Nocturia in patients with benign prostatic hyperplasia: evaluating the significance of ageing, co-morbid illnesses, lifestyle and medical therapy in treatment outcome in real life practice

Abstract

Aim: The aim of study was to evaluate the influence of ageing, lifestyle, and co morbid illnesses on treatment outcome of nocturia among men with BPH.

Methods: Patients with BPH on medical therapy of least 6 months and up to 48 months were interviewed. Nocturia episodes, co morbid illnesses, beverage intake frequency, medications and work history were documented. Body Mass Index (BMI), waist circumference (WC), prostate volume, and prostate specific antigen (PSA) were recorded. Treatment failure is defined as persistent nocturia despite on medical therapy for BPH.

Results: In 156 patients, the prevalence of nocturia was 96.7% while nocturia of 2 or more was 85.9%. Factors associated with treatment failure was older age (p < 0.01), usage of diuretics (p = 0.03), and antimuscarinics (p < 0.01), while active working status (p < 0.01), use of desmopression (p = 0.01), and increased coffee intake (p = 0.02) were associated with nocturia improvement. Co-morbid illnesses, obesity, WC, alcohol intake, PSA, prostate volume, and use of BPH medical therapy did not influence treatment outcome.

Conclusion: Advancing age has a significance negative outcome on nocturia treatment, while standard BPH medical therapy and co morbid illnesses have an insignificant impact. However, alleviation of bothersome symptoms is possible with the understanding of its patho-physiology and individual-based approach to treatment and expected outcome.

• Malaysia
• nocturia
• prevalence
• prostate

Introduction

Nocturia is defined as the need to awaken at night 1 or more times to void [1]. It is a common symptom among men suffering from benign prostatic hyperplasia (BPH) and has significant impact on their quality of life [2,3]. The incidence of nocturia among BPH patients range from 70 to 90% [4,5] while its incidence in the general community range from 68% to 93% [6–12]. Modifiable diseases and lifestyle factors associated with the prevalence of nocturia among men and women in the general population are obesity, metabolic syndrome, an increased waist circumference, cardiac disease, obstructive sleep apnea, diabetes mellitus, renal disease, medication usage, types, and frequency of beverage intake and sleep patterns [13,14]. Sleep disruptions resulting from nocturia lead to cognitive dysfunction, poor concentration, mood changes, and impaired work-related productivity among the working individuals [15] and is associated with higher mortality, cardiac disease and bone fractures among the elderly [9,10,16].

Medical treatment for BPH using either alpha blocker, 5 alpha-reductase inhibitor (5ARI), or anti-muscarinic as a single agent or in combination often alleviate other storage and voiding symptoms but have lesser effect on nocturia. This is because its cause is multifactorial and it is believed to be due to combination of nocturnal polyuria, decreased nocturnal bladder capacity, overactive bladder, reduced functional bladder capacity, bladder outlet obstruction, and urogenital ageing [7].

In this study, we set out to determine the significance of ageing, co-morbid illnesses, lifestyle factors, and use of medical therapy on the treatment outcome of nocturia among BPH patients in a real-life urology practice.

Methods and material

This was an observational cross section study done in Universiti Kebangsaan Malaysia Medical Center (UKMMC) for a period of 8 months (November 2010–June 2011). It was approved by the local hospital board of ethics. All patients with BPH under medical treatment for a minimum period of 6 months and maximum of 48 months were interviewed. Standard medical treatment used for BPH were alpha blocker, five ARI and anti-muscarinic as monotherapy or in combination. Oral desmopressin was added only in selected cases of nocturia. Patients with uro-genital cancer, urolithitasis, previous prostate related surgery, active urinary tract infection, and without consent were excluded.

Patients were interviewed by the urology doctors to obtain information on their age, presence of persistent nocturia, improvement of nocturia from baseline (baseline being defined as number of nocturia prior to any medical treatment for BPH, persistent nocturia defined as on-going nocturia episodes despite on medical treatment and nocturia improvement defined as a reduction of nocturia episode by 1 or more times from baseline), lower urinary tract symptoms, co- morbid illnesses, beverage-frequency intake, working status, and current medication usage. Patients were made to re-call their baseline nocturia. If they had forgotten, then documented nocturia episodes during their first urology consultation will be taken as baseline.

