ± 3.9497IIEF5  
 Storage symptoms7.4 ± 3.3497Total8.3 ± 7.1191
 Incomplete emptying2.4 ± 1.7498Q12.0 ± 0.9191
 Frequency2.8 ± 1.5498Q21.7 ± 1.4191
 Intermittent stream2.3 ± 1.7498Q31.5 ± 1.6191
 Urgency2.0 ± 1.7498Q41.8 ± 2.0191
 Slow stream3.4 ± 1.6498Q51.5 ± 1.7191
 Straining2.0 ± 1.8497   
 Nocturia2.6 ± 1.4498   
 QOL index4.6 ± 1.0496   
Table 2.  Most bothersome symptom (%) of patients at baseline
 nAge (years)
Total≤5960–6970–79≥80
Incomplete emptying4510.119.413.86.67.1
Frequency5311.927.89.711.210.0
Intermittent stream245.45.65.55.64.3
Urgency5011.22.813.112.28.6
Slow stream8819.727.826.914.814.3
Straining337.45.64.89.28.6
Nocturia13530.25.623.435.242.9
Nothing194.35.62.85.14.3
Total447100100100100100
Figure 1.

Relationship between age and most bothersome symptom.

The number of patients who described nocturia as the most bothersome symptom plateaued at two or three points for Question 7 of the IPSS (Fig. 2). In contrast, the number of patients reporting slow stream as the most bothersome symptom increased with symptom score in the IPSS. Maximum flow rate (Qmax) steadily decreased in an age-dependent manner, and residual urine volume and prostate volume showed a slightly increasing tendency with aging (data not shown). IPSS total score and QOL index were roughly constant irrespective of age (Table 3). Correlations between nocturia score from IPSS or IIEF5 total score and age were significant (Table 4), with correlation coefficients of 0.323 and 0.534, respectively. IIEF5 total score also correlated with IPSS nocturia score and age, with correlation coefficients of 0.325 and 0.534, respectively. Logistic regression analysis on the impacts of age, IPSS on each item and comorbidities (e.g. cardiovascular disease, hypertension and diabetes) for erectile function confirmed significant associations between age or nocturia and erectile function as independent factors, with odds ratio of 1.13 (P < 0.001) and 1.41 (P < 0.05), respectively. These results suggested that nocturia has at least some effect on erectile function. Also, the number of patients who completed the IIEF5 questionnaire was 191 at the start of medication administration in the present study. Patients with comorbidities of cardiovascular disease (17/191 cases), hypertension (20/191 cases) and diabetes (2/191 cases) represented a minor proportion of the present study. The number of patients with depression was zero.

Figure 2.

Number of patients who described slow stream (A) or nocturia (B) as the most bothersome symptom.

Table 3.  Lower urinary tract symptoms in each age group at baseline
 Age (years)
≤5960–6970–79≥80
  1. Data are expressed as mean ± SD (n). IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; PRV, post-void residual urine volume; PV, prostate volume; Qmax, maximum flow rate; QOL, quality of life.

