The Causes of Nocturnal Polyuria
Recently, it has been reported that the occurrence of nocturia can be attributed to nocturnal polyuria and/or diminished nocturnal bladder capacity [10,16]. Regarding nocturnal polyuria, it has been reported that the prevalence of nocturia in persons with hypertension is 68% for both men and women [25], and that the mean blood pressure is higher in men with nocturnal polyuria than in controls [34,35]. Therefore, hypertension may be one factor contributing to nocturnal polyuria. Hypertension caused by an increased noradrenaline and dopamine during the daytime would increase renal arterial resistance, decrease renal blood flow, and lead to insufficient daytime urine production [25,34] (Fig. 8). In the present study, the daytime plasma noradrenaline and dopamine levels, as well as the blood pressure, were significantly higher in the elderly nocturia group than the elderly control group, although there was no significant difference of daytime urine volume between these groups. Therefore, the daytime urine production may not be adequate in the elderly nocturia group with high catecholamine levels even though they have an excessive fluid intake. However, plasma noradrenaline and dopamine levels were lower at night than during the daytime in the elderly nocturia group. When catecholamines decrease at night, renal arterial resistance would also decrease and renal blood flow would increase, allowing urine production to increase in order to excrete water stored during the daytime. The decrease of arginine vasopressin in the elderly nocturia group might also be the result of excessive fluid intake and water retention based on an increase of circulating catecholamines and hypertension.
In this study, we performed body composition analysis to explore the basis of nocturia from a new perspective. The body composition analyzer that we employed could rapidly provide detailed body composition data (weight, water volume, edema ratio, body mass index, fat mass, etc.) without the inconvenience of more invasive traditional methods [29,3638].
Figure 8. Relationship between hypertension and nocturia.
Clinically, this machine is used to measure the dry weight of hemodialysis patients or to control the fluid balance in patients with end-stage renal failure [36,38]. In the present study, body composition analysis revealed that the edema ratio showed a gradual increase from morning to evening in all 3 groups. In the elderly nocturia group, the edema ratio before sleeping was higher than in the young and elderly control groups. This suggests that water accumulated in the extracellular compartment of the elderly nocturia group due to a decrease of renal blood flow and/or inadequate muscle pump function during the daytime. Water that has accumulated in the extracellular compartment during the daytime may enter the intravascular compartment at night and increase the circulating blood volume, thus bringing about a rise of HANP and BNP to increase urine production. It has been reported that daytime diuretic therapy is useful to prevent nocturia because it increases both frequency and urine volume during the day and decreases nocturnal frequency [39], and patients with nocturia who respond to diuretic therapy (azosemide) have high HANP levels [40].
Therefore, a high fluid intake is another factor contributing to nocturnal polyuria, and excess water stored in the extracellular compartment may need to be voided before sleeping to prevent nocturia. The sleep apnea syndrome also induces nocturnal polyuria [41]. Venous return increases rapidly when inspiration occurs after apnea, and increased venous return releases HANP and BNP from the heart. This phenomenon may induce nocturnal polyuria (Fig. 9).
Figure 9. relationship between sleep disturbance and nocturia.
The Causes of Diminished Nocturnal Bladder Capacity
Sleep disturbance are a major factor related to nocturia in elderly persons [10,17,22]. Melatonin is one of the strongest natural antioxidants, and is produced by the pineal gland; it also has a close relation to the timing of sleep in humans [42-45]. In the present study, nighttime plasma melatonin level was found to be significantly lower in both elderly groups than the young control group, and the melatonin level of the elderly nocturia group was lower than that of the elderly control group. In young persons, the single voided urine volume in the morning is 1.5- to 2-fold larger than the mean single voided urine volume during the daytime [46]. In the present study, however, the single voided urine volume of elderly persons showed no significant difference between daytime and nighttime. Therefore, it is possible that a higher melatonin level increases the waking threshold in young persons, while a decrease of plasma melatonin leads to sleep disturbance and a lower waking threshold in older persons (Fig. 9). Elderly people with sleep disturbance may wake up to urinate at least once during the night because of both diminished nocturnal bladder capacity and shallower sleep. Indeed, administration of melatonin safely improves nocturia in patients with bladder outlet obstruction [47], while treatment with melatonin (3 mg per day) for up to 6 months improved the sleep quality and decreased the sleep onset latency in patients with insomnia [48]. In addition to melatonin, hypnotics are reported to be useful for treating nocturia [21,22,49]. Fujikawa et al. have reported that minor tranquilizers are especially effective for controlling nocturia in patients with low HANP levels [40]. Therefore, sleep disturbance may be one of the factors that diminish nocturnal bladder capacity, and treatment of sleep problems may be important to improve nocturia.
