- Email: [email protected]
Impaired Sleep Quality is Associated With More Significant Lower Urinary Tract Symptoms in Male Shift Workers
Accepted Manuscript Title: Impaired Sleep Quality is Associated with More Significant Lower Urinary Tract Symptoms in Male Shift Workers Author: Jason M. Scovell, Alexander W. Pastuszak, Jeremy Slawin, Justin Badal, Richard E. Link, Larry I. Lipshultz PII: DOI: Reference:
S0090-4295(16)30610-0 http://dx.doi.org/doi: 10.1016/j.urology.2016.05.076 URL 20023
To appear in:
Urology
Received date: Accepted date:
28-10-2015 31-5-2016
Please cite this article as: Jason M. Scovell, Alexander W. Pastuszak, Jeremy Slawin, Justin Badal, Richard E. Link, Larry I. Lipshultz, Impaired Sleep Quality is Associated with More Significant Lower Urinary Tract Symptoms in Male Shift Workers, Urology (2016), http://dx.doi.org/doi: 10.1016/j.urology.2016.05.076. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Impaired Sleep Quality Is Associated With More Significant Lower Urinary Tract Symptoms in Male Shift Workers Jason M. Scovell*1,2, Alexander W. Pastuszak*1,2, Jeremy Slawin3, Justin Badal3, Richard E. Link1,2, Larry I. Lipshultz1,2
1
Scott Department of Urology, Baylor College of Medicine, Houston, TX Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 3 Baylor College of Medicine, Houston, TX 2
MeSH Key Words: lower urinary tract symptoms, LUTS, sleep, shift work disorder, prostate
Abstract Word Count: 258 Word Count: 1904 * - These authors contributed equally to the preparation of this manuscript Correspondence: Alexander W. Pastuszak, MD, PhD Assistant Professor Division of Male Reproductive Medicine and Surgery Scott Department of Urology Baylor College of Medicine 6624 Fannin St, Suite 1700 Houston, Texas 77030 Phone (713) 798-6163 Email: [email protected]
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2
Abbreviations: Lower Urinary Tract Symptoms (LUTS) Shift Work Disorder (SWD) Body Mass Index (BMI) International Prostate Symptom Score (IPSS) Abstract Objective: To determine the association between sleep quality and lower urinary tract symptom (LUTS) severity in men working non-standard shifts, a population at risk for poor sleep quality. Materials and Methods: Men who presented to a single andrology clinic between July and October 2014 and worked non-standard shifts completed the International Prostate Symptom Score (IPSS) and responded to questions regarding their work habits, sleepquality, and physical/cognitive function. We assessed the relationship between age, sleep-quality, physical/cognitive function and severity of LUTS. Results: 228 men with a mean±SD age of 41.8±5.7 (range 21-76) years reported working non-standard shifts with the majority working these for more than 1 year (81%). Men with difficulties falling asleep reported more severe LUTS than men who did not have difficulty falling asleep (IPSS score 9 vs. 6, p<0.001). Men who reported difficulty staying asleep or falling back asleep after awakening also reported more severe LUTS (IPSS scores 6 vs. 13, p=0.004; 5 vs. 13, p<0.001, respectively). Men with a decreased sense of wellbeing or decreased physical/cognitive function also reported more severe LUTS (IPSS score 6 vs. 9, p<0.0010; 6 vs. 10, p=0.016, respectively). All findings were independent of subject age.
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3 Conclusion: Men working non-standard shifts who have difficulty falling asleep, staying asleep, and falling back asleep report more severe LUTS than men without similar sleep difficulties. Men with a decreased sense of wellbeing or decreased physical/cognitive function also report worse LUTS. These findings implicate sleep quality as a possible risk factor for LUTS symptom severity.
INTRODUCTION Lower urinary tract symptoms (LUTS) are one of the most common and problematic medical conditions in older men. LUTS may be present in up to 97% of men ≥ 65 years old and are associated with worse health quality.1 Sequelae of LUTS include nocturia and consequent sleep disturbances, and more severe LUTS increases the risk for impaired sleep quality.2 Conversely, improvement in LUTS results in improved sleep.3 Impaired sleep quality may contribute to numerous other conditions including hypertension, diabetes mellitus, arteriosclerosis,4 and cardiovascular events.5 However, the relationship between sleep quality and LUTS remains unclear.
Sleep quality can be affected by abnormal sleep schedules, and shift workers often cannot maintain a normal sleep pattern as a result of their work schedule. Shift workers comprise 15-25% of the workforce and often develop impaired sleep quality, with 1032% developing shift work disorder (SWD).6
SWD is a circadian rhythm disorder
characterized by insomnia and sleepiness in people whose working hours overlap those of a normal sleep period, typically at night. Patients with SWD are more likely to have
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4 decreased daytime alertness and impaired cognitive function,7 higher body mass indices (BMIs), cholesterol levels, triglycerides, and rates of hypertension than non-shift workers.7,
8
The prevalence of depression is also greater in night shift workers when
compared with daytime workers. The mechanisms underlying development of SWD sequelae are unclear, although obesity,9 inflammation,10 autonomic dysregulation,11 and metabolic dysregulation12 can all result from sleep impairment; dysregulated neurotransmission may also result from SWD.13, 14 Since LUTS can arise from these same factors,12, 15 impaired sleep quality may not only be a consequence of, but also an exacerbating factor for LUTS.
Whether impaired sleep quality predisposes to LUTS or vice versa (bidirectional causality) has not been extensively studied. However, evidence suggests that poor sleep quality increases the risk of developing LUTS within 5 years of diagnosis.
15
Here,
we identify a relationship between the level of sleep quality and severity of LUTS in male non-standard shift workers.
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5 METHODS All men presenting to a single academic men’s health clinic between July and October 2014 were asked to complete an electronic survey about their work schedules, specifically regarding whether or not they worked non-standard shifts. Survey respondents were not selected for presenting symptoms, age, or race. As defined in the literature, men who work non-standard shifts begin work before 7 a.m. or after 2 p.m., regularly rotate between standard and non-standard formats, or regularly work hours outside of a standard 7 a.m. to 6 p.m. workday.16 Men who work non-standard shifts were asked how long they have been working these shifts, and were asked to complete the validated International Prostate Symptom Score (IPSS) questionnaire,17 as well as non-validated questionnaires to inform quality of life and cognitive function (Supplementary Data Figure 1).
Responses were collected electronically, and only responses with complete questionnaire data were included for analysis. We associated sleep quality (falling asleep, staying asleep, and getting back to sleep), quality of life, and cognitive/physical function with IPSS data. Because age is an important risk factor for LUTS,18 we compared subject ages across all response groups to determine whether or not the relationship between sleep, quality of life and LUTS were independent of age. We compared means using Student’s t-test, MANOVA, and linear regression where appropriate.
SPSS version 22 (IBM Corporation, Somers, NY) was used for all
statistical analyses, with p<0.05 considered statistically significant.
