Risk factors Conditions

Benign prostatic obstruction (BPO): Overall, “LUTS suggestive of BPO” constitute a well-recognized risk factor for nocturia (102,113,114). In the FINNO Study (102), half of the subjects with phys-ician-diagnosed benign prostatic enlargement (BPE) reported at least 2 voids per night; however, only a third of the men with nocturia had BPE. Indeed, the impact of BPE causing BPO may be overesti-mated (nocturic men probably are more likely to be diagnosed with BPO than men without nocturia, and women do not have substantially less nocturia despite not having prostates). Nocturia was the least-specific LUTS associated with BPO, and treatment to relieve BPO had less effect on nocturia than on other LUTS in Japanese studies (115,116). Furthermore, in a Veterans Affairs study on men with bothersome LUTS, those receiving doxazosin had very modest net reductions in nocturia, while finasteride had an effect indistinguishable from placebo (117). Furthermore, nocturia is one of the most persistent LUTS following prostate surgery (118,119), if not the single most persistent.

Depression: In a Swedish population-based study (81), subjects with major depression (assessed by the Major Depression Inventory) reported substantially more nocturia than those without. The associ-ation was especially strong among men (odds ratio (OR 6.5, 95% confidence interval, CI [2.6, 15.6]

for men; and OR 2.8, 95% CI [1.3, 6.3] for women, adjusted for age and somatic health). However, in a subsequent analysis from the same database (120), the authors reported that both major depres-sion (OR 4.6, 95% CI [2.8, 7.5]) and taking an SSRI (OR 2.2, 95% CI [1.1, 4.5]) were associated with increased prevalence of nocturia (gender was deleted by the logistic regression model). In the TAMUS (83) cohort study (conducted among men aged 50 years and older), those with depressive symptoms at study entry were at 2.8 times higher risk (95% CI [1.5, 5.2]) for moderate or severe nocturia (defined as ≥3 voids/night) than those without depressive symptoms, but nocturia had no effect on depres-sive symptoms during the 5-year follow-up. In the FINNO Study (102), nocturia was associated with antidepressant use only in men (OR 3.2, 95% CI [1.3, 7.7]). Depression itself was not associated with nocturia after adjustment for other factors, despite associations in the age-adjusted analyses (OR 2.8, 95% CI [1.6, 5.0] for men; and OR 2.0, 95% CI [1.2, 3.3] for women). In the BACH Survey (121), nocturia was associated with both depression (defined as score of 5 or more on the Center for Epidemiological Studies Depression Scale) and use of antidepressants in both genders, particularly in younger age groups. While 10.1% of men and 15.6% of women reported depression among those without nocturia, corresponding figures were 15.6% and 30.0% for those with nocturia (80).

Hypertension and coronary artery disease: The connection between nocturia and hypertension is not clear. It has been suggested that essential hypertension and NP are part of the same pathophysiological process (122). In a Japanese study (123) and in a US (39,55) study, hypertension was associated with nocturia, although effect sizes were modest (ORs, 1.5–1.6). However, in studies conducted in Europe (102,124), neither NP nor nocturia was associated with hypertension. In a secondary analysis from the BACH Survey (125), nocturia was not generally associated with antihypertensive use. However, monotherapy with calcium channel blockers in women (OR 2.65, 95% CI [1.04, 6.74]), and combin-ation therapy with loop diuretics in men was associated with nocturia (combincombin-ation therapy OR 2.55, 95% CI [1.26, 5.14]) (125). No other significant associations for nocturia with angiotensin-con-verting enzyme inhibitors, beta blockers, calcium channel blockers, or loop and thiazide diuretics were found. While the treatment for hypertension may cause (10,125,126) or alleviate nocturia (127) in some cases, appropriate methods are of particular importance when assessing this relation.

Earlier studies in men (38,123,124) did not find a relation between nocturia and cardiac disease.

However, in these studies, an association between cardiac symptoms or disease and nocturia was found in the preliminary analyses before multivariate models. In more recent studies (98,102,121,128), coronary disease has been shown to be associated with nocturia. In the FINNO Study, coronary artery disease was associated with nocturia in the age-adjusted analyses in both sexes; but after adjustment for other factors, the association persisted only for women (OR 3.1, 95% CI [1.5, 6.6]) (102).