It is also possible that an increase of plasma catecholamine levels is not only related to nocturnal polyuria but also to diminished nocturnal bladder capacity. Intrathecal injection of an alpha-1 adrenergic receptor antagonist inhibits isovolumetric bladder contraction without affecting the amplitude of bladder contraction in rats [50]. This suggests that an increase of plasma catecholamine levels may influence the ascending limb of the micturition reflex in the spinal cord and induce the urge to urinate at lower bladder volumes. This phenomenon may be similar to the feeling of urgency associated with stress. Indeed, administration of an alpha-1 adrenergic receptor antagonist before sleeping to patients with morning hypertension has been shown to decrease nocturnal urinary frequency [51]. Moreover, administration of an alpha-1D adrenergic receptor antagonist inhibits the ATP release from the bladder urothelium [52,53]. The ATP activates afferent terminals of the bladder, and induces the urge to urinate. The catecholamines also activate the smooth muscles in the prostate and the proximal urethra, and induce the bladder outlet obstruction. The obstructive bladder also affects the spinal cord [54,55], bladder urothelium, and bladder smooth muscle structure [56], and induces easy appearance of the urge to urinate [57] (Fig. 8). Therefore, the increase of plasma catecholamine levels diminish bladder capacity.
Why Nocturia is Troublesome?
Nocturia is the complaint that the individual has to wake at night one or more times to void [6]. However, some elderly persons do not consider nocturnal urination to be bothersome even if they have a number of episodes, while other persons feel bothered even if they wake up once per night. Accordingly, a therapy to target the perception of nocturnal urination as non-bothersome seems worthwhile to pursue, even though the actual decrease in the number of urinations may be small. Therefore, we investigated the factors related to nocturnal urination that was not considered bothersome by comparing various parameters between subjects who felt nocturnal urination as bothersome and those who did not [58].
The subjects were selected from among our outpatients. Patients who met the following criteria were enrolled: 1) their lower urinary tract symptoms –except for nocturnal urination-were controlled by medication (adrenergic alpha-1 receptor antagonists, anti-muscarinic agents, and/or herbal medicines) over a period of 2 months; 2) they had urination once per night; 3) they did not have neurological or psychological abnormalities, hepatic dysfunction, renal dysfunction, diabetes mellitus, or cardiovascular disease; and 4) they were not taking either tranquilizers, hypnotics, or melatonin. Patients with bacterial cystitis, bacterial prostatitis, urinary tract cancer, hematuria, or proteinuria were excluded. A total of 94 persons (50 males and 44 females aged 26-93 years) consented to this study and were enrolled. All 50 male patients had benign prostatic enlargement with or without an overactive bladder, while the 44 female patients had urethral syndrome and/or overactive bladder. Their residual urine volume was <20 mL on abdominal ultrasonography.
We examined the average number of daytime urinations over one month, the average number of nocturnal urinations during the sleeping period, the International Prostatic Symptom Score questionnaire (IPSS) [59], the QOL score (happy: 0, satisfied: 1, almost satisfied: 2, not satisfied/not dissatisfied: 3, slightly dissatisfied: 4, dissatisfied: 5, unhappy: 6), and the perception of nocturnal urination (not bothersome, slightly bothersome, bothersome, or very bothersome). Subjects who stated that it was not or slightly bothersome were assigned to the non-bothersome group. When subjects stated that it was bothersome or very bothersome, they were assigned to the bothersome group. These groups were also stratified into subgroups by the frequency of nocturnal urination.
Blood samples were taken from all subjects at 10-12 a.m. Then the complete blood count (white blood cells: WBC, red blood cells: RBC, hemoglobin: Hb, hematocrit: Ht, platelets: Plt) was measured, and biochemistry tests (serum total protein: TP, albumin: ALB, aspartate aminotransferase: AST, alanine aminotransferase: ALT, lactate dehydrogenase: LDH, cholinesterase: ChE, gamma-glutamyl transpeptidase: -GT, total bilirubin: T-Bil, blood urea nitrogen: BUN, creatinine, melatonin, and plasma arginine-vasopressin: AV, adrenalin, noradrenalin, dopamine, serotonin, human atrial natriuretic peptide: HANP, brain natriuretic peptide: BNP) were performed. The blood viscosity and the plasma osmotic pressure were also measured. These data were compared between the two groups and the subgroups.
