Negoro et al.
Journal of Physiological Anthropology(2023) 42:27
https://doi.org/10.1186/s40101-023-00346-z

Journal of
Physiological Anthropology

ORIGINAL ARTICLE

Open Access

Diurnal differences in urine flow in healthy
young men in a light‑controlled environment:a randomized crossover design
Hiromitsu Negoro1* , Isuzu Nakamoto2, Sayaka Uiji3, Yoshiko Matsushima3, Bryan J. Mathis4,
Dominika Kanikowska5 and Tomoko Wakamura3

Abstract
Background Older men often experience nocturnal urination difficulties, reflected by diurnal differences in maximum urine flow (Qmax). Since lower urinary tract symptoms and pathological comorbidities are frequent in oldermen, it remains unclear whether this diurnal variation is a physiological or pathological phenomenon. Our aim
was to quantify the diurnal variability of Qmax in healthy young participants under varying daylight conditions
in a stable environment to discern potential underlying causes of nocturnal urination difficulties.
Methods Twenty-one healthy young men were recruited in a 4-day study utilizing daytime (08:00–18:00) exposure
with two light conditions in randomized order: dim (< 50 lx) or bright (~2500 lx). Day 1 was for acclimation, and urine
flow was assessed from day 2. The participants urinated ad libitum during day 2 and then at fixed 3–4-h intervals
thereafter (days 3–4). Regular urination Qmax at late night (04:00) on day 4 was compared with the nearest voided
volume during daytime of day 3 (mDay).
Results Morning Qmax scores (after bed—11:00) on day 2 were significantly lower than evening (17:00—before
pre-sleep) in bright conditions and those of daytime (11:00–17:00), evening (17:00—before pre-sleep), and pre-sleep
in dim conditions. Pre-sleep Qmax during the ad libitum period was significantly higher in dim than bright conditions.
Late-night Qmax values (04:00) on day 4 were significantly lower than Qmax scores of mDay on day 3 in both light
conditions.
Conclusions Healthy young men had a clear diurnal Qmax difference that decreased during late night and morning. In addition, the pre-sleep Qmax values in dim daylight were significantly higher than in bright daylight. Taken
together, we conclude that late-night and morning decreases in Qmax are an instinctive physiological phenomenon
in humans, and the diurnal difference of Qmax can be influenced by daylight conditions.
Keywords Bladder, Light, Maximum urine flow, Qmax

*Correspondence:
Hiromitsu Negoro
negoro-jua@umin.ac.jp
Full list of author information is available at the end of the article© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Negoro et al. Journal of Physiological Anthropology(2023) 42:27

Background
Men over 50 may experience difficult nocturnal or morning urination, and objective assessment of urinary function in this population includes evaluation of maximum
urine flow rate (Qmax) by uroflowmetry. Qmax, which
represents the peak flow rate during urination, is a pivotal metric in urology [1]. Expressed in milliliters per
second (ml/s), it offers insights into how efficiently thelower urinary tract (including bladder and urethra) functions. A Qmax of less than 15 ml/s is generally considered abnormal [1, 2]. Diurnal differences in Qmax havebeen reported in both older men with lower urinary
tract symptoms and hospitalized patients in the urology department [3–8]. However, older men with lower
urinary tract symptoms often have pathological comorbidities (e.g., benign prostatic obstruction, overactive
bladder, or underactive bladder) that complicate determination of diurnal Qmax differences due to other ageor disease-specific conditions. Consequently, erroneous
assumptions that difficulties with nocturnal or morning urination are indicative of deteriorating pathologicalconditions could persist. However, if Qmax variation isproven to be a physiological phenomenon, patients, medical staff, and the general public could recognize such
diurnal differences as natural, and this would significantly
reduce anxiety associated with potential pathologicalissues.
What might be the possible root of this diurnal difference in Qmax? Physiological functions, such as urine
production, body temperature, blood pressure, andsleep/awake cycles, are controlled via diurnal rhythms
mediated by the endogenous circadian clock [9]. Melatonin, a chronobiotic hormone released from the pineal
gland under the regulation of light exposure duration andtiming, plays a key role in modulating the cyclic functionof this system [10]. Since the circadian clock system isstrongly believed to control urination rhythm and functional bladder capacity [11, 12], any observed diurnal differences in Qmax are presumed to be similarly cyclical.
In spite of this, the effect of circadian rhythms on Qmax
variations has yet to be explored in young healthy men
without urinary comorbidities in a controlled environment. It is crucial to conduct experiments in a stable,
controlled environment when investigating physiological phenomena, especially those as sensitive as urination, which can be influenced by both environmental andemotional factors. Light stimuli, acting as cues for thecentral master clock, have a significant impact on diurnal physiological variations. In light of this, we chose to
examine Qmax under two distinct but physiologically
relevant conditions: one mirroring the bright illumination typical of our daily rhythms and another that minimizes the pronounced external influence of light [13].