IPSS
 Total17.1 ± 6.7 (39)17.4 ± 6.9 (164)17.5 ± 6.5 (215)17.1 ± 6.5 (81)
 Voiding symptoms7.9 ± 4.3 (39)8.1 ± 4.1 (164)7.3 ± 3.7 (214)7.3 ± 3.7 (80)
 Storage symptoms6.2 ± 3.2 (39)6.8 ± 3.2 (164)7.9 ± 3.4 (214)7.7 ± 3.2 (80)
 Incomplete emptying3.0 ± 1.5 (39)2.5 ± 1.7 (164)2.2 ± 1.7 (215)2.2 ± 1.7 (80)
 Frequency3.0 ± 1.5 (39)2.8 ± 1.6 (164)2.8 ± 1.5 (215)2.6 ± 1.5 (80)
 Intermittent stream2.4 ± 1.8 (39)2.6 ± 1.8 (164)2.1 ± 1.6 (215)2.2 ± 1.7 (80)
 Urgency1.7 ± 1.6 (39)1.8 ± 1.6 (164)2.2 ± 1.7 (215)2.1 ± 1.6 (80)
 Slow stream3.4 ± 1.7 (39)3.5 ± 1.6 (164)3.3 ± 1.5 (215)3.3 ± 1.6 (80)
 Straining2.1 ± 1.9 (39)2.1 ± 1.7 (164)1.9 ± 1.8 (214)1.9 ± 1.7 (80)
 Nocturia1.5 ± 1.1 (39)2.3 ± 1.3 (164)2.9 ± 1.3 (215)3.0 ± 1.3 (80)
 QOL index4.6 ± 1.1 (39)4.6 ± 1.1 (163)4.6 ± 1.0 (214)4.7 ± 1.0 (80)
Qmax, mL/sec11.7 ± 5.4 (11)10.1 ± 4.7 (60)9.7 ± 5.0 (78)8.4 ± 4.3 (17)
PRV, mL30.0 ± 39.6 (19)56.6 ± 72.0 (86)63.7 ± 105.1 (115)50.6 ± 59.6 (34)
PV, mL31.5 ± 10.0 (18)39.5 ± 21.5 (95)37.6 ± 18.7 (116)40.3 ± 20.7 (32)
Table 4.  Correlation between LUTS and age or IIEF5
AgeIIEF5
 Correlation coefficientP-value Correlation coefficientP-value
  1. IIEF, International Index of Erectile Function; IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms.

IPSSIPSS
 Total0.0010.976 Total−0.2200.002
 Incomplete emptying−0.1090.014 Incomplete emptying−0.0990.175
 Frequency−0.0740.097 Frequency0.0010.991
 Intermittent stream−0.0880.048 Intermittent stream−0.1030.159
 Urgency0.1150.009 Urgency−0.0270.715
 Slow stream−0.0610.174 Slow stream−0.1880.010
 Straining−0.0630.158 Straining−0.1360.062
 Nocturia0.323<0.001 Nocturia−0.325<0.001
IIEF5 total−0.534<0.001Age−0.534<0.001

3.2. Efficacy and safety of naftopidil

The efficacy and safety of naftopidil is summarized as follows. IPSS total score improved significantly from 17.7 ± 6.6 to 12.4 ± 6.7 after 8 weeks (n = 299, P < 0.001). IPSS nocturia score improved significantly from 2.6 ± 1.4 to 2.1 ± 1.2 after 8 weeks (n = 304, P < 0.001). QOL index improved significantly from 4.6 ± 1.1 to 3.4 ± 1.3 after 8 weeks (n = 299, P < 0.001). Qmax increased significantly from 9.6 ± 5.1 mL/sec to 10.6 ± 5.6 mL/sec after 8 weeks of naftopidil administration (n = 87, P = 0.020). Residual urine volume decreased significantly from 66.0 ± 82.4 to 49.6 ± 63.3 mL after 8 weeks (n = 119, P = 0.007). However, IIEF5 total score was almost unchanged after 8 weeks (n = 150, P = 0.231).

We performed additional analyses on amelioration of ED using the response status for nocturia to compare groups with ≤1 episode per night and with ≥2 episodes per night. The IPSS and IIEF5 were completed by 141 of 500 patients both before starting and after 8 weeks of naftopidil treatment. Among those patients, the number of responders for nocturia (defined as those patients showing a beneficial decrease of ≥1 in the IPSS nocturia subscore after treatment) was 58, the number without changes was 66, and the number with exacerbation was 17. This analysis was therefore conducted with 58 cases. Among the responders for nocturia, IIEF5 total score at baseline showed no significant difference between patients with an IPSS nocturia score ≤1 and patients with a score ≥2 at end-point (P = 0.186). However, IIEF5 total score after 8 weeks of naftopidil administration was significantly better in patients with an IPSS nocturia score ≤1 than in those with a score ≥2 (P = 0.038, Fig. 3).