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6 RESULTS We hypothesized that sleep quality would impact LUTS severity, as it has been shown to exacerbate numerous other conditions. We asked men who work non-standard shifts to report their quality of sleep and LUTS severity using the IPSS. A total of 228 men reported working non-standard shifts and were included in the study with a mean±SD age of 41.8±5.7 (range 21-76) years (Table 1). Men reported working an average of 3.8±1.9 non-standard shifts per week, and 81% of men (n=186) reported working nonstandard shifts for greater than 1 year. The average IPSS score for non-standard shift workers was 6.0±5.6 with an average quality of life score of 1.4±1.4.
To identify poor sleep as a potential risk factor for LUTS severity, we used sleep quality as the independent variable. Men who reported difficulty falling asleep had more severe LUTS than men without difficulty falling asleep (IPSS score 7.1 vs. 4.6, p<0.001) (Figure 1). Because of the independent associations between age, sleep quality, and LUTS, we confirmed that the relationship between impaired sleep quality and LUTS severity was independent of subject age. Importantly, there was no difference in mean age between men who did not report difficulty falling asleep or men with such difficulties (43.1 vs. 41.7 years old, p=0.08). A direct relationship was observed between LUTS severity and difficulty staying asleep or falling back asleep (p<0.001) (Figure 2). Similarly, these findings were independent of subject age across all levels of sleep difficulties (p>0.05).
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7 Because physical and psychological wellbeing increases the risk for other conditions and because LUTS have been associated with decreased emotional and physical wellbeing, we examined the relationship between self-reported sense of wellbeing or physical/cognitive function and LUTS severity. Men who reported a decreased sense of wellbeing or decreased physical and cognitive function had more severe LUTS than men who did not report such changes (p<0.001 and p=0.016, respectively) (Figure 3). Importantly, neither sense of wellbeing nor physical or cognitive function were associated with age in the cohort. These findings suggest a potential role for sleep quality and physical/mental wellbeing on the severity of LUTS.
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8 DISCUSSION While the prevalence of LUTS varies based on sampling methods and diagnostic criteria, these symptoms are common and can negatively impact quality of life.19 We identified an inverse relationship between sleep quality and LUTS severity in men working non-standard shifts. Importantly, the majority of men in our cohort reported working non-standard shifts for more than a year, increasing the likelihood that the impact of suboptimal sleep had already manifested. LUTS can reduce sleep quality, resulting in repeated awakening at night to urinate. Poor sleep, in turn, has numerous negative effects on quality of life and can increase the risk of depression, dysthymia, cardiovascular pathology, musculoskeletal pain,20, 21 and can have negative impacts on mood, subjective well-being, and overall functioning.20 LUTS can result from numerous conditions, including prostatic hyperplasia as well as systemic conditions such as cardiac failure, diabetes mellitus, sleep apnea, spinal cord injury, Parkinson’s disease, and medications, emotional and psychological factors, and patient lifestyle.22 Because of the relationship between poor sleep and the development or exacerbation of many common diseases, poor sleep may also exacerbate LUTS. Identifying sleep quality as an exacerbating factor for, rather than merely a result of, LUTS can provide an opportunity for intervention in affected men.
Our data suggest a bidirectional association between sleep quality and LUTS; we observed that men working non-standard shifts who reported difficulty falling asleep had more severe LUTS than men who were able to fall sleep without difficulty. This finding suggests that nighttime awakening resulting from nocturia is not the sole factor leading
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9 to impaired sleep quality in these men. Other data support a bidirectional relationship between LUTS severity and sleep quality, as patients with poor sleep quality have an increased incidence of nocturia, and significant nocturia and urinary frequency are risk factors for an undiagnosed sleep disorder.15,
23
Sleep is important in maintaining a
healthy autonomic nervous system and metabolism, and poor sleep can lead to impaired neural control and metabolic abnormalities, both of which are important in regulating the smooth muscle tone in the urinary tract.12-14, 24 It is tempting to speculate that several homeostatic mechanisms including the neural and metabolic pathways that are important for normal urinary function, and are impaired by poor sleep, may be a potential mechanism for how sleep quality may impact LUTS severity. Improvement in sleep habits and other lifestyle factors, including increased exercise, can reduce the incidence of nocturia and result in improved sleep quality and may reduce LUTS severity.25
The psychological impact on disease may often be overlooked as a cause of symptom development or exacerbation. Men in our cohort who reported a worse sense of wellbeing or impaired physical/cognitive function also reported more severe LUTS. The impact of shift work on physical and cognitive function has been described, with night shift workers having more severe fatigue than daytime workers, leading to reduced alertness and work performance as well as temporary declines in cognitive function.26 The psychological impact of impaired sleep resulting from shift work is not limited to fatigue-related causes. Nurses who work night shifts report more psychological issues including anxiety, obsessive-compulsive traits, somatization, interpersonal sensitivity,
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10 and paranoid symptoms, than nurses working during the day.27 The mechanism by which impaired sleep leads to increased psychological stress that exacerbates urinary symptoms is complex and incompletely defined.
However, psychological stress
activates the hypothalamic-pituitary-adrenal axis and may disrupt brain-bladder signaling at the level of the urothelium, potentially predisposing to LUTS.28-30 Thus, LUTS, poor sleep quality, and impaired physical and cognitive function are likely intertwined, and amelioration of symptoms in one category may result in improvement in the others.
The association between age and LUTS severity is well known, with a large epidemiological study of 4,737 Australian men providing an effective group to which other populations of similarly aged men can be compared. IPSS scores increased from 2.7 in healthy men 40-49 years old with no reproductive health issues to 6.2 in men ≥70 years old.18 Despite the relatively young mean age of men in our cohort (42 years), the average IPSS score (6.0) was closer to that of men ≥70 years old. Men with the most severe issues with sleep, quality of life, and cognitive function had more significant LUTS, which were independent of age. This contrast between IPSS scores and symptoms in night shift workers, when compared with the above healthy age-matched male cohort supports a direct relationship between sleep quality and LUTS. Nevertheless, direct comparisons between our cohort and other patient populations are limited by variations between these groups.
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11 Our study has several key strengths and limitations that merit discussion. The large sample size of non-standard shift workers who maintained this schedule for a long duration (81% >1 year) increases the likelihood that reported symptoms are related to work schedules. In our study, the majority of IPSS symptoms were significantly worse in men with sleep dysfunction.
However, we were unable to identify a particular
relationship between a specific symptom or cluster of symptoms that further associated with poor sleep. The lack of association between age and sleep quality supports the conclusion that impaired sleep and worsening LUTS are not solely a function of age. This study was limited by its retrospective design and the inherent limitations associated with this approach, as well as a lack of data regarding many of the comorbidities and lifestyle factors that may impact LUTS, limiting our ability to comment on the impact of these variables on our findings. The use of non-standardized questionnaires regarding sleep symptoms, quality of life, and cognitive function limits the findings of this study. This study is also limited by the lack of a comparison group of standard or daytime shift workers, and men with diagnosed SWD and those without. Presence of a control group would have improved the strength of findings and will be an important component in future studies on this subject. It is also important to discuss that the difference between a clinical and statistical difference in IPSS scores is important in this context. The correlation and trend associating worse sleep quality with worse IPSS score suggests that in some patients, sleep dysfunction may be related to their urinary symptoms. Future work will incorporate these comparisons and further our understanding of how impaired sleep may exacerbate LUTS.