History of co morbid illness was taken from patient and re-confirmed from previous medical documentation. If patients could not recall their list of medications, then case notes were obtained to get list of current medication and presence of other co-morbid illness. Patients were also asked to state their current most bothersome symptom. They then had their height, weight, and waist circumference (WC) measured. A digital rectal examination was performed to assess prostate size while most recent serum prostate specific antigen (PSA) values were obtained from computerized medical records.

Nocturia was defined based on the International Continence Society 2002 definition [1]. Statistical analysis was done comparing patient with and without improvement of nocturia. SPSS version 17 (SPSS Inc., Chicago, IL) was used for analysis. Univariate analysis using the Chi-square and the ‘t’-test was used to assess significance between the two groups while multivariate analysis was performed using the logistics regression model. Significance was true if p < 0.05.

Results

A total of 156 men fulfilled the inclusion criteria and were successfully interviewed. The mean age of patients was 69.1 ± 6.7 years old. The racial distribution was Chinese 63.5%, Malay 26.9%, and Indians 9.6%. The prevalence of nocturia (>1 episode per night) was 96.7% while nocturia of 2 or more episodes was 85.9%. Despite this high prevalence, 51.3% of patients actually reported improvement in nocturia episodes from baseline. Table 1 shows the average number of baseline and persistent nocturia episodes despite on medical therapy and percentage of reduction in nocturia voids based on the age range. In general, there is a decreasing trend of improvement with advancing age range. Table 2 shows the various monotherapy and combination therapies used and its relation to nocturia improvement.

Table 1. Mean number of nocturia episodes and improvement based on the age range.

Age range (years)	Mean baseline nocturia (n)	Mean persistent nocturia (n)	% reduction of nocturia from baseline (%)
50–55	4.75	2.5	47.4
56–60	2.73	1.67	38.8
61–65	3.42	2.16	36.8
66–70	3.0	2.45	18.3
71–75	3.95	2.9	26.6
76–80	4.28	3.5	18.2
81–85	4.42	3.0	32.1

Table 2. Standard medical therapy used as monotherapy or in combination for BPH patients and treatment outcome for nocturia.

Nocturia improvement	Yes	No	Total, n (%)
Alpha blocker alone	57	39	96 (62)
5ARI alone	1	3	4 (2.5)
Anti muscarinic alone	1	0	1 (0.64)
Desmopressin alone	0	0	0
Alpha blocker + 5ARI	12	12	24 (15)
Alpha blocker + antimuscarinic	3	11	14 (9)
Anti muscarinic + 5ARI	0	1	1 (0.64)
Alpha blocker + desmopression	3	0	3 (2)
Alpha blocker + 5AR Inb + antimuscarinic	0	8	8 (5)
Alpha blocker + 5AR Inb + Desmopression	5	0	5 (3)
	82	74	156 (100)

Out of 88 patients whom answered question ‘what is your single most bothersome symptom’, 42 (47.7%) answered nocturia. Other bothersome symptoms in the descending order are poor flow (n = 20 [22.7%]), frequency (n = 13 [14.7%]), urgency (n = 10 [11.3%]), and urge incontinence (n = 2 [2.2%])

Table 3 displays patients’ characteristics, studied co-morbid illnesses and other life-style factors which were evaluated for their influence on treatment for nocturia. Factors that negatively influenced nocturia treatment were advancing age, current use of diuretics, and anti-muscarinics. Factors that positively influenced nocturia treatment outcome were active working status, frequency of coffee intake and use of desmopressin.

Table 3. Patient’s characteristics, presence of co morbid illness, beverage intake, and use of medical therapy and its influence on nocturia improvement.

