Indoor cold exposure and nocturia: a cross-sectional analysis of the HEIJO-KYO study

Commented by Prof. Karl-Erik Andersson

It is well known that cold environmental temperatures can influence bladder function in healthy individuals, often provoking urgency, particularly in patients with the overactive bladder (OAB) syndrome. Epidemiological studies have suggested that the prevalence of nocturia is higher in winter than in summer (Yoshimura et al., 2007), but how low environmental temperatures may cause nocturia has not been established.

Saeki et al. (2016) investigated the association between indoor cold exposure and the prevalence of nocturia in an elderly population by measuring the temperature in the living rooms and bedrooms of 1 065 home-dwelling elderly volunteers (aged ≥60 years) for 48 h. Nocturia (≥2 voids per night) and nocturnal urine production were determined using a urination diary and nocturnal urine collection. The mean + SD age of participants was 71.9 + 7.1 years, and the prevalence of nocturia was 30.8%. Saeki et al. (2016) found that a 1 °C decrease in daytime indoor temperature was associated with a higher odds ratio (OR) for nocturia (1.075, 95% confidence interval, [CI] 1.026–1.126; P = 0.002), independently of outdoor temperature and other potential confounders such as basic characteristics (age, gender, body mass index, alcohol intake, smoking), comorbidities (diabetes, renal dysfunction), medications (calcium channel blocker, diuretics, sleeping pills), socio-economic status (education, household income), night-time dipping of ambulatory blood pressure, daytime physical activity, and objectively measured sleep efficiency. The association remained significant after adjustment for nocturnal urine production rate (OR 1.095 [95% CI 1.042–1.150]; P < 0.001). Saeki et al. (2016) concluded that indoor cold exposure during the daytime was independently associated with nocturia among elderly participants, and suggested that the mechanism for this association could partly be explained by cold stress-induced detrusor overactivity. They based this conclusion on the finding in rats that exposure to environmental low temperature evoked increased bladder contractile activity (Imamura et al., 2008). However, a more likely explanation seems to be that the participants had an increased perception of overactive (OAB) symptoms (urgency, nocturia). But by what mechanisms could a low environmental temperature induce detrusor overactivity (in animals) and urgency/nocturia (in man)?
In children younger than 4 years and in patients with lower urinary tract (LUT) disorders due to neurological pathology, intravesical ice-cold water instillation can evoke bladder contraction (the bladder cooling reflex). However, it does not seem reasonable that this reflex can be activated by low environmental temperature, since the afferent part of the reflex cannot be the same. There is considerable evidence that the bladder cooling reflex is initiated by activation of cold-sensitive C fibers in the bladder wall (Geirsson et al., 1999). It is also known that in normal adult individuals this reflex is suppressed. Imamura et al. [2008] found in rats that exposure to a temperature of 4oC for 40 min provoked increased bladder activity that, at least partly, was mediated by resiniferatoxin sensitive pathways, supporting the involvement of C-fibers (not necessarily in the bladder wall, since the resiniferatoxin treatment was systemic). Chen et al. (2010) found that the transient receptor potential melastatin (TRPM)8 is expressed in rat skin, and that spraying menthol solution onto the skin induced detrusor overactivity, an effect suggested to be mediated by stimulation of TRPM8 receptors. Lei et al. (2013) demonstrated that the TRPM8 channel antagonist, N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide (BCTC), inhibited detrusor overactivity in rats sprayed with the TRPM8 channel agonist, menthol, and the drug also inhibited cold stress-induced detrusor overactivity. They concluded that TRPM8 channels mediate, at least partially, detrusor overactivity elicited by exposure to low temperatures. Uvin et al. (2015), using more sophisticated methodology, including mice with genetic ablation of TRPM8 and the selective TRPM8 antagonist (N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl] oxy}-N-(2-thienyl methyl) benzamide (AMTB), confirmed and extended the previous findings. They found that bladder contraction and bladder voiding in anesthetized mice and rats could be reproducibly evoked by brief, innocuously cold stimuli applied to different parts of the skin. These responses were strongly attenuated in Trpm8-/- mice and in rats treated with AMTB, supporting involvement of TRPM8 channels. Uvin et al. (2015) also concluded from their experiments that acute cold-induced urgency is an evolutionarily conserved reflex rather than Pavlovian conditioning and or subconscious automatic behavior, but they stressed that “as rodent bladder physiology differs from that of humans, it is difficult to directly extrapolate our findings to human patients.” Never the less they concluded that “Pharmacological inhibition of TRPM8 may be useful for treating acute cold-induced symptoms in patients”. Whether this also includes nocturia associated with a more long-term exposure to low temperatures is an open question. Saeki et al (2016), studying long-lasting exposure to cold environment, suggested that the prevalence of nocturia could be reduced by modification of the indoor thermal environment. Do these findings mean that there can be two new possibilities to treat nocturia? Since both increasing environmental temperature and TRPM8 antagonists may have effect only if low temperatures are involved in the pathogenesis of nocturia, this may be a limiting factor. Furthermore, if both interventions act like other OAB drugs by reducing daytime/night time micturition frequency, the effects on nocturia may be modest, since the effects of e.g., antimuscarinics and 3-adrenoceptor agonists, have not been very successful.  Thus, the clinical usefulness of these new principles for nocturia treatment may be limited.