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12
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13 CONCLUSION Men working non-standard shifts who have difficulty falling asleep, staying asleep, and falling back asleep report more severe LUTS than men who do not have similar sleep difficulties. Men who report a decreased sense of wellbeing and decreased physical/cognitive function also have more severe LUTS. These findings implicate sleep quality as a potential risk factor for LUTS severity, suggesting that poor sleep may be a causal factor and not just a consequence of LUTS.
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14 REFERENCES: 1.
2.
3.
4.
5. 6.
7. 8. 9. 10.
11.
12.
13.
14.
15.
16.
Taylor BC, Wilt TJ, Fink HA, et al. Prevalence, severity, and health correlates of lower urinary tract symptoms among older men: the MrOS study. Urology. 2006;68:804-809. Helfand BT, McVary KT, Meleth S, et al. The relationship between lower urinary tract symptom severity and sleep disturbance in the CAMUS trial. The Journal of urology. 2011;185:2223-2228. Helfand BT, Lee JY, Sharp V, et al. Associations between improvements in lower urinary tract symptoms and sleep disturbance over time in the CAMUS trial. The Journal of urology. 2012;188:2288-2293. Knutson KL, Van Cauter E, Rathouz PJ, et al. Association between sleep and blood pressure in midlife: the CARDIA sleep study. Archives of internal medicine. 2009;169:1055-1061. Sabanayagam C, Shankar A. Sleep duration and cardiovascular disease: results from the National Health Interview Survey. Sleep. 2010;33:1037-1042. Wright KP, Jr., Bogan RK, Wyatt JK. Shift work and the assessment and management of shift work disorder (SWD). Sleep medicine reviews. 2013;17:4154. Vogel M, Braungardt T, Meyer W, Schneider W. The effects of shift work on physical and mental health. Journal of neural transmission. 2012;119:1121-1132. Froy O. Metabolism and circadian rhythms--implications for obesity. Endocrine reviews. 2010;31:1-24. Patel SR, Hu FB. Short sleep duration and weight gain: a systematic review. Obesity. 2008;16:643-653. Grandner MA, Sands-Lincoln MR, Pak VM, Garland SN. Sleep duration, cardiovascular disease, and proinflammatory biomarkers. Nature and science of sleep. 2013;5:93-107. Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best practice & research. Clinical endocrinology & metabolism. 2010;24:775-784. Gacci M, Vignozzi L, Sebastianelli A, et al. Metabolic syndrome and lower urinary tract symptoms: the role of inflammation. Prostate cancer and prostatic diseases. 2013;16:101-106. Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep. 2004;27:1453-1462. Meyer JH, Ginovart N, Boovariwala A, et al. Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Archives of general psychiatry. 2006;63:1209-1216. Araujo AB, Yaggi HK, Yang M, McVary KT, Fang SC, Bliwise DL. Sleep related problems and urological symptoms: testing the hypothesis of bidirectionality in a longitudinal, population based study. The Journal of urology. 2014;191:100-106. Presser HB. Job, family, and gender: determinants of nonstandard work schedules among employed Americans in 1991. Demography. 1995;32:577-598.
Page 14 of 25
15 17.
18.
19. 20.
21.
22.
23. 24. 25.
26.
27.
28.
29. 30.
Barry MJ, Fowler FJ, Jr., O'Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. The Journal of urology. 1992;148:15491557; discussion 1564. Holden CA, McLachlan RI, Pitts M, et al. Men in Australia Telephone Survey (MATeS): a national survey of the reproductive health and concerns of middleaged and older Australian men. Lancet. 2005;366:218-224. Milsom I CR. Incontinence, 5th ed. Paris: International Consultation on Urological Diseases and European Association of Urology. 2013. Bliwise DL, Rosen RC, Baum N. Impact of nocturia on sleep and quality of life: a brief, selected review for the International Consultation on Incontinence Research Society (ICI-RS) nocturia think tank. Neurourology and urodynamics. 2014;33 Suppl 1:S15-18. Parthasarathy S, Fitzgerald M, Goodwin JL, Unruh M, Guerra S, Quan SF. Nocturia, sleep-disordered breathing, and cardiovascular morbidity in a community-based cohort. PloS one. 2012;7:e30969. Gratzke C, Bachmann A, Descazeaud A, et al. EAU Guidelines on the Assessment of Non-neurogenic Male Lower Urinary Tract Symptoms including Benign Prostatic Obstruction. European urology. 2015;67:1099-1109. Rai A, Nimeh T, Sood A, et al. Could nocturia be an indicator of an undiagnosed sleep disorder in male veterans? Urology. 2015;85:641-647. Yaggi HK, Araujo AB, McKinlay JB. Sleep duration as a risk factor for the development of type 2 diabetes. Diabetes care. 2006;29:657-661. Soda T, Masui K, Okuno H, Terai A, Ogawa O, Yoshimura K. Efficacy of nondrug lifestyle measures for the treatment of nocturia. The Journal of urology. 2010;184:1000-1004. Takeyama H, Matsumoto S, Murata K, et al. Effects of the length and timing of nighttime naps on task performance and physiological function. Revista de saude publica. 2004;38 Suppl:32-37. Selvi Y, Aydin A, Boysan M, Atli A, Agargun MY, Besiroglu L. Associations between chronotype, sleep quality, suicidality, and depressive symptoms in patients with major depression and healthy controls. Chronobiology international. 2010;27:1813-1828. Bonfiglio JJ, Inda C, Refojo D, Holsboer F, Arzt E, Silberstein S. The corticotropin-releasing hormone network and the hypothalamic-pituitary-adrenal axis: molecular and cellular mechanisms involved. Neuroendocrinology. 2011;94:12-20. Larauche M, Mulak A, Tache Y. Stress and visceral pain: from animal models to clinical therapies. Experimental neurology. 2012;233:49-67. Aberg KM, Radek KA, Choi EH, et al. Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. The Journal of clinical investigation. 2007;117:3339-3349.
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16
FIGURE LEGENDS Figure 1 - Relationship between difficulty falling asleep and LUTS severity (p<0.001). 9
7.1
8
IPSS Score
7 4.6
6 5
4 3 2 1 0
No Difficulty
Difficulty Present
Figure 2 - Relationship between difficulty staying asleep or falling back asleep and LUTS severity (p<0.001). 25
10.9 12.9
IPSS Score
20 15 10 5 0
6.5
8.1
4.2
Difficulty Staying Asleep* *p<0.001
7.5 5
5.9
No Problem Minor Problem Considerable Problem Serious Problem
Difficulty Getting Back to Sleep*
Figure 3 - Relationship between sense of wellbeing or physical/cognitive function and LUTS severity (p<0.001, p=0.016).
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17 7.7
16
IPSS Score
7.6
9.2
14
7.6
12 10 8 6
6.8
6.3 4.8
4.9
Slightly Decreased
4
Somewhat Decreased
2
0
Normal
Very Decreased Sense of Well-Being*
Physical and Cognitive Functioning**
*p<0.001 *p=0.016 Supplement 1 – Shift work questionnaire.