	Nocturia
	Improved	No improvement	p value
Age (years)	66.6	72.4	<0.01
Race			0.68
Chinese	51	47
Indian	7	8
Malay	24	18
PSA (ng/ml)	1.92	1.97	0.89
Prostate volume (cc)	33.7	34.1	0.80
BMI (kg/m^2)	25.8	25.2	0.32
≤25	35	38	0.38
25.1–30	36	24
≥30.1	9	8
WC (cm)	91.2	89.7	0.46
Hypertension (n)			0.19
Yes	43	45
No	37	25
Diabetes mellitus			0.36
Yes	24	26
No	56	44
Chronic renal failure			0.81
Yes	6	6
No	74	64
Ischemic heart disease			0.83
Yes	16	15
No	64	55
Use of diuretics			0.029
Yes	2	8
No	78	62
Work status			<0.01
Fulltime	11	2
Part time	11	1
Retired	58	67
Alcohol intake			0.12
None	58	57
Once a month	11	10
Once fortnightly	5	3
Once a week	6	0
Coffee/tea intake			0.01
Nil to 1 cup/d	25	38
2–4 cups/d	50	31
More than 4/d	5	1
Use of alpha blocker			0.22
Yes	77	67
No	3	6
Use of 5 AR Inb			0.29
Yes	19	22
No	61	48
Use of anti-muscarinic			<0.01
Yes	3	77
No	18	52
Use of oral desmopressin			0.02*
Yes	8	0
No	72	70

*Yates correction.

Other known co-morbid illnesses which have been shown to be associated with nocturia were not found to be significantly important in determining treatment outcome of nocturia. The use of standard medical therapy for BPH as well did not significantly impact nocturia treatment.

Discussion

In this study, we find that nocturia continues to bother men with BPH despite on medical therapy. Nocturia of 1 or more is present in 96.7% of our patients while significant nocturia of 2 or more voids is present in 85.9%. A similar observation among men with BPH in Malaysia supported our findings [4,15]. The cause of nocturia is mutifactorial and, therefore, difficult to treat in the majority of patients. A study by Yoong et al. [17] in Malaysia showed that nocturnal polyuria was present in 85.4% while polyuria was seen in 9.8% of BPH patients. In a study comparing Asians and Caucasian men with LUTs and causes of nocturia, Asian men were found to have a reduced nocturnal bladder capacity with lesser nocturnal production while Caucasian men suffered from nocturnal polyuria. This would implicate different management strategies in treating nocturia among different ethnic groups [18].

Advancing age was a significant negative factor to nocturia treatment among BPH patients in our study. With advancing age, the percentage of nocturia reduction from baseline gets smaller, and treatment success diminishes. Previous population-based studies and randomized trials have consistently shown a positive correlation with increasing age and treatment outcome of nocturia [19]. Hakkinen et al. showed that incidence of mild nocturia (1–2 voids per night) increases in men when they age from 50 to 60 years old. The incidence of severe nocturia (five voids or more) increases significantly after age of 75 years old [20]. An increasing age would worsen nocturia by possibly a multifactorial and complex manner such as an enlarging prostate gland, reduced functional bladder capacity, presence of co morbid illness, changes in endogenous vasopression release, alterations in neuro-urological and renal patho-physiology and sleep habits.

Advancing age is associated with decreasing concentration of serum total testosterone (TT). Kim et al. showed significant negative impact of TT levels and storage symptoms and significant lower TT levels among patients with >4 nocturia voids versus <3 voids. However, the actual pathway of this patho-physiology is still debatable [21].

Nocturnal polyuria was shown to increase with age while nocturnal bladder capacity decreased with advancing age [22]. A previous study on an antimuscarinic has observed the adverse effect advancing age with treatment-associated symptom improvement and the global efficacy of a medication [23].