Among the 94 subjects with urination once per night, 60 subjects (32 males and 28 females aged 56 16 years) were in the non-bothersome group, and 34 subjects (18 males and 16 females aged 57 17 years) were in the bothersome group. However, the rate of subjects in the non-bothersome group gradually decreased with an increase in frequency of nocturnal urination, and the number of subjects in the bothersome group became larger than that in the non-bothersome group when the subjects were limited to those with urination 4 times per night.
Figure 10. Hie daytime melatonin, arginine vasopressin and HANP levels in patients with non-troublesome or troublesome nocturumal urination once per night.
Among the 94 subjects with urination once per night, the serum melatonin level of the bothersome group was significantly lower (p=0.047) than that of the non-bothersome group (Fig. 10). The urinary frequency at nighttime, the total score of the IPSS, and the QOL score of the bothersome group were significantly higher (p=0.004, p=0.049 and p<0.001, respectively) than those of the non-bothersome group. There were no significant differences in other parameters between the two groups.
Figure 11. The daytime melatonin, arginine vasopressin and HANP levels in patients with non-troublesome or troublesome nocturumal urination twice per night.
In this study, biochemical parameters were compared between subjects with non-bothersome nocturnal urination and those with bothersome nocturnal urination. The serum melatonin level was lower in subjects with bothersome nocturnal urination regardless of the frequency of urination ( once per night and twice per night). In subjects with bothersome nocturnal urination once per night, the urinary frequency at nighttime, the total score of the IPSS, and the QOL score were higher compared with those in subjects with non-bothersome nocturnal urination once per night. However, among subjects with nocturnal urination twice per night, only the QOL score was significantly higher in the subjects with bothersome nocturnal urination. The parameters of the IPSS did not differ between the subjects with and without bothersome nocturnal urination because their lower urinary tract symptoms were controlled by medication, suggesting that the main cause of the increased scores of the IPSS and the QOL in subjects with bothersome nocturnal urination was nocturia itself.
The melatonin level is significantly higher at night, with a significant correlation between daytime and nighttime melatonin levels [28]. Therefore, the difference in daytime melatonin levels between the two groups in the present study is thought to reflect a difference in the nighttime melatonin level. The decrease in the serum melatonin level in subjects with bothersome nocturnal urination suggests that they may have a sleep disturbance, which is one of the main causes of nocturia, rather than the decrease in the melatonin being produced by a lack of sleep due to nocturia.
Administration of melatonin was found to improve nocturia in patients with bladder outlet obstruction [47]. Administration of melatonin (3 mg/day) for up to 6 months was reported to improve sleep quality and decrease the sleep onset latency in patients with insomnia [48]. In addition to melatonin, hypnotics are reported to be useful for treating nocturia [21,40]. Fujikawa et al. found that minor tranquilizers are especially effective for controlling nocturia in patients with low HANP levels [40]. Therefore, treatment of sleep problems is important for improving nocturia. Besides medication, walking for 30 minutes or more in the evening also decreases the number of nocturnal urinations and induces better sleep [60]. The main factor related to the influence of walking on nocturia is that sleep becomes deeper, which may increase the arousal threshold bladder volume. Therefore, any therapy for sleep disturbance may also become a therapy for nocturia.
Nocturnal urinary frequency, a common symptom in the elderly, is one of the most bothersome urologic symptoms [1]. However, we found that the number of subjects in the non-bothersome group was larger than in the bothersome group. Among the subjects with nocturnal urination 4 times per night, however, the number in the bothersome group was larger than that in the non-bothersome group. Therefore, simply decreasing the number of nocturnal episodes of urination is not an effective therapy for nocturia. From the present findings, nocturnal urination being perceived as non-bothersome was thought to be related to maintaining a higher level of melatonin (a sleep inducer) and obtaining sufficient sleep. Therefore, any therapy for improving sleep will also be able to improve nocturia, even if the number of nocturnal urinations does not decrease significantly.