Figure 3.

Relationship between nocturia and International Index of Erectile Function (IIEF5).

Of the 698 patients for whom safety was analyzed, 34 patients (4.9%) experienced adverse events. Major events included postural hypotension (2.0%) and dizziness (0.9%), but all events were mild in severity.

4. DISCUSSION

The novel finding of this investigation is that nocturia, commonly described as the most bothersome symptom by BPH patients, may impact ED. The percentage of patients with slow stream as the most bothersome symptom increased with increasing IPSS subscore for slow stream. Conversely, the percentage of patients with nocturia as the most bothersome symptom reached a plateau from a relatively low IPSS subscore for nocturia. Patients who feel that nocturia represents the most bothersome symptom may thus need to improve to an IPSS nocturia score ≤1 before achieving substantial relief from finding this symptom bothersome. Meanwhile, slow stream seemed relatively tolerable as a symptom, with many patients not describing this as the most bothersome symptom until reaching an IPSS subscore of 5.

Another novel finding was that a moderate correlation existed between IPSS nocturia score and IIEF5 total score, but not any other IPSS items. Nocturia could thus play an important role in ED. The relationship between IIEF5 total score and improvement of IPSS nocturia score was interesting, revealing a difference between the group with an IPSS nocturia score ≤1 and the group with a score ≥2. That is, erectile function might be maintained if nocturnal voiding can be kept to a maximum of one episode a night, or reduced to a maximum of one episode a night with appropriate treatment. IIEF5 total score for the group in which the IPSS nocturia score improved to ≤1 by naftopidil was significantly higher than in the group with improvement to a score ≥2. Keeping episodes of nocturia to once a night at most may thus be important in maintaining erectile function. The difference between ≤1 episode of nocturia and ≥2 episodes in terms of erectile function in the present investigation is interestingly consistent with a previous study into bone fracture and mortality rate, both of which appeared significantly higher in a group with nocturnal voiding ≥ 2 episodes/night as compared to ≤1 episode/night.13 However, further research is needed to clarify the impact of nocturia on ED, and the preliminary results from this investigation need to be validated in patients with nocturia.

In the present results, the most bothersome symptom in BPH patients was analyzed for each generation. Interestingly, only nocturia increased in frequency in an age-dependent manner. No other LUTS were considered as more bothersome in association with aging. Age-stratified normal values for measures such as IPSS were established in a community-dwelling population of healthy German men > 50 years old to judge patients with LUTS due to BPH.26 Two interesting points were identified: (i) IPSS total score was basically consistent across age groups; and (ii) IPSS nocturia score and urgency score increased steadily with aging. In an Austrian population-based cross-sectional survey on LUTS, IPSS also correlated significantly with age.27 Those studies showed a common characteristic, with general residents showing mild or weak LUTS. The discrepancy between previous studies and the present investigation in terms of transitional changes in IPSS total score might be due to the subject background of moderate or severe LUTS. Severe LUTS thus might not proceed with age, at least as evaluated by IPSS total score.

In terms of nocturia, the population-based prevalence of needing to get up twice or more a night to urinate increases with age from 8.2% in men at 20–34 years old to 55.8% in men at ≥75 years old.28 Nocturnal episodes thus increase with aging. This supports the present data that IPSS nocturia score increased with aging. The fact that the percentage of patients feeling that nocturia represents the most bothersome symptom increased with age seems to be associated with the escalation of nocturnal frequency.