The above observations explain the insignificant impact of standard medical therapy on the treatment of nocturia as we demonstrated. The distribution of various medical therapy used to treat BPH in our group of patients are probably similar to other community-based urology practices, where alpha blocker usage dominates as monotherapy, followed by various combinations. We found no significant improvement in nocturia among patients using alpha blockers. It has been previously shown that among all symptoms evaluated in the International Prostate Symptom Score (IPSS), the degree of improvement for nocturia has been the lowest. However, alpha blocker such as tamsulosin has been shown to reduce nocturia by 13.9% while other formulations have been shown to reduce nocturia by 0.4–0.8 episodes per night during treatment periods of 1–4 years [5,24–27]. These findings were not significant when compared to placebo effect and maybe of in-significant benefit to the BPH patient.

We also found a negative impact of antimuscarinic on treatment outcome for nocturia. Although not specifically meant for treatment of nocturia, patients with nocturia associated with overactive bladder (OAB) have often been prescribed this medication. Double-blinded studies using solefinacin and tolterodine have shown to reduce nocturia episodes by 0.71 and 0.63, respectively [28]. Solefinacin when used in men and women with OAB, reduced nocturia episodes by 0.46 per night [29]. These reductions may be significant statistically but not from a clinical point of view and from patients perspective. However, Kaplan et al. did demonstrate that among patients with BPH-related LUTs, the use of tolterodine improved nocturia from 4.1 to 2.9 episodes per night [30]. The negative association of antimuscarinic in our study is a result of three possible factors. First, majority of patients were not evaluated for nocturnal polyuria when commencing anti-muscarinic therapy, hence the in-effectiveness of treatment. Second, the adverse effect of dry mouth and thirst may encourage patients to drink more fluids as night thus worsening nocturia. Third, it is the effect of advancing age and global reduction in efficacy of treatment in an elderly patient.

Additional treatment with desmopressin may be needed to address this issue. Long-term results on safety and efficacy of desmopressin as a treatment for nocturia have been proven [31].

Our observation also shows significant improvement of nocturia among patients on desmopressin. However, only 8% of our patients were on desmopressin, despite 85.9% of them suffering from two or more nocturia voids. We believe that the majority of patients may be suffering from nocturnal polyuria and have gone undiagnosed and under treated. There are cautions in the usage of desmopressin especially among the elderly for fear of hyponatremia and patients compliance to strict biochemical monitoring.

EAU guidelines state that desmopressin should only be used in cases of nocturnal polyuria [32]. However, several studies have evaluated the effectiveness and the safety of desmopressin in patients only with significant nocturia (two or more voids per night) with or without nocturnal polyuria. These studies showed that significant decrease of nocturnal voids, decrease in nocturnal dieresis, and increase in sleep time before first nocturnal void were achieved among nocturic patients and were generally safe with good long-term effect [31,33,34]. Tine et al. in also noted that among BPH patients whom had persistent nocturia of two or more voids, despite on the best medical therapy, benefited from the use of desmopressin. These patients were not evaluated for the presence of nocturnal polyuria prior to treatment. Patients with a normal and high nocturnal bladder capacity index (higher values indicate reduced bladder capacity), as well as the elderly, benefited from therapy with normalization of nocturia in 51% of patients. Hyponatremia was reported in 14.5% of patients but was clinically insignificant [35].

We believe that the effect of age contributed to the significance of working status in the treatment of nocturia. Younger patients, especially with regular or part-time work, are likely more compliant to medication and lifestyle changes to overcome nocturia. Other reasons why retired men suffer more nocturia may be the possibility of a sedentary lifestyle, an associated impaired cognition and frequent napping through-out the day. Foley et al. observed that prevalence of frequent napping ranged from 10% among 55–64 years to 25% among 75–84 years old. Frequent napping was independently associated with nocturia [36]. A higher Mini Mental state examination (MMSE) was also found to be a protective factor against nocturia (odd ratio 0.96) [12] while moderate to vigorous physical activity decreases risk of LUTs by 25% relative to sedentary lifestyle [37].