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Our primary objective was to investigate the underlying cause of urinary difficulties at night or early inthe morning often observed in elderly men. To achievethis, we examined potential diurnal Qmax variations inhealthy young men, with a focus on the effects of inherent diurnal regulation.

Participants and methods
This study was performed concurrently with the otherexperiments previously described [13]. All participants
provided their informed written consent to take part inthis study. The study was endorsed by the Ethics Committee of Kyoto University (no. C1449) in accordancewith the principles of the Declaration of Helsinki and registered in the database of the University Hospital Medical
Information Network (UMIN000038350). From November 2019 to February 2020, 21 healthy young men (21–27
years old) were recruited from Kyoto University. Starting 5 days prior to the examination, participants were
instructed to go to bed at 24:00 (midnight) and wake up
at 8:00 while abstaining from alcohol, ensuring a regulated lifestyle. Sleep habits prior to the experiment wereconfirmed by sleep diaries written by the participants.
They participated in a 4-day study (4-day study ×2) withrandom order of exposure to two light conditions during the day (08:00–18:00), dim and bright (Figure 1). In
the experiment, we set the dim daylight condition to lessthan 50 lx (10 μW/cm2, 2822 K, 14 lx melanopic equivalent daylight illuminance [EDI]). This was based on ourprevious study, which demonstrated a delay in melatoninsecretion under this condition [14]. On the other hand,the bright daylight condition was set to approximately
2500 lx (734 μW/cm2, 3923 K, 1442 lx melanopic EDI)
because, in earlier findings, it was not 1500 lx but 2500
lx that influenced nocturnal melatonin secretion [15,16]. Light intensity was gauged vertically at eye level by
a researcher in a seated position, using a Lighting Passport spectrometer from Asensetek Inc., Taipei, Taiwan.
The light sources utilized were fluorescent lamps, which
illuminated the experimental room through a pseudowindow [13]. Melanopic EDI was calculated using a new
SI-compliant measurement system (CIE S 026:2018) [17].
The study room had a controlled air temperature (25 ± 2°C) and humidity (55 ± 5%). Rectal temperature was continuously recorded during the experiment. All urination
was counted, and Qmax was evaluated by P-Flowdiary®
(Micronix Inc., Kyoto, Japan). On the second day of theexperiment (day 2), participants were allowed to urinate
ad libitum but directed to urinate regularly at fixed intervals (every 3–4 h) thereafter (day 3).
In the free urination protocol, the specific act of urination was separately categorized as pre-sleep, considering its unique occurrence at the end and later part of theNegoro et al. Journal of Physiological Anthropology(2023) 42:27