In previous studies, α1-blockers have been suggested to improve erectile function only slightly if at all.20,21,29,30 The present investigation showed that naftopidil did not have any such beneficial effect for erectile function, although excellent improvements in male LUTS were achieved. Some studies have revealed that sexual dysfunction correlates with the severity of LUTS.17,31,32 Likewise, we found a significant correlation between LUTS (e.g. IPSS total score, and IPSS scores for nocturia and slow stream) and ED. Logistic regression analysis did not identify any influence of comorbidities (e.g. cardiovascular disease, hypertension and diabetes) on ED severity in the present study. By contrast, in the previous investigation of prevalence, cardiovascular disease, hypertension, diabetes and depression were each associated with ED in a large number of patients.33–36 These findings indicate that, in terms of prevalence, some comorbidities may be associated with the incidence of ED. The relationship between ED severity and etiology of various comorbidities need to be moreover clarified in studies with a larger sample size. The finding of nocturia and slow stream as the two most bothersome symptoms was interesting. Among these, nocturia showed a moderate correlation with erectile function, whereas slow stream did not. Nocturia thus appears associated with decreased QOL and increased prevalence of depressive symptoms.37,38 Nocturia in particular might impact ED through decreased QOL due to sleep disturbance. Most elderly men with suggested BPH clearly appeared to be suffering from nocturia in this research. A significant correlation has been reported to exist between nocturia and depression.39 A previous investigation showed that depressive condition correlates with ED.36 We therefore guess that nocturia has some kind of impact on ED, at least in patients with BPH. In addition, risk of diabetes also increases with age,40 and the presence of diabetes significantly raises the risk of ED.33–34 These findings could suggest associations between diabetes and either nocturia or ED. Furthermore, Johannes reported that the risk of ED was also increased with heart disease and hypertension. We therefore speculate that heart disease and/or hypertension is the biological linkage between nocturia and ED in elderly men.

In conclusion, nocturnal frequency was identified as the most bothersome symptom correlated with aging. Nocturia could associate ED, and limiting the frequency of nocturia to ≤1 episode a night might be meaningful for maintaining QOL in elderly men.

Disclosure

There are no financial or commercial interests concerned for the authors of the present paper.

Appendix

5. APPENDIX I

5.1. KING Study Group

Arida Municipal Hospital, Asahikawa Medical University Hospital, Dokkyo Medical University Hospital, Fujita Health University Hospital, Fukui University Hospital, Hamamatsu Minami Hospital, Hamamatsu University School of Medicine University Hospital, Hashimoto Municipal Hospital, Hiroshima City Asa Hospital, Hiroshima Prefectural Hospital, Hiroshima University Hospital, Hiroshima-Nishi Medical Center, Horigome Clinic, Irisawa Hospital, Isahaya Health Insurance General Hospital, Kaetsu Hospital, Kagawa University Hospital, Kanmon Medical Center, Kido Hospital, Kishiwada City Hospital, Kitasaito Hospital, Kochi Medical School Hospital, Koseki Urological Clinic, Kouseikai Hospital, Kouseiren Hiroshima General Hospital, Maezawa Urology Clinic, Matsushita Clinic, Megumino Hospital, Miyoshi Central Hospital, Nagasaki Goto Chuoh Hospital, Nagasaki Medical Center, Nagasaki Municipal Hospital, Nagasaki Prefecture Shimabara Hospital, Nagasaki Rousai Hospital, Nagasaki University Hospital, Nihon University Itabashi Hospital, Nihon University Nerima Hikarigaoka Hospital, Niigata Rinko Hospital, Obama Municipal Hospital, Okitama Nanyo Public Hospital, Okitama Public General Hospital, Rinku General Medical Center, Sakae Clinic, Sanjou General Hospital, Sapporo Medical University Hospital, Sasebo City General Hospital, Sasebo Kyosai Hospital, Sawamura Clinic, Shinshu University Hospital, Shizuoka Kohseiren Enshu Hosupital, Shoji Clinic, Syunan City Shinnanyou Hospital, Takahata Public Hospital, The Japanese Red Cross Nagasaki Genbaku Hospital, Toyoura Hospital, Ube Industries LTD Central Hospital, Ureshino Medical Center, Yaguchi Clinic, Yamagata University Hospital, Yamaguchi Grand Medical Center, Yamaguchi Red Cross Hospital, Yamaguchi University Hospital, Yamanashi University Hospital.

Ancillary