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18 Table 1. Cohort Demographics Variable Age (mean ± SD) (years) Number of Days Per Week Working Non-standard Shifts (mean ± SD) Duration of Non-Standard Shift Work (N(%)) < 1 month 1-6 months 7-12 months 1-5 years > 5 years IPSS Score (mean ± SD) IPSS Quality of Life Score (mean ± SD)
Value 41.8 ± 5.7 3.8 ± 1.9
16 (7%) 17 (7%) 9 (4%) 60 (26%) 126 (55%) 6.0 ± 5.6 1.4 ± 1.4
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19 Editorial Comment on: “Impaired Sleep Quality is Associated with More Significant Lower Urinary Tract Symptoms in Male Shift Workers”
Alex Gomelsky, M.D. Department of Urology Louisiana State University Health-Shreveport Shreveport, LA
Corresponding Author Alex Gomelsky, M.D. Professor of Clinical Urology LSU Health – Shreveport Department of Urology 1501 Kings Highway Shreveport, LA 71130 Phone (318) 675-5601 (318) 675-5665 Fax [email protected]
It has been traditionally thought that lower urinary tract symptoms (LUTS) such as nocturia result in poor sleep quality, and subsequently greater impact on quality of life. The authors of this study found a bidirectional relationship between LUTS severity and sleep quality in men working non-standard shifts, thus demonstrating that poor sleep quality in a population already at high risk for sleep disorders resulted in more LUTS. Their findings are thought-provoking in that, perhaps, sleep quality should be an area of interest and a target for treatment by the urologist.
The relationship between sleep quality and LUTS has already drawn attention in the literature. The human body has a master circadian clock in a hypothalamic control center known as the suprachiasmatic nucleus (SCN) and the primary circadian rhythm that this clock controls is the
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20 sleep-wake cycle. The circadian clock is “set” primarily by visual cues of light and darkness and this keeps the clock synchronized to the 24-hour day. Circadian rhythms and their sensitivity to time cues may change as a person ages and certain types of circadian rhythm sleep conditions, such as shift work disorder, may result in poor sleep quality. Persons with comorbid medical or psychiatric conditions, or those with other sleep disorders such as sleep apnea, may be at higher risk of developing circadian sleep disorders.
Melatonin may be the link between sleep quality and LUTS. The SCN directly regulates the synthesis of melatonin (N-acetyl-5-methoxytryptamine) within the pineal gland at night.1 Melatonin functions as a type of pacemaker by relaying time-of-day information to various organs, and feeding-back to the SCN itself. The phase-shifting effects of melatonin are essentially opposite to those of light and melatonin facilitates sleep in humans. The relationship of melatonin levels to LUTS has been explored in a recent cross-sectional study of 861 elderly Japanese individuals.2 Melatonin secretion was significantly and inversely associated with nocturia in a multivariate analysis. Additional evidence suggests that melatonin may also influence the circadian rhythm of other hormones, such as antidiuretic hormone, atrial natriuretic peptide, and angiotensin II, and thus may indirectly impact urine production.3
In clinical studies, melatonin has shown some positive impact on the treatment of micturition disorders. In a small, double-blind, randomized, placebo-controlled trial, 2 mg of melatonin was associated with a significant improvement in nocturia episodes and nocturia bother score in men with urodynamically-confirmed bladder outlet obstruction.4 In another study randomizing
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21 elderly patients with nocturia to 2 mg of melatonin or rilmazafone (a hypnotic agent), there was a similar and significant improvement in nocturia episodes and quality of life indices.5
Pharmacologic options for nocturnal urinary symptoms remain sparse, with afternoon diuretics, antimuscarinics, and desmopressin encompassing the majority of our armamentarium. As there is currently no melatonin formulation approved for urologic indications, it is premature to anoint this hormone as promising. At the least, it should serve as an area of significant interest and a focus for future research. Furthermore, questions regarding sleep quality should become a standard part of the genitourinary history and physical.
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22
References 1. Smolensky MH, Hermida RC, Reinberg A, Sackett-Lundeen L, Portaluppi F. Circadian
disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention. Chronobiol Int 2016 Jun 16: 1-19. [Epub ahead of print] 2. Obayashi K, Saeki K, Kurumatani N. Association between melatonin secretion and
nocturia in elderly individuals: a cross-sectional study of the HEIJO-KYO cohort. J Urol 2014; 191: 1816-1821. 3. Goessaert AS, Vande Walle J, Everaert K. Hormones and nocturia: guidelines for
medical treatment? J Steroids Hormon Sci 2014; 5: 130-136. 4. Drake MJ, Mills IW, Noble JG. Melatonin pharmacotherapy for nocturia in men with
benign prostatic enlargement. J Urol 2004; 171: 1199-1202. 5. Sugaya K, Nishijima S, Miyazato M, Kadekawa K, Ogawa Y. Effects of melatonin and
rilmazafone on nocturia in the elderly. J Int Med Res 2007; 35: 685-691.
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23 Author Reply to Comment on Impaired Sleep Quality Is Associated With More Significant Lower Urinary Tract Symptoms in Male Shift Workers Jason M. Scovell*1,2, Alexander W. Pastuszak MD, PhD*1,2, Jeremy Slawin MD3, Justin Badal MD3, Richard E. Link MD, PhD1,2, Larry I. Lipshultz MD1,2
1
Scott Department of Urology, Baylor College of Medicine, Houston, TX Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 3 Baylor College of Medicine, Houston, TX 2
MeSH Key Words: lower urinary tract symptoms, LUTS, sleep, shift work disorder, prostate
Word Count: 304 * - These authors contributed equally to the preparation of this manuscript Correspondence: Alexander W. Pastuszak, MD, PhD Assistant Professor Division of Male Reproductive Medicine and Surgery Scott Department of Urology Baylor College of Medicine 6624 Fannin St, Suite 1700 Houston, Texas 77030 Phone (713) 798-6163 Email: [email protected]
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24 As our understanding of the biological systems that affect bladder function evolves, our model that lower urinary tract symptoms (LUTS) are simply a result of biomechanical obstructive forces is being challenged. Our study identifies the possibility that poor sleep may predispose men for worse LUTS. The commenters have provided a very interesting discussion on recent literature regarding the circadian hormone melatonin and its relationship with nocturia. The hypothesis is that complex interactions between melatonin levels and other hormones may result in more nighttime urine production and as a result may exacerbate LUTS. Another potential mechanism may include the dampening effect of melatonin on bladder contractility. Recent animal model studies have identified that melatonin receptors in the bladder can reduce the contractile response elicited by muscarinic agonists or electrical field stimulation.1 It is tempting to speculate that as melatonin levels decrease with increasing age, loss of melatonin’s protective function on bladder contractility exacerbates the mechanical obstruction that results from benign prostatic hyperplasia and the increase in urine output resulting from altered hormone signaling. In 1995, Garfinkel and colleagues published a landmark study in Lancet demonstrating the efficacy of melatonin to improve sleep quality in elderly subjects.2 We support this idea that melatonin should be investigated as a potential therapeutic for LUTS. Melatonin is a promising link that may explain the complex relationship between impaired sleep quality as a driving force and not just a symptom of LUTS. References 1.