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Fig. 1 A schema of the study protocolday. The time intervals of 11:00–17:00 and 17:00—before
pre-sleep were adopted to represent approximately 6-hintervals, equating to a quarter of a 24-h day, capturing
the daytime and evening periods, respectively. As no
participants urinated during nighttime, the period was
designated as “after bed~11.” Consequently, for analyzing morning urination, the timeframe was set until 11:00.
When there were multiple urination events, the averagevalue was calculated. Regarding the urine production
rate, the volume from a single urination was divided by
the time elapsed between urinations to determine theurine production rate per time unit [18]. This rate wasfurther broken down into intervals: from wake-up to
11:00, 11:00 to 17:00, 17:00 to before sleep, and the sleep
period, given that urine production continues during
nighttime sleep. For urination frequency, we employeda similar approach as that used for the urine production
rate. Qmax is known to correlate with the amount ofvoided volume [19], and there are significant individual
differences in this respect [20].
In addition to the free urination protocol, we utilized
and adopted a regular urination protocol experiment
by Nakamoto et al. [13] However, the Nakamoto study
was primarily focused on changes in diurnal urine volume and urine electrolytes, while the present study was
not intended to elucidate complete and comprehensive
diurnal variations of Qmax. Instead, our objective was tocompare Qmax data from 4 a.m. urination with daytime

data, aiming to examine periods not observed during
spontaneous urination. It is crucial to note that regularurination is not prompted by a natural urge, and the bladder is not fully filled during daytime urination. Additionally, while Qmax is known to correlate with the amountof voided volume [19], there are significant individual
differences in this respect [20]. Therefore, to ensure an
accurate comparison of Qmax values, we designed a protocol to compare these data with daytime urination of asimilar volume from a clinical standpoint of nocturnal
urination difficulties. Considering these variations, theQmax at 04:00 on the fourth day was compared with theclosest amount of voided volume during the day from11:00 to 18:00 (matched day: mDay).
Sleep time was fixed from 24:00 to 08:00. Identicalmeals (700 kcal each: 60% carbohydrates, 25% fat, and
15% protein; 3.8 g salt) were provided to participants at
08:00, 13:00, and 18:00. Participants consumed a totalof 25 ml/kg body weight of water per day in doses given
every 2 h between 08:00 and 24:00. Not required to follow a strict daily routine, but to avoid extreme measurements, participants were discouraged from strenuous
exercise or napping. The exclusion criteria for this study
were the presence of sleep disturbances as measured
by the Pittsburgh Sleep Quality Index (PSQI) [21] andextreme morning or evening sleep events as measured
by the Morningness-Eveningness Questionnaire [22].
According to Cornell Medical Index values [23] andNegoro et al. Journal of Physiological Anthropology(2023) 42:27

International Prostate Symptom Scores [24], all participants were in good health and did not have urinary problems. None of them smoked cigarettes, took medication,
had food allergies, or travelled across time zones in the 3months leading up to the start of the experiment.
Statistical analyses

For the comparison between time periods, we used
one-way ANOVA with Dunnet’s post hoc test. Two-way
repeated measures ANOVA was used to compare differences between the dim and bright daylight conditions,while timepoints were compared with Sidak’s post hoc
test. Symbols or bars represent mean ± standard error of
the mean. All statistical analyses were performed using
the commercially available software package GraphPad
Prism v8.43 (GraphPad Software Inc., CA, USA).

Results
The mean ± standard deviation age, BMI, PSQI, andMEQ of the participants were 23.9 ± 1.6 years old, 21.6
± 1.5 kg/m2, 4.2 ± 1.7, and 49.2 ± 8.0, respectively. The
participants were generally of average build and heightand believed to have regular lifestyles without sleep disorders, making them suitable for this experiment. Threeparticipants were excluded due to lack of Qmax data.
In the remaining participants, morning Qmax (afterbed—11:00) values were significantly lower than evening
Qmax (17:00–23:00) values obtained in bright daylightunder free urination conditions (p < 0.01) (Fig. 2a) andat 11:00–17:00, 17:00–23:00, and pre-sleep timepoints
in the dim daylight experiment (p < 0.05 each) (Fig. 2b).
The pre-sleep Qmax values in dim daylight were significantly higher than in bright daylight (p < 0.05) (Fig. 2c).