Several community-based surveys have resulted in equivocal outcome about the influence of co-morbid illness (such as diabetes mellitus, hypertension, renal impairment, and ischemic heart disease) on the prevalence of nocturia. Mary et al. from the Boston Area Community Health (BACH) study demonstrated positive correlation among the number of nocturia voids with age, type II DM, increasing BMI, cardiac disease, and use of diuretics [14]. These findings are supported by other large cross-sectional and longitudinal studies which noted independent association among hypertension, age, diuretic use, increasing BMI, and diabetes mellitus with 2 or more nocturia voids [8,11,38]. However, in our observation, these co-morbid illnesses did not significantly affect treatment outcome of nocturia. Therefore, although they do increase the prevalence, we believe their influence on treatment among men with BPH and nocturia is insignificant.

Obesity and an increased WC have also been shown to increase prevalence of nocturia by virtue of its association with other illnesses such as hypertension, diabetes mellitus, obstructive sleep apnea, depression, excessive eating, and drinking. The exact patho-physiology of obesity and LUTs is unclear. Men in all age group whom are overweight and obese had higher prevalence of nocturia. The odds ratio of suffering from nocturia compared with non-overweight individuals are 1.3 and 2.0 for overweight and obese men, respectively [13,39]. Obesity was positively correlated with prostate volume. Each 1 kg/m² increase in BMI lead to a 0.41 cc increase in prostate volume. A BMI of 30–34 kg/m² is associated with increase 30% risk of BPH compared with normal BMI.

WC, as opposed to BMI, is thought to be a better representation of body fat distribution and WC of >90 cm represents central obesity. In a study of Korean patients, patients with WC >90 cm experience higher incidence of storage LUTs (nocturia and urgency) and have larger prostate volumes [40,41]. Rohrmann et al. also noted among men in the United States, waist circumference of more than 102 cm had a 1.48 odds ratio of developing nocturia compared with men with smaller waist circumference [42]. We did not find significant influence of BMI and WC to nocturia improvement possibly due to a small sample size. It is also possible that the pathway taken with medical therapy to improve bladder dysfunction and nocturia is not influenced by the metabolic and anatomical changes associated with obesity.

Interestingly, we found that an increased coffee intake helped with nocturia improvement. The reason is unclear and unexpected and the increased caffeine taken is supposed to worsen bladder storage symptoms. Community-based studies have revealed positive correlation among severe BPH symptoms, nocturia, and coffee intake [43,19], while others have actually shown no relationship and even a decreasing risk of BPH symptoms in relation to coffee intake [8,39,44,45]. Coffee is postulated to increase serum low-density lipids (LDL) and indirectly worsening of LUTs [46]. A morning coffee intake was thought to act as a daytime diuretic and, therefore, reduce night-time voids [8]. All this is not proven and remains to be investigated. From our observation, we feel that patients with nocturia improvement, while on medical therapy, are not particularly concerned about reducing frequency of coffee intake.

Alcohol intake with its diuretic effect was thought to positively contribute to increases of noctural voids. However, current reports show no significant relation between the amount of alcohol intake with number of nocturia and any improvement in nocturia voids [11]. Some studies even noted inverse relation between moderate alcohol intake and nocturia [43]. Individuals with alcohol consumption less than 150 g per week were found to have lower risk of moderate to severe nocturia than abstainers. The authors of this findings postulated that mild to moderate alcohol consumption may protect against development of nocturia [45]. We found no such correlation between the frequency of alcohol intake and the treatment outcome for nocturia.

The limitations encountered in this study were that patients were not asked to fill a frequency volume chart during this interview, therefore, we could not document the prevalence of nocturnal polyuria. The presence of obstructive sleep apnea was not evaluated. The time and exact milliliters of coffee and alcohol intake were not specified. We also could not verify the effect of newer medications for diabetes and hypertension on the patho-physiology of nocturia.

In conclusion, nocturia continues to be a significant bothersome symptom among patients with BPH, despite on standard medical therapy. Advancing age is a significant negative factor for treatment success of nocturia. Although co-existing medical illnesses and obesity are associated with increased prevalence of nocturia, it does not affect treatment outcome. Frequency volume charts should be used especially in patients with persistent bothersome nocturia to allow selection of an appropriate medical therapy.

Declaration of interest

The authors report no declarations of interest.