Nocturia is defined by the International Continence Society as “the number of times urine is passed during the main sleep period. Having woken to pass urine for the first time, each urination must be followed by sleep or the intention to sleep.”¹ Two or more nocturnal voids are considered to be an important clinical threshold associated with significant negative outcomes for well-being and health in individuals.² Nocturia affects up to 18% of women under the age of 40 years old and up to 61.5% of women above the age of 70 years old.³ Nocturia can be categorized as (1) nocturnal polyuria, (2) diminished global or low nocturnal bladder capacity, or (3) polyuria.⁴ Nocturia is often multifactorial with underlying causative factors, including intake, urological/gynecological, nephrological, hormonal, sleep, and cardiovascular concerns (Table).⁵ Frequent nighttime urination can have a profound impact on the overall quality of life in many patients, with reports of sleeplessness, decreased slow-wave sleep, and daytime somnolence.³ Individuals with nocturia who wake up 3 or more times at night have a significantly higher rate of mortality than the general public.^3,6 Nocturia not only impacts one’s ability to rest, but it also impacts day-to-day activities such as work, household chores, exercise, and intimacy.⁷ Despite its prevalence, only 1.5 million individuals out of the 50 million individuals affected by nocturia receive treatment.⁶ The pathophysiology of nocturia is often complex, which makes it difficult to treat patients with current therapies.⁷

Table. Summary of Nocturia Causative Factors, Underlying Pathophysiology, and Lifestyle Interventions

Light is the primary zeitgeber for the circadian rhythm system as it acts through the retina to regulate the suprachiasmatic nucleus or the master circadian oscillator.⁸ The circadian rhythm modulates many visceral organs, including the bladder, through peripheral clocks.⁹ This is ultimately facilitated by the detection of light changes throughout the day via photoreceptors in the retina. In response, there is an increase or decrease in the expression of certain genes, such as CLOCK and Bmal1. Typically, during the awake phase, there is increased arousal, increased urine output, and decreased functional bladder capacity.^9,10 The opposite is seen during the nocturnal sleeping phase. There is an intricate balance that determines functional capacity and the bladder’s ability to store urine. Capacity may be determined by the 24-hour circadian cycle, and it is postulated that capacity is regulated at the ion channel level by CLOCK-related genetic machinery.¹⁰ Further research needs to be conducted on patients experiencing nocturia to understand how CLOCK gene transcription regulates urothelial signaling in the bladder. In the long term, we hope that the molecular information will guide the creation of novel therapeutic agents to improve the symptoms and, even more importantly, the quality of life of the millions of patients suffering from nocturia.

The extensive impact that nocturia has on the lives of patients has prompted it to be studied in animal models. Early studies assessing micturition and the circadian rhythm in the bladder used rodents as animal models.¹⁰ Rodents are nocturnal animals in that their sleep-wake cycle is opposite of humans. Initial studies have shown that the bladder capacity of rats is elevated during the lights-on sleep phase cycle and decreased during the lights-off wake phase cycle. Oscillations in the circadian clock influence the transcription of certain genes, including Per, Cry, and Bmal1.¹⁰

Additional studies have been conducted using mouse models. Ihara et al evaluated restraint stress on mice to investigate the circadian bladder function and rhythmicity of gene expression.^9,11 Investigators found that intermittent stress results in a loss of Per2 rhythm. Ultimately, restraining resulted in the loss of animals’ innate rhythm of void volume and frequency.^9,11 Control mice showed typical circadian expression of bladder genes Per2, Bmal1, and Rev-erbα. Similarly, when assessing the knockout of mammalian cryptochrome proteins, Cry1 and Cry2, in mice, it was found that those with a genetic knockout of both proteins resulted in free-running circadian rhythms.⁹ The study ultimately demonstrated that both proteins are essential for maintaining intrinsic circadian rhythm.

Bladder circadian rhythm genes in rodents can be altered based on induced stress. The bladders of rodents, including mice and rats, are sufficiently similar to the human urinary tract to warrant investigation. In humans, despite specific lifestyle interventions directed at the underlying pathophysiology of each of the 6 main causative factors resulting in nocturia (Table),⁵ nocturia may be refractory, leading us to pursue further investigations into the study of nocturia as a circadian bladder dysfunction.

We hope to fill this knowledge gap by determining the impact of sleep interruption on circadian bladder gene expression. Using such an approach, it should be possible to extrapolate information from animal models to the human urinary tract and better understand the pathophysiology of gene regulation for patients with nocturia.