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Urinary frequencies and urine production rates during the sleep period were significantly lower than in themorning (wake-up—11:00), daytime (11:00–17:00), andevening (17:00—before sleep) periods in both bright anddim daylight (Supplementary Fig. 1). The volumes voided
per micturition or average flow rates during sleep period
were not significantly different in both bright and dim
daylight (Supplementary Fig. 2). An analysis was conducted to examine the relationship between the deltamagnitude of phase advance of core body temperatureand the difference in Qmax during the pre-sleep periodusing Spearman’s correlation. The results indicated a certain trend suggesting an association between the deltacore body temperature (dim-bright) and the delta Qmax
(dim-bright) (r = −0.356, p = 0.157); however, this association did not reach statistical significance. Regarding
fixed-time urination periods, late-night (04:00) Qmax
values were significantly lower than mDay under bothbright and dim daylight (*p < 0.05 by two-way repeatedmeasures ANOVA followed by Sidak’s multiple comparison test) (Fig. 3), while the average flow rates or volumes
voided per micturition at late night (04:00) were not significantly different versus mDay under each condition(Supplementary Fig. 3).

Discussion
We observed clear diurnal differences in Qmax in healthy
young men under both dim and bright daylight. Morning Qmax values were significantly lower than the bright
daylight evening and the daytime, evening, and pre-sleep
timepoints in dim daylight. The pre-sleep Qmax values in dim daylight were significantly higher than bright
daylight, while late-night Qmax values in the fixed-time

Fig. 2 Diurnal differences in maximum flow rates (Qmax) during the free urination period in bright daylight conditions (white circle) in a, in dim
daylight conditions (filled circle) in b, and the merged graph in c (*p < 0.05, **p < 0.01 by Dunnett’s multiple comparison test, one-way ANOVA; #p< 0.05 by two-way repeated measures ANOVA followed by Sidak’s multiple comparison test). Error bars represent SEM. Br indicates bright daylight
conditions

Negoro et al. Journal of Physiological Anthropology(2023) 42:27

Fig. 3 Diurnal differences in maximum flow rates (Qmax)
during the regular urination period in bright and dim daylight
conditions (*p < 0.05 by two-way repeated measures ANOVA
followed by Sidak’s multiple comparison test). mDay, matchedday, indicating closest amount of volume voided per micturitionin the daytime compared with 4 a.m. Error bars represent SEM. Br
indicates bright daylight conditions

urination period were significantly lower than mDay
under both the bright and dim daylight conditions.
Diurnal differences in Qmax values were observed inyoung, healthy men in a light-controlled environment,suggestive of a physiological phenomenon under controlof the endogenous central clock system as well as local
regulation by bladder-specific timing. The central clock,influenced by light exposure, is located in the supurachiasmatic nucleus and tunes peripheral clocks in organs
such as the bladder to coordinate circadian rhythms of
intraorgan activities [9]. Qmax is determined by boththe contractility of the urinary bladder and resistance of
the urethra; greater contractions with lower resistancegenerate a higher Qmax [25]. Thus, diurnal micturition
rhythms are transduced from the circadian clock system[9] to the peripheral bladder clock to prevent urination
at night for sound sleep [18]. This shift from voluntary “voiding” mode to “storage” mode at night can bereflected by decreases in bladder contractility.
In addition, we found that bright daylight significantly
decreased before sleep Qmax versus dim daylight. Thissuggests that the pre-sleep bladder may have shifted to“storage” mode under bright daylight conditions, but“voiding” mode might have persisted under dim daylight
conditions. In other words, bright daylight could regulatea phase-advancing shift in Qmax diurnal variation, similar to shifts of urinary N­ a+, ­Cl−, uric acid excretion, andPage 5 of 8