Han JH, Chang IH, Myung SC, et al. A novel pathway underlying the inhibitory effects of melatonin on isolated rat urinary bladder contraction. The Korean journal of physiology
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25
2.
& pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology. 2012;16:37-42. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346:541-544.
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S0090-4295(16)30610-0 http://dx.doi.org/doi: 10.1016/j.urology.2016.05.076 URL 20023
To appear in:
Urology
Received date: Accepted date:
28-10-2015 31-5-2016
Please cite this article as: Jason M. Scovell, Alexander W. Pastuszak, Jeremy Slawin, Justin Badal, Richard E. Link, Larry I. Lipshultz, Impaired Sleep Quality is Associated with More Significant Lower Urinary Tract Symptoms in Male Shift Workers, Urology (2016), http://dx.doi.org/doi: 10.1016/j.urology.2016.05.076. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Impaired Sleep Quality Is Associated With More Significant Lower Urinary Tract Symptoms in Male Shift Workers Jason M. Scovell*1,2, Alexander W. Pastuszak*1,2, Jeremy Slawin3, Justin Badal3, Richard E. Link1,2, Larry I. Lipshultz1,2
1
Scott Department of Urology, Baylor College of Medicine, Houston, TX Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 3 Baylor College of Medicine, Houston, TX 2
MeSH Key Words: lower urinary tract symptoms, LUTS, sleep, shift work disorder, prostate
Abstract Word Count: 258 Word Count: 1904 * - These authors contributed equally to the preparation of this manuscript Correspondence: Alexander W. Pastuszak, MD, PhD Assistant Professor Division of Male Reproductive Medicine and Surgery Scott Department of Urology Baylor College of Medicine 6624 Fannin St, Suite 1700 Houston, Texas 77030 Phone (713) 798-6163 Email: [email protected]
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2
Abbreviations: Lower Urinary Tract Symptoms (LUTS) Shift Work Disorder (SWD) Body Mass Index (BMI) International Prostate Symptom Score (IPSS) Abstract Objective: To determine the association between sleep quality and lower urinary tract symptom (LUTS) severity in men working non-standard shifts, a population at risk for poor sleep quality. Materials and Methods: Men who presented to a single andrology clinic between July and October 2014 and worked non-standard shifts completed the International Prostate Symptom Score (IPSS) and responded to questions regarding their work habits, sleepquality, and physical/cognitive function. We assessed the relationship between age, sleep-quality, physical/cognitive function and severity of LUTS. Results: 228 men with a mean±SD age of 41.8±5.7 (range 21-76) years reported working non-standard shifts with the majority working these for more than 1 year (81%). Men with difficulties falling asleep reported more severe LUTS than men who did not have difficulty falling asleep (IPSS score 9 vs. 6, p<0.001). Men who reported difficulty staying asleep or falling back asleep after awakening also reported more severe LUTS (IPSS scores 6 vs. 13, p=0.004; 5 vs. 13, p<0.001, respectively). Men with a decreased sense of wellbeing or decreased physical/cognitive function also reported more severe LUTS (IPSS score 6 vs. 9, p<0.0010; 6 vs. 10, p=0.016, respectively). All findings were independent of subject age.
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3 Conclusion: Men working non-standard shifts who have difficulty falling asleep, staying asleep, and falling back asleep report more severe LUTS than men without similar sleep difficulties. Men with a decreased sense of wellbeing or decreased physical/cognitive function also report worse LUTS. These findings implicate sleep quality as a possible risk factor for LUTS symptom severity.
INTRODUCTION Lower urinary tract symptoms (LUTS) are one of the most common and problematic medical conditions in older men. LUTS may be present in up to 97% of men ≥ 65 years old and are associated with worse health quality.1 Sequelae of LUTS include nocturia and consequent sleep disturbances, and more severe LUTS increases the risk for impaired sleep quality.2 Conversely, improvement in LUTS results in improved sleep.3 Impaired sleep quality may contribute to numerous other conditions including hypertension, diabetes mellitus, arteriosclerosis,4 and cardiovascular events.5 However, the relationship between sleep quality and LUTS remains unclear.
Sleep quality can be affected by abnormal sleep schedules, and shift workers often cannot maintain a normal sleep pattern as a result of their work schedule. Shift workers comprise 15-25% of the workforce and often develop impaired sleep quality, with 1032% developing shift work disorder (SWD).6
SWD is a circadian rhythm disorder
characterized by insomnia and sleepiness in people whose working hours overlap those of a normal sleep period, typically at night. Patients with SWD are more likely to have
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4 decreased daytime alertness and impaired cognitive function,7 higher body mass indices (BMIs), cholesterol levels, triglycerides, and rates of hypertension than non-shift workers.7,
8
The prevalence of depression is also greater in night shift workers when
compared with daytime workers. The mechanisms underlying development of SWD sequelae are unclear, although obesity,9 inflammation,10 autonomic dysregulation,11 and metabolic dysregulation12 can all result from sleep impairment; dysregulated neurotransmission may also result from SWD.13, 14 Since LUTS can arise from these same factors,12, 15 impaired sleep quality may not only be a consequence of, but also an exacerbating factor for LUTS.
Whether impaired sleep quality predisposes to LUTS or vice versa (bidirectional causality) has not been extensively studied. However, evidence suggests that poor sleep quality increases the risk of developing LUTS within 5 years of diagnosis.
15
Here,
we identify a relationship between the level of sleep quality and severity of LUTS in male non-standard shift workers.
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5 METHODS All men presenting to a single academic men’s health clinic between July and October 2014 were asked to complete an electronic survey about their work schedules, specifically regarding whether or not they worked non-standard shifts. Survey respondents were not selected for presenting symptoms, age, or race. As defined in the literature, men who work non-standard shifts begin work before 7 a.m. or after 2 p.m., regularly rotate between standard and non-standard formats, or regularly work hours outside of a standard 7 a.m. to 6 p.m. workday.16 Men who work non-standard shifts were asked how long they have been working these shifts, and were asked to complete the validated International Prostate Symptom Score (IPSS) questionnaire,17 as well as non-validated questionnaires to inform quality of life and cognitive function (Supplementary Data Figure 1).
Responses were collected electronically, and only responses with complete questionnaire data were included for analysis. We associated sleep quality (falling asleep, staying asleep, and getting back to sleep), quality of life, and cognitive/physical function with IPSS data. Because age is an important risk factor for LUTS,18 we compared subject ages across all response groups to determine whether or not the relationship between sleep, quality of life and LUTS were independent of age. We compared means using Student’s t-test, MANOVA, and linear regression where appropriate.
SPSS version 22 (IBM Corporation, Somers, NY) was used for all
statistical analyses, with p<0.05 considered statistically significant.
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6 RESULTS We hypothesized that sleep quality would impact LUTS severity, as it has been shown to exacerbate numerous other conditions. We asked men who work non-standard shifts to report their quality of sleep and LUTS severity using the IPSS. A total of 228 men reported working non-standard shifts and were included in the study with a mean±SD age of 41.8±5.7 (range 21-76) years (Table 1). Men reported working an average of 3.8±1.9 non-standard shifts per week, and 81% of men (n=186) reported working nonstandard shifts for greater than 1 year. The average IPSS score for non-standard shift workers was 6.0±5.6 with an average quality of life score of 1.4±1.4.