Irrespective of the mechanisms involved, the observations made by Saeki et al. (2016) are of interest since, as pointed out by van Kerrebroeck (2016), “these findings could be used as a population approach to reduce the prevalence of nocturia and hence the eventual impact on quality of life and morbidity that is known to go together with nocturia.”

References

• Saeki K, Obayashi K, Kurumatani N. Indoor cold exposure and nocturia: a cross-sectional analysis of the HEIJO-KYO study. BJU Int. 2016 May;117(5):829-35.
• Yoshimura K, Kamoto T, Tsukamoto T, Oshiro K, Kinukawa N, Ogawa O. Seasonal alterations in nocturia and other storage symptoms in three Japanese communities. Urology 2007; 69: 864–70
• Geirsson G, Lindström S, Fall M. The bladder cooling reflex and the use of cooling as stimulus to the lower urinary tract. J Urol. 1999 Dec;162(6):1890-6
• Imamura T, Ishizuka O, Aizawa N, Zhong C, Ogawa T, Nakayama T, Tanabe T, Nishizawa O. Cold environmental stress induces detrusor overactivity via resiniferatoxin-sensitive nerves in conscious rats. Neurourol Urodyn 2008; 27: 348–52
• Chen Z, Ishizuka O, Imamura T, Aizawa N, Kurizaki Y, Igawa Y, Nishizawa O, Andersson KE. Stimulation of skin menthol receptors stimulates detrusor activity in conscious rats. Neurourol Urodyn. 2010 Mar;29(3):506-11.
• Lei Z, Ishizuka O, Imamura T, Noguchi W, Yamagishi T, Yokoyama H, Kurizaki Y, Sudha GS, Hosoda T, Nishizawa O, Andersson KE. Functional roles of transient receptor potential melastatin 8 (TRPM8) channels in the cold stress-induced detrusor overactivity pathways in conscious rats. Neurourol Urodyn. 2013 Jun;32(5):500-4
• Uvin P, Franken J, Pinto S, Rietjens R, Grammet L, Deruyver Y, Alpizar YA, Talavera K, Vennekens R, Everaerts W, De Ridder D, Voets T. Essential role of transient receptor potential M8 (TRPM8) in a model of acute cold-induced urinary urgency. Eur Urol. 2015 Oct;68(4):655-61.
• Van Kerrebroeck P. Does cold exposure cause nocturia? BJU Int. 2016 May;117(5):714. 

Commented by Prof. Donald L. Bliwise
This is an interesting epidemiologic study suggesting that colder ambient temperatures may predispose for nocturia. Previous literature has not investigated a role of room temperature in nocturnal voiding, although one study reported higher rates of nocturia in winter, relative to summer months. Basic science studies suggest that detrusor activity is heightened by cold. The current study used a somewhat novel method of recording bedroom temperature over 48 hour period (daytime and nighttime) to determine if environmental temperature would be associated with relatively greater or fewer nocturia episodes.
Several features of this study bear mention. First, of course, these are observational data, and they are not based on interventions adjusting room temperatures. Ultimately, interpreting descriptive data as useful for practice would require an appropriately powered randomized clinical trial to test the intervention. Secondly, this study can be framed differently, if one approaches the more fundamental question as to whether it is nocturia that is responsive to temperature or whether it is sleep per se that responds to temperature, nocturia being relegated to simply being an outcome of disrupted sleep. From this perspective, the effect of ambient temperature on sleep could be the ultimate cause of nocturia, rather than detrusor overactivity or excess nocturnal urine production.
Sleep in mammals is highly dependent on temperature. Indeed, one of the numerous putative functions of sleep is to preserve thermoregulatory function, and in animal models, when sleep deprivation is prolonged, an animal’s ability to thermoregulate becomes severely compromised. In humans, sleep is associated with a shunting of core heat to the periphery and a subsequent cooling of internal temperature. Dutch researchers (Professor Van Someren et al) have shown that the efficiency with which heat is lost depends on the complete ambient environment for the sleeper, i.e., not merely air temperature but also temperature of the sleeper’s skin, which depends on factors like bedding (type and number of blankets, sheets, etc). Other studies have suggested that quality and depth of sleep can be strongly influenced by such “local” (in bed) temperature, which then may affect the sleeper’s ability to shunt heat. Suffice it to say, room temperature may have less bearing upon an individual’s sleep (and nocturia) than do nightclothes and type or quantity of bedding. The study by Saeki et al is quite provocative in suggesting that daytime (but not nighttime) room temperature may be associated with nocturia, but we know nothing in this study about the bed conditions in which people slept. Future studies should certainly pursue this line of inquiry, including more detailed measurements of skin temperature and polysomnographic measurements of sleep, as manipulations of environmental heating and cooling could potentially open new, non-pharmacologic avenues of treatment for nocturia.