rectal temperature rhythms reported by Nakamoto et al.
[13]. However, the mechanism of daylight exposure on
Qmax pre-sleep is largely unknown. One possible explanation is the advancement of the master clock phase bybright compared with dim light [26]. In such cases, themode shift of the bladder would have been advanced inline with the advanced master clock signals. Melatoninmight precipitate this effect since onset time of melatonin secretion in the evening was reported to be earlier
in bright daylight versus dim daylight conditions [27]. In
addition to its role in chronobiologic regulation, melatonin also inhibits bladder contraction and is known toincrease bladder capacity [28–30]; thus, the early initiation of nocturnal melatonin secretion by bright light
exposure during the day may have downregulated Qmax
pre-sleep. Given the reported high correlation between
core body temperature and melatonin [31], the observed
trend in the association between differences in core bodytemperature and Qmax could align with this hypothesis,
despite the limited number of participants.
Psychological influence from the dim daylight condition may have also influenced our results [32, 33]. Since
urination is also under voluntary control and this situation was unusual for some participants, it is possible thatsome participants willingly urinated more strongly thantheir normal level before going to bed.
In clinical settings, complaints about difficult nighttime
urination are common. As a result, one of our objectives
was to compare the Qmax at 4 a.m., a time in the middleof the sleep period that is unassociated with urination on
demand, with daytime urination. This comparison was a
subsidiary study to a previous experiment that focusedon measuring urinary components [13]. The data in Supplementary Figure 4 show that, even when participants
did not feel the need to urinate based on the fixed interval protocol, there was still a diurnal variation in Qmax,
which was lowest in the early morning. Considering thatthe volume voided per micturition also decreased, it ischallenging to determine whether the diurnal variationin Qmax is physiological from this fixed-time urination
protocol. This is because Qmax is known to increase as
the volume voided per micturition increases and there
are significant individual differences in this relationship.
Hence, for the statistical analysis of Qmax during scheduled urination, we compared the Qmax during forced
urination at 04:00, the actual target time corresponding
to sleep, with the value closest to the volume of daytime
forced urination.
Diurnal rhythms of urination typically show a decreasein urinary frequency and an increase in volume voided
per micturition upon waking or during nighttime [11]. In
contrast, our study of healthy young participants revealed
diurnal variations in frequency but no such pattern for

Negoro et al. Journal of Physiological Anthropology(2023) 42:27

volume voided per micturition. This could result fromthe adequate suppression of nocturnal urine productionin these young individuals, leading to morning urination
before complete filling of the bladder.
The present study has several limitations. First, the origin of diurnal Qmax differences in healthy young men is
unreported. While bladder and urethral tension studies
in healthy volunteers are possible, invasive catheter insertion is difficult to accomplish [25]. Thus, we could only
speculate that melatonin or some psychological effecton bladder/urethral dynamics influenced our observed
results. Second, the data obtained in the present study
cannot easily be compared with the classical method of
constant-routine protocols where participants are in
fixed positions and experience sleep deprivation underconditions of constant dim light to determine individual
circadian rhythms [34]. Since results from that method
are not comparable to real-life situations that may influence circadian patterns, we opted for our novel method,standardizing whatever environmental variables we
could; temperature and humidity were constant, while
food and water were consumed in fixed quantities andat fixed times. Furthermore, strenuous exercise and napping were prohibited, but no constant positioning or
sleep restrictions were imposed [13]. As for the potential
masking effect of sleep, a study has shown that Qmax is
not related to arousal conditions, as evidenced in newborn experiments [35]. Concerning diet, since elements
like caffeine and alcohol are known to influence urination patterns [36], we standardized meal content to control for these dietary effects. Nonetheless, the precise
influence of diet on Qmax is still not fully understood.
While it remains a challenge to entirely offset the potential masking effects from sleep and diet, our protocol, we
believe, effectively captures the variation in Qmax due toinherent diurnal rhythms. Third, the regular urination
protocol did not accurately reflect the diurnal variation in
Qmax, since it largely depends on bladder capacity andconsiderable individual differences exist. Therefore, we
compared the Qmax at 4 a.m. to daytime values to ensure
similar voided volumes. To study the diurnal rhythm ofQmax more precisely, one could monitor the amountof urine accumulating in the bladder continuously andinduce urination once a certain volume is reached. However, this method also has limitations: the urination timing might be inconsistent, and there is a continuous needto monitor bladder capacity that could change voluntary
voiding choice due to irritation or enhanced bladderfocus during measuring. Fourth, concerning average flow
rates, there were no diurnal differences observed in thefree-urination protocol, nor in the comparison between 4a.m. and mDay during the regular urination protocol. In
light of this, Qmax might be more sensitive than average