To identify poor sleep as a potential risk factor for LUTS severity, we used sleep quality as the independent variable. Men who reported difficulty falling asleep had more severe LUTS than men without difficulty falling asleep (IPSS score 7.1 vs. 4.6, p<0.001) (Figure 1). Because of the independent associations between age, sleep quality, and LUTS, we confirmed that the relationship between impaired sleep quality and LUTS severity was independent of subject age. Importantly, there was no difference in mean age between men who did not report difficulty falling asleep or men with such difficulties (43.1 vs. 41.7 years old, p=0.08). A direct relationship was observed between LUTS severity and difficulty staying asleep or falling back asleep (p<0.001) (Figure 2). Similarly, these findings were independent of subject age across all levels of sleep difficulties (p>0.05).
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7 Because physical and psychological wellbeing increases the risk for other conditions and because LUTS have been associated with decreased emotional and physical wellbeing, we examined the relationship between self-reported sense of wellbeing or physical/cognitive function and LUTS severity. Men who reported a decreased sense of wellbeing or decreased physical and cognitive function had more severe LUTS than men who did not report such changes (p<0.001 and p=0.016, respectively) (Figure 3). Importantly, neither sense of wellbeing nor physical or cognitive function were associated with age in the cohort. These findings suggest a potential role for sleep quality and physical/mental wellbeing on the severity of LUTS.
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8 DISCUSSION While the prevalence of LUTS varies based on sampling methods and diagnostic criteria, these symptoms are common and can negatively impact quality of life.19 We identified an inverse relationship between sleep quality and LUTS severity in men working non-standard shifts. Importantly, the majority of men in our cohort reported working non-standard shifts for more than a year, increasing the likelihood that the impact of suboptimal sleep had already manifested. LUTS can reduce sleep quality, resulting in repeated awakening at night to urinate. Poor sleep, in turn, has numerous negative effects on quality of life and can increase the risk of depression, dysthymia, cardiovascular pathology, musculoskeletal pain,20, 21 and can have negative impacts on mood, subjective well-being, and overall functioning.20 LUTS can result from numerous conditions, including prostatic hyperplasia as well as systemic conditions such as cardiac failure, diabetes mellitus, sleep apnea, spinal cord injury, Parkinson’s disease, and medications, emotional and psychological factors, and patient lifestyle.22 Because of the relationship between poor sleep and the development or exacerbation of many common diseases, poor sleep may also exacerbate LUTS. Identifying sleep quality as an exacerbating factor for, rather than merely a result of, LUTS can provide an opportunity for intervention in affected men.
Our data suggest a bidirectional association between sleep quality and LUTS; we observed that men working non-standard shifts who reported difficulty falling asleep had more severe LUTS than men who were able to fall sleep without difficulty. This finding suggests that nighttime awakening resulting from nocturia is not the sole factor leading
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9 to impaired sleep quality in these men. Other data support a bidirectional relationship between LUTS severity and sleep quality, as patients with poor sleep quality have an increased incidence of nocturia, and significant nocturia and urinary frequency are risk factors for an undiagnosed sleep disorder.15,
23
Sleep is important in maintaining a
healthy autonomic nervous system and metabolism, and poor sleep can lead to impaired neural control and metabolic abnormalities, both of which are important in regulating the smooth muscle tone in the urinary tract.12-14, 24 It is tempting to speculate that several homeostatic mechanisms including the neural and metabolic pathways that are important for normal urinary function, and are impaired by poor sleep, may be a potential mechanism for how sleep quality may impact LUTS severity. Improvement in sleep habits and other lifestyle factors, including increased exercise, can reduce the incidence of nocturia and result in improved sleep quality and may reduce LUTS severity.25
The psychological impact on disease may often be overlooked as a cause of symptom development or exacerbation. Men in our cohort who reported a worse sense of wellbeing or impaired physical/cognitive function also reported more severe LUTS. The impact of shift work on physical and cognitive function has been described, with night shift workers having more severe fatigue than daytime workers, leading to reduced alertness and work performance as well as temporary declines in cognitive function.26 The psychological impact of impaired sleep resulting from shift work is not limited to fatigue-related causes. Nurses who work night shifts report more psychological issues including anxiety, obsessive-compulsive traits, somatization, interpersonal sensitivity,
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10 and paranoid symptoms, than nurses working during the day.27 The mechanism by which impaired sleep leads to increased psychological stress that exacerbates urinary symptoms is complex and incompletely defined.
However, psychological stress
activates the hypothalamic-pituitary-adrenal axis and may disrupt brain-bladder signaling at the level of the urothelium, potentially predisposing to LUTS.28-30 Thus, LUTS, poor sleep quality, and impaired physical and cognitive function are likely intertwined, and amelioration of symptoms in one category may result in improvement in the others.
The association between age and LUTS severity is well known, with a large epidemiological study of 4,737 Australian men providing an effective group to which other populations of similarly aged men can be compared. IPSS scores increased from 2.7 in healthy men 40-49 years old with no reproductive health issues to 6.2 in men ≥70 years old.18 Despite the relatively young mean age of men in our cohort (42 years), the average IPSS score (6.0) was closer to that of men ≥70 years old. Men with the most severe issues with sleep, quality of life, and cognitive function had more significant LUTS, which were independent of age. This contrast between IPSS scores and symptoms in night shift workers, when compared with the above healthy age-matched male cohort supports a direct relationship between sleep quality and LUTS. Nevertheless, direct comparisons between our cohort and other patient populations are limited by variations between these groups.
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11 Our study has several key strengths and limitations that merit discussion. The large sample size of non-standard shift workers who maintained this schedule for a long duration (81% >1 year) increases the likelihood that reported symptoms are related to work schedules. In our study, the majority of IPSS symptoms were significantly worse in men with sleep dysfunction.
However, we were unable to identify a particular
relationship between a specific symptom or cluster of symptoms that further associated with poor sleep. The lack of association between age and sleep quality supports the conclusion that impaired sleep and worsening LUTS are not solely a function of age. This study was limited by its retrospective design and the inherent limitations associated with this approach, as well as a lack of data regarding many of the comorbidities and lifestyle factors that may impact LUTS, limiting our ability to comment on the impact of these variables on our findings. The use of non-standardized questionnaires regarding sleep symptoms, quality of life, and cognitive function limits the findings of this study. This study is also limited by the lack of a comparison group of standard or daytime shift workers, and men with diagnosed SWD and those without. Presence of a control group would have improved the strength of findings and will be an important component in future studies on this subject. It is also important to discuss that the difference between a clinical and statistical difference in IPSS scores is important in this context. The correlation and trend associating worse sleep quality with worse IPSS score suggests that in some patients, sleep dysfunction may be related to their urinary symptoms. Future work will incorporate these comparisons and further our understanding of how impaired sleep may exacerbate LUTS.