Neurological diseases: Most patients with multiple sclerosis have bladder dysfunction, which may also lead to nocturia (129). In studies conducted among elderly people, nocturia was associated with stroke and cerebrovascular disease (128–130). Moreover, in a study among patients with Parkinson’s disease, severity of disease was also associated with increased nocturia (mean number of nocturia episodes was 1.8 in the mild, and 2.9 in the severe Parkinson’s groups) (131). A relationship of nocturia with restless legs syndrome (RLS) was found in the FINNO Study (102). Subjects of both sexes with RLS (compared with those without) had almost triple the risk of having nocturia. However, only 1

of 8 with nocturia had RLS. Increased risk for nocturia in patients with RLS may relate to disturbed sleep (132). Furthermore, patients with RLS use antidepressants, gastrointestinal medications, and asthma/allergy drugs more frequently than subjects free of them (133).

Menopause and hormone therapy: In the FINNO Study, the postmenopausal period was associated with increased nocturia (OR 2.3; compared with premenopausal women) (134), consistent with a population-based study conducted on middle-aged women in Denmark (OR 2.4) (135). Two other studies also reported increased nocturia in the postmenopausal period (136,137), whereas another attributed this to aging rather than to menopausal transition (138). The menopausal period is often associated with sleep disturbances for other reasons including hot flashes, mood disorders, and increased sleep disordered breathing (139); therefore, individuals reporting nocturia may be awak-ening due to non-bladder causes. There are few studies evaluating the effect of menopausal hormone replacement therapy on nocturia. In Finnish and Swedish population-based studies, there were indi-cations for increased nocturia among women with menopausal hormone therapy, but the findings were statistically insignificant in the multivariate analysis (134,140). In a small, randomized trial (151), those with menopausal hormone therapy did not report less (or more) nocturia than those with placebo. This finding was confirmed in randomized, controlled trials of an estradiol vaginal ring (152) and vaginal estradiol on urinary storage symptoms after sling surgery (143).

Nocturnal polyuria: The ICS defines NP as an increased proportion of the 24-hour output of urine volume occurring at night (2). However, there is a paucity of studies providing reference values. In the Krimpen study, average nocturnal urine production was slightly more than 60 mL/hr. The auth-ors suggested that nocturnal urine production exceeding 90 mL/hr is abnormal (144). However, the authors concluded that “nocturnal urine production as an explanatory variable for nocturnal voiding frequency is of little value.” What is the fundamental pathogenesis of NP? Congestive heart failure,

“third spacing” (venous insufficiency, nephrosis), or late-night diuretic administration are potential underlying causes. Using bioelectric impedance analysis, nocturnal urine volume has been shown to correlate with the difference in fluid volume in the legs (r=0.53; p=0.002) and extracellular fluid volume (r=0.38; p=0.02) between the morning and evening (145). This is indirectly supported by the results of a non-randomized study, where the number of nocturia episodes decreased significantly from 3.3 to 1.9 after 8 weeks of walking exercise in elderly men (146). Possible other pathways to nocturnal polyuria also include impaired renal concentrating capacity, diminished sodium conserv-ing ability, dysfunction of antidiuretic hormone secretion, and increased secretion of ANP (e.g. due to sleep apnea), leading to increased nighttime urine production (147–149). The pathophysiology of NP merits further studies.

Obesity and diabetes: Several studies have shown the relation of being overweight or obese with nocturia. Obesity was associated with more than 3-fold risk for nocturia in a Swedish study among middle-aged women (150), and with more than 2-fold risk in the FINNO Study (151). Confirmatory findings have been reported (39,121,152,153). In the longitudinal TAMUS study among men aged 50 years and older (154), obese men were at higher risk for mild nocturia, and particularly for moderate or severe nocturia (relative risk [RR] 2.3, 95% CI [1.1, 4.7]), compared with normal-weight men. The frequency of nocturia at baseline did not increase the incidence for obesity at follow-up (154). An association between diabetes and nocturia has been reported in most (102,114,121,123,128,150,153, 155,156), but not all reports (38,132). In the BACH Survey (126) and in a Danish study that included

patients aged 60–80 years (164), nocturia was associated with a doubled risk for diabetes (OR 1.7 in the Boston and OR 2.0 in the Danish study). In these surveys, it remained unreported whether there were gender differences. In the FINNO Study (102), diabetes was associated with nocturia in the age-adjusted analyses in both sexes, but after adjustment for other factors, the association persisted only for women (OR 2.7, 95% CI [1.4, 5.2]).