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flow rate, as it more closely reflects the maximal detrusor pressure. We posit that variability in the somewhat
lower detrusor pressure possibly remains low between
day and night. Further research is required to elucidate
this disparity between the diurnal differences of Qmax
and average flow rates. Fifth, a standardized comparisons between Qmax and body clock with bright light
exposure at night have not yet been reported. Next, only
male participants were recruited since complaints of difficult urination at night/early in the morning are uncommon in older women. However, gender differences incircadian rhythms, including renal function, have beenreported [37, 38], and we acknowledge that important
diurnal Qmax variations may exist between the genders.
Finally, the effect of the prostate peripheral clock on thisphenomenon remains unknown and a topic for moredetailed future studies [39]. In spite of these limitations,
we are the first to report Qmax variations in healthy
young men that can be used as a baseline to develop further gender-, condition-, and age-based studies.

Conclusions
Healthy young men had a clear diurnal Qmax difference
that decreased during late night and morning. Bright
daylight seems to influence this difference pre-sleep byadvancing the circadian phase shift, making this process
a regulated physiological phenomenon that is instinctive
in humans.
Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s40101-​023-​00346-z.
Additional file 1: Supplementary figures: Supplementary Figure 1.
Diurnal differences in frequency and urine production rates during freeurination period. Clear diurnal differences in frequency were observed inboth bright daylight conditions in (a) and in dim daylight conditions in(b). Clear diurnal differences in urine production rates were also observed
both in bright (c) and dim daylight (d) conditions (*p < 0.05, **p < 0.01,****p < 0.0001 by Dunnett’s multiple comparison test, One-way ANOVA).
No significant differences were observed between the Dim and Brightconditions in terms of frequency or urine production rate . by Twoway
repeated measures ANOVA. Error bars represent s.e.m. Br indicatesbright daylight conditions. Supplementary Figure 2. Diurnal differences
in volume voided per micturition and average flow rates during freeurination period. No significant diurnal variation of volume voided per
micturition was observed in both bright daylight conditions in (a) andin dim daylight conditions in (b). No significant diurnal variation of urine
production rates was also observed both in bright (c) and dim daylight(d). No significant differences by One-way ANOVA in a−d. No significant
differences were observed between Dim and Bright conditions in volume
voided per micturition or average flow rate by Twoway repeated measures
ANOVA. Error bars represent s.e.m. Br indicates bright daylight conditions.
Supplementary Figure 3. Diurnal differences of average flow rates during
fixed-time urination in bright daylight conditions and in dim daylight in(a). mDay: matched Day, indicating closest amount of volume voided
per micturition in the daytime compared with 4 a.m. shown in (b). No
significant differences were observed between 4 a.m. and mDay in (a)or (b) by Two-way repeated measures ANOVA. Error bars represent s.e.m.

Negoro et al. Journal of Physiological Anthropology(2023) 42:27

Br indicates bright daylight conditions. Supplementary Figure 4. Diurnal
variations of Qmax and volume voided per micturition during fixed-time
urination under both bright and dim daylight conditions are shown in (a)and (b) respectively. Error bars represent s.e.m. Br indicates bright daylight
conditions.
Authors’ contributions
HN, IN, and TW conceived and designed the study. HN analyzed and interpreted the data and wrote and edited the manuscript. IN, SU, YM, DK, and TW
contributed to the data collection and reviewed the manuscript critically. BJM
reviewed the manuscript critically.
Funding
This work was supported by JSPS KAKENHI (Grant nos. 17H04430 and
15H05682) and Takeda Science Foundation.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are
not publicly available but are available from the corresponding author on
reasonable request.

Declarations
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Urology, Institute of Medicine, University of Tsukuba, Ibaraki 305‑8575, Japan. 2 Department of Gerontological and Home Healthcare
Nursing, Graduate School of Medicine, Tohoku University, Miyagi, Japan.
3
Human Health Sciences, Graduate School of Medicine, Kyoto University,
Kyoto, Japan. 4 International Medical Center, University of Tsukuba AffiliatedHospital, Ibaraki, Japan. 5 Department of Pathophysiology, Poznan Universityof Medical Sciences, Poznan, Poland.
Received: 27 June 2023 Accepted: 8 November 2023

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