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12
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13 CONCLUSION Men working non-standard shifts who have difficulty falling asleep, staying asleep, and falling back asleep report more severe LUTS than men who do not have similar sleep difficulties. Men who report a decreased sense of wellbeing and decreased physical/cognitive function also have more severe LUTS. These findings implicate sleep quality as a potential risk factor for LUTS severity, suggesting that poor sleep may be a causal factor and not just a consequence of LUTS.
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14 REFERENCES: 1.
2.
3.
4.
5. 6.
7. 8. 9. 10.
11.
12.
13.
14.
15.
16.
Taylor BC, Wilt TJ, Fink HA, et al. Prevalence, severity, and health correlates of lower urinary tract symptoms among older men: the MrOS study. Urology. 2006;68:804-809. Helfand BT, McVary KT, Meleth S, et al. The relationship between lower urinary tract symptom severity and sleep disturbance in the CAMUS trial. The Journal of urology. 2011;185:2223-2228. Helfand BT, Lee JY, Sharp V, et al. Associations between improvements in lower urinary tract symptoms and sleep disturbance over time in the CAMUS trial. The Journal of urology. 2012;188:2288-2293. Knutson KL, Van Cauter E, Rathouz PJ, et al. Association between sleep and blood pressure in midlife: the CARDIA sleep study. Archives of internal medicine. 2009;169:1055-1061. Sabanayagam C, Shankar A. Sleep duration and cardiovascular disease: results from the National Health Interview Survey. Sleep. 2010;33:1037-1042. Wright KP, Jr., Bogan RK, Wyatt JK. Shift work and the assessment and management of shift work disorder (SWD). Sleep medicine reviews. 2013;17:4154. Vogel M, Braungardt T, Meyer W, Schneider W. The effects of shift work on physical and mental health. Journal of neural transmission. 2012;119:1121-1132. Froy O. Metabolism and circadian rhythms--implications for obesity. Endocrine reviews. 2010;31:1-24. Patel SR, Hu FB. Short sleep duration and weight gain: a systematic review. Obesity. 2008;16:643-653. Grandner MA, Sands-Lincoln MR, Pak VM, Garland SN. Sleep duration, cardiovascular disease, and proinflammatory biomarkers. Nature and science of sleep. 2013;5:93-107. Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best practice & research. Clinical endocrinology & metabolism. 2010;24:775-784. Gacci M, Vignozzi L, Sebastianelli A, et al. Metabolic syndrome and lower urinary tract symptoms: the role of inflammation. Prostate cancer and prostatic diseases. 2013;16:101-106. Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep. 2004;27:1453-1462. Meyer JH, Ginovart N, Boovariwala A, et al. Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Archives of general psychiatry. 2006;63:1209-1216. Araujo AB, Yaggi HK, Yang M, McVary KT, Fang SC, Bliwise DL. Sleep related problems and urological symptoms: testing the hypothesis of bidirectionality in a longitudinal, population based study. The Journal of urology. 2014;191:100-106. Presser HB. Job, family, and gender: determinants of nonstandard work schedules among employed Americans in 1991. Demography. 1995;32:577-598.
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15 17.
18.
19. 20.
21.
22.
23. 24. 25.
26.
27.
28.
29. 30.
Barry MJ, Fowler FJ, Jr., O'Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. The Journal of urology. 1992;148:15491557; discussion 1564. Holden CA, McLachlan RI, Pitts M, et al. Men in Australia Telephone Survey (MATeS): a national survey of the reproductive health and concerns of middleaged and older Australian men. Lancet. 2005;366:218-224. Milsom I CR. Incontinence, 5th ed. Paris: International Consultation on Urological Diseases and European Association of Urology. 2013. Bliwise DL, Rosen RC, Baum N. Impact of nocturia on sleep and quality of life: a brief, selected review for the International Consultation on Incontinence Research Society (ICI-RS) nocturia think tank. Neurourology and urodynamics. 2014;33 Suppl 1:S15-18. Parthasarathy S, Fitzgerald M, Goodwin JL, Unruh M, Guerra S, Quan SF. Nocturia, sleep-disordered breathing, and cardiovascular morbidity in a community-based cohort. PloS one. 2012;7:e30969. Gratzke C, Bachmann A, Descazeaud A, et al. EAU Guidelines on the Assessment of Non-neurogenic Male Lower Urinary Tract Symptoms including Benign Prostatic Obstruction. European urology. 2015;67:1099-1109. Rai A, Nimeh T, Sood A, et al. Could nocturia be an indicator of an undiagnosed sleep disorder in male veterans? Urology. 2015;85:641-647. Yaggi HK, Araujo AB, McKinlay JB. Sleep duration as a risk factor for the development of type 2 diabetes. Diabetes care. 2006;29:657-661. Soda T, Masui K, Okuno H, Terai A, Ogawa O, Yoshimura K. Efficacy of nondrug lifestyle measures for the treatment of nocturia. The Journal of urology. 2010;184:1000-1004. Takeyama H, Matsumoto S, Murata K, et al. Effects of the length and timing of nighttime naps on task performance and physiological function. Revista de saude publica. 2004;38 Suppl:32-37. Selvi Y, Aydin A, Boysan M, Atli A, Agargun MY, Besiroglu L. Associations between chronotype, sleep quality, suicidality, and depressive symptoms in patients with major depression and healthy controls. Chronobiology international. 2010;27:1813-1828. Bonfiglio JJ, Inda C, Refojo D, Holsboer F, Arzt E, Silberstein S. The corticotropin-releasing hormone network and the hypothalamic-pituitary-adrenal axis: molecular and cellular mechanisms involved. Neuroendocrinology. 2011;94:12-20. Larauche M, Mulak A, Tache Y. Stress and visceral pain: from animal models to clinical therapies. Experimental neurology. 2012;233:49-67. Aberg KM, Radek KA, Choi EH, et al. Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. The Journal of clinical investigation. 2007;117:3339-3349.
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16
FIGURE LEGENDS Figure 1 - Relationship between difficulty falling asleep and LUTS severity (p<0.001). 9
7.1
8
IPSS Score
7 4.6
6 5
4 3 2 1 0
No Difficulty
Difficulty Present
Figure 2 - Relationship between difficulty staying asleep or falling back asleep and LUTS severity (p<0.001). 25
10.9 12.9
IPSS Score
20 15 10 5 0
6.5
8.1
4.2
Difficulty Staying Asleep* *p<0.001
7.5 5
5.9
No Problem Minor Problem Considerable Problem Serious Problem
Difficulty Getting Back to Sleep*
Figure 3 - Relationship between sense of wellbeing or physical/cognitive function and LUTS severity (p<0.001, p=0.016).
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17 7.7
16
IPSS Score
7.6
9.2
14
7.6
12 10 8 6
6.8
6.3 4.8
4.9
Slightly Decreased
4
Somewhat Decreased
2
0
Normal
Very Decreased Sense of Well-Being*
Physical and Cognitive Functioning**
*p<0.001 *p=0.016 Supplement 1 – Shift work questionnaire.