Overactive bladder and detrusor overactivity: According to the ICS, OAB is a symptom-defined condi-tion characterized by urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia (2). Urinary urgency is commonly proposed as the primary driver of all symptoms of the OAB constellation, including increased nocturia (157). Recent evidence using nocturnal cystometrogram testing has confirmed a temporal relationship between nocturnal detrusor overactivity and nocturic voids in some patients with nocturia (158). Urinary urgency was a clear risk factor for nocturia in the FINNO Study (OR 7.4, 95% CI [4.5, 12] for men; and OR 4.9, 95%

CI [3.2, 7.7] for women) (102). However, while half of subjects with urgency also reported at least 2 voids per night, only 1 in 3 with nocturia reported urgency (51). As most people with nocturia do not report frequent urgency, it is not surprising that the treatment for nocturia with bladder relaxants (antimuscarinics) is often unsuccessful (159).

Pelvic surgery–hysterectomy and stress urinary incontinence (SUI) operations: Results are inconsistent regarding nocturia and hysterectomy, with hysterectomy variously being associated with decreased (160–162) or increased prevalence for nocturia (135), or not associated with nocturia (163,164). In the FINNO Study, hysterectomized women had an OR of 1.8 for nocturia, with borderline statistical significance, whereas surgery for SUI was not associated with nocturia despite an association of urgency with SUI surgery (134). However, statistical power was limited regarding analyses on SUI surgery in this study.

Prostate cancer: Many men with LUTS express a fear for prostate cancer (165); however, whether LUTS (including nocturia) really are suggestive of prostate cancer is not well known (166). In the large substudy of the Nord-Trøndelag Health Study 1995–1997 (HUNT-2) (167), LUTS severity was posi-tively associated with the subsequent diagnosis of localized prostate cancer but not with advanced or fatal disease. In the FINNO Study (102), more than 70% of men with physician-diagnosed prostate cancer reported at least 2 voids per night, while 7% of men with nocturia reported prostate cancer.

Are men with nocturia more vulnerable to be diagnosed (due to use of prostate-specific antigen [PSA] among men with LUTS), or does prostate cancer really cause nocturia, or is nocturia a side effect of various prostate cancer treatments (19,168)? Following radical prostatectomy, more SUI and less obstructive symptoms have been reported, whereas the impact on nocturia has been neutral or negative (i.e. increased nocturia) (169,171).

Lifestyle

Coffee and alcohol: Nocturia treatment guidelines usually recommend decreasing (bedtime) fluid intake, particularly coffee and alcohol. However, most studies have not demonstrated a rela-tion between nocturia and consumprela-tion of alcohol (55,75,102,123,153,172) or coffee/caffeine (29,102,154,173). In some studies, moderate alcohol consumers had less nocturia than abstainers (128,154,174). These findings could be explained by a systematic misclassification error (people

decrease or cease alcohol intake due to ill health) (175,176) or residual confounding (moderate drink-ers have many favouring social and lifestyle factors) (177,178), although there could theoretically be several biological factors behind this association.

Smoking: Most studies have not found an association between nocturia and smoking (98,102,153,154,172,173,179). Some conflicting results have also been reported: in a Swedish study (150), smoking was associated with increased nocturia, but in Austrian (180) and Japanese (123) studies, with decreased nocturia.

Physical activity: Physical activity has been reported to be protective against LUTS in men (181–183), and against nocturia specifically in women (150). In an Austrian health-screening study (75), no relation was found between physical activity and nocturia. However, as exercise programmes appear to improve nocturia (184), these effects deserve to be further explored.

Race/ethnicity and socio-economic status

In several US studies, it is consistently noted that black men are approximately twice as likely to report nocturia as other ethnic groups (39–41). This effect persisted, although attenuated, after adjusting for comorbidities and socio-economic status. Similar effects were reported for women participating in the BACH Survey (121), and the Penn Ovarian study (44), with black women being almost twice as likely to report nocturia even after multivariable adjustment. In addition to these population-based studies, reports from secondary care populations (45,46) have also suggested in a population seek-ing care that black women commonly reported more nocturia. However, conflictseek-ing results were found in a Kaiser Permanente study (47). Less is known about the relationship between ethnicity and nocturia outside the US. In small studies in Taiwan (48,49) and Scotland (50), association of nocturia with ethnicity has been found. In the Scottish study, the prevalence for nocturnal polyuria was significantly higher in 200 Caucasian men compared with 93 Asian men. Overall, the underlying mechanisms for the possible association of nocturia with race/ethnicity remain unknown. In the previous studies, some of the risk factors for nocturia (such as sleep apnea) remained unmeasured.