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18 Table 1. Cohort Demographics Variable Age (mean ± SD) (years) Number of Days Per Week Working Non-standard Shifts (mean ± SD) Duration of Non-Standard Shift Work (N(%)) < 1 month 1-6 months 7-12 months 1-5 years > 5 years IPSS Score (mean ± SD) IPSS Quality of Life Score (mean ± SD)
Value 41.8 ± 5.7 3.8 ± 1.9
16 (7%) 17 (7%) 9 (4%) 60 (26%) 126 (55%) 6.0 ± 5.6 1.4 ± 1.4
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19 Editorial Comment on: “Impaired Sleep Quality is Associated with More Significant Lower Urinary Tract Symptoms in Male Shift Workers”
Alex Gomelsky, M.D. Department of Urology Louisiana State University Health-Shreveport Shreveport, LA
Corresponding Author Alex Gomelsky, M.D. Professor of Clinical Urology LSU Health – Shreveport Department of Urology 1501 Kings Highway Shreveport, LA 71130 Phone (318) 675-5601 (318) 675-5665 Fax [email protected]
It has been traditionally thought that lower urinary tract symptoms (LUTS) such as nocturia result in poor sleep quality, and subsequently greater impact on quality of life. The authors of this study found a bidirectional relationship between LUTS severity and sleep quality in men working non-standard shifts, thus demonstrating that poor sleep quality in a population already at high risk for sleep disorders resulted in more LUTS. Their findings are thought-provoking in that, perhaps, sleep quality should be an area of interest and a target for treatment by the urologist.
The relationship between sleep quality and LUTS has already drawn attention in the literature. The human body has a master circadian clock in a hypothalamic control center known as the suprachiasmatic nucleus (SCN) and the primary circadian rhythm that this clock controls is the
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20 sleep-wake cycle. The circadian clock is “set” primarily by visual cues of light and darkness and this keeps the clock synchronized to the 24-hour day. Circadian rhythms and their sensitivity to time cues may change as a person ages and certain types of circadian rhythm sleep conditions, such as shift work disorder, may result in poor sleep quality. Persons with comorbid medical or psychiatric conditions, or those with other sleep disorders such as sleep apnea, may be at higher risk of developing circadian sleep disorders.
Melatonin may be the link between sleep quality and LUTS. The SCN directly regulates the synthesis of melatonin (N-acetyl-5-methoxytryptamine) within the pineal gland at night.1 Melatonin functions as a type of pacemaker by relaying time-of-day information to various organs, and feeding-back to the SCN itself. The phase-shifting effects of melatonin are essentially opposite to those of light and melatonin facilitates sleep in humans. The relationship of melatonin levels to LUTS has been explored in a recent cross-sectional study of 861 elderly Japanese individuals.2 Melatonin secretion was significantly and inversely associated with nocturia in a multivariate analysis. Additional evidence suggests that melatonin may also influence the circadian rhythm of other hormones, such as antidiuretic hormone, atrial natriuretic peptide, and angiotensin II, and thus may indirectly impact urine production.3
In clinical studies, melatonin has shown some positive impact on the treatment of micturition disorders. In a small, double-blind, randomized, placebo-controlled trial, 2 mg of melatonin was associated with a significant improvement in nocturia episodes and nocturia bother score in men with urodynamically-confirmed bladder outlet obstruction.4 In another study randomizing
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21 elderly patients with nocturia to 2 mg of melatonin or rilmazafone (a hypnotic agent), there was a similar and significant improvement in nocturia episodes and quality of life indices.5
Pharmacologic options for nocturnal urinary symptoms remain sparse, with afternoon diuretics, antimuscarinics, and desmopressin encompassing the majority of our armamentarium. As there is currently no melatonin formulation approved for urologic indications, it is premature to anoint this hormone as promising. At the least, it should serve as an area of significant interest and a focus for future research. Furthermore, questions regarding sleep quality should become a standard part of the genitourinary history and physical.
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22
References 1. Smolensky MH, Hermida RC, Reinberg A, Sackett-Lundeen L, Portaluppi F. Circadian
disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention. Chronobiol Int 2016 Jun 16: 1-19. [Epub ahead of print] 2. Obayashi K, Saeki K, Kurumatani N. Association between melatonin secretion and
nocturia in elderly individuals: a cross-sectional study of the HEIJO-KYO cohort. J Urol 2014; 191: 1816-1821. 3. Goessaert AS, Vande Walle J, Everaert K. Hormones and nocturia: guidelines for
medical treatment? J Steroids Hormon Sci 2014; 5: 130-136. 4. Drake MJ, Mills IW, Noble JG. Melatonin pharmacotherapy for nocturia in men with
benign prostatic enlargement. J Urol 2004; 171: 1199-1202. 5. Sugaya K, Nishijima S, Miyazato M, Kadekawa K, Ogawa Y. Effects of melatonin and
rilmazafone on nocturia in the elderly. J Int Med Res 2007; 35: 685-691.
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23 Author Reply to Comment on Impaired Sleep Quality Is Associated With More Significant Lower Urinary Tract Symptoms in Male Shift Workers Jason M. Scovell*1,2, Alexander W. Pastuszak MD, PhD*1,2, Jeremy Slawin MD3, Justin Badal MD3, Richard E. Link MD, PhD1,2, Larry I. Lipshultz MD1,2
1
Scott Department of Urology, Baylor College of Medicine, Houston, TX Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 3 Baylor College of Medicine, Houston, TX 2
MeSH Key Words: lower urinary tract symptoms, LUTS, sleep, shift work disorder, prostate
Word Count: 304 * - These authors contributed equally to the preparation of this manuscript Correspondence: Alexander W. Pastuszak, MD, PhD Assistant Professor Division of Male Reproductive Medicine and Surgery Scott Department of Urology Baylor College of Medicine 6624 Fannin St, Suite 1700 Houston, Texas 77030 Phone (713) 798-6163 Email: [email protected]
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24 As our understanding of the biological systems that affect bladder function evolves, our model that lower urinary tract symptoms (LUTS) are simply a result of biomechanical obstructive forces is being challenged. Our study identifies the possibility that poor sleep may predispose men for worse LUTS. The commenters have provided a very interesting discussion on recent literature regarding the circadian hormone melatonin and its relationship with nocturia. The hypothesis is that complex interactions between melatonin levels and other hormones may result in more nighttime urine production and as a result may exacerbate LUTS. Another potential mechanism may include the dampening effect of melatonin on bladder contractility. Recent animal model studies have identified that melatonin receptors in the bladder can reduce the contractile response elicited by muscarinic agonists or electrical field stimulation.1 It is tempting to speculate that as melatonin levels decrease with increasing age, loss of melatonin’s protective function on bladder contractility exacerbates the mechanical obstruction that results from benign prostatic hyperplasia and the increase in urine output resulting from altered hormone signaling. In 1995, Garfinkel and colleagues published a landmark study in Lancet demonstrating the efficacy of melatonin to improve sleep quality in elderly subjects.2 We support this idea that melatonin should be investigated as a potential therapeutic for LUTS. Melatonin is a promising link that may explain the complex relationship between impaired sleep quality as a driving force and not just a symptom of LUTS. References 1.
Han JH, Chang IH, Myung SC, et al. A novel pathway underlying the inhibitory effects of melatonin on isolated rat urinary bladder contraction. The Korean journal of physiology
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25
2.
& pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology. 2012;16:37-42. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346:541-544.
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