- Email: [email protected]
Sleep Problems are Associated with Development and Progression of Lower Urinary Tract Symptoms: Results from REDUCE
Sleep Problems are Associated with Development and Progression of Lower Urinary Tract Symptoms: Results from REDUCE Brandee L. Branche, Lauren E. Howard, Daniel M. Moreira, Claus Roehrborn, Ramiro Castro-Santamaria, Gerald L. Andriole, Martin L. Hopp and Stephen J. Freedland* From the Surgery Section, Durham Veterans Affairs Medical Center (BLB, LEH, SJF) and Department of Biostatistics and Bioinformatics, Duke University School of Medicine (LEH), Durham, North Carolina, University of Illinois at Chicago (DMM), Chicago, Illinois, University of Texas Southwestern Medical Center (CR), Dallas, Texas, Metabolic Pathways and Cardiovascular R&D Unit, GlaxoSmithKline, Inc. (RC-S), King of Prussia, Pennsylvania, Washington University School of Medicine in St. Louis (GLA), St. Louis, Missouri, and Cedars-Sinai Medical Center (MLH, SJF), Los Angeles, California
Abbreviations and Acronyms BACH ¼ Boston Area Community Health BMI ¼ body mass index BPH ¼ benign prostatic hyperplasia CAMUS ¼ Complementary and Alternative Medicine for Urological Symptoms DRE ¼ digital rectal examination I-PSS ¼ International Prostate Symptom Score LUTS ¼ lower urinary tract symptoms MOS-Sleep ¼ Medical Outcomes Study Sleep Scale PSA ¼ prostate specific antigen REDUCE ¼ Reduction by Dutasteride of Prostate Cancer Events SCN ¼ suprachiasmatic nucleus
Purpose: Although lower urinary tract symptoms and sleep problems often develop together, to our knowledge it is unknown whether sleep disturbances are linked to lower urinary tract symptoms development and progression. As measured by the 6-item MOS-Sleep (Medical Outcomes Study Sleep Scale) survey we examined the relationship between sleep problems, and the development and progression of lower urinary tract symptoms in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study. Materials and Methods: REDUCE was a randomized trial testing prostate cancer chemoprevention with dutasteride in men with prostate specific antigen 2.5 to 10 ng/ml and a negative biopsy. At baseline men completed MOS-Sleep and a scaled average was used to calculate the sleep score. Men were followed for 4 years and I-PSS (International Prostate Symptom Score) was completed at baseline and every 6 months. Asymptomatic men had I-PSS less than 8 while symptomatic men had I-PSS 8 or greater. In the placebo arm of 2,588 men not receiving a-blockers or 5a-reductase inhibitors at baseline we tested the association between sleep problems and lower urinary tract symptom development and progression using Cox models. Results: During followup lower urinary tract symptoms developed in 209 of 1,452 asymptomatic men (14%) and 580 of 1,136 (51%) with lower urinary tract symptoms demonstrated progression. On multivariable analysis higher sleep scores were suggestively associated with increased lower urinary tract symptoms in asymptomatic men (quartile 4 vs 1 HR 1.41, 95% CI 0.92e2.17, p ¼ 0.12) and with lower urinary tract symptom progression in symptomatic men (per 10 points of sleep score HR 1.06, 95% CI 1.01e1.12, p ¼ 0.029). Accepted for publication August 27, 2017. No direct or indirect commercial incentive associated with publishing this article. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. Supported by the Department of Veterans Affairs, GlaxoSmithKline and National Institutes of Health K24 CA160653. * Correspondence: Cedars-Sinai Medical Center, 8635 West 3rd St., Suite 1070W, Los Angeles, California 90048 (telephone: 310-423-3497; FAX: 310-423-4711; e-mail: [email protected]).
Editor’s Note: This article is the fifth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 578 and 579.
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0022-5347/18/1992-0536/0 THE JOURNAL OF UROLOGY® Ó 2018 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
https://doi.org/10.1016/j.juro.2017.08.108 Vol. 199, 536-542, February 2018 Printed in U.S.A.
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Conclusions: Among men with lower urinary tract symptoms worse sleep scores were associated with the progression of lower urinary tract symptoms and among asymptomatic men worse sleep scores were suggestively associated with the development of lower urinary tract symptoms. If confirmed, these data suggest that sleep problems may precede such symptoms. Whether treating sleep problems would improve lower urinary tract symptoms requires further testing. Key Words: prostate, prostatic hyperplasia, lower urinary tract symptoms, sleep, patient reported outcome measures
AMONG patients with LUTS nocturia is a common complaint.1 Sleep disturbances associated with nocturia may worsen not only sleep quality but also quality of life.2,3 Additionally, the effects of sleep disturbance could have long-lasting consequences, including increased type 2 diabetes and cardiovascular disease.4 Despite the common co-development of LUTS and sleep problems, the relationship between the 2 conditions remains unclear. The CAMUS trial examined the relationship between sleep problems and LUTS in men with preexisting LUTS.5 This randomized North American trial compared saw palmetto extract vs placebo for LUTS in men with moderate to severe LUTS during 72 weeks and showed that saw palmetto was ineffective. A secondary analysis in 366 men examined baseline LUTS and sleep disturbance.6 Sleep disturbance was quantified by a 4-item Jenkins sleep scale, which assesses trouble falling asleep and staying asleep, waking up several times per night and waking up tired. Higher Jenkins scores, indicating more sleep disturbance, were associated with worse baseline LUTS.7 Another study in 339 participants from CAMUS showed a positive association between improved sleep and improved LUTS.8 LUTS improvement was more strongly associated with improved sleep than nocturia. However, these studies were limited in sample size, were done for only 72 weeks and only included men with LUTS in North America. BACH was an observational, longitudinal study of urological symptoms in 1,610 men and 2,534 women who completed data on LUTS and sleep quality, sleep restriction and sleep medications.9 Sleep symptoms and LUTS were assessed at baseline and 5 years. Outcomes included the development of incident LUTS in men with sleep problems but no baseline LUTS and the development of incident sleep problems in men with LUTS but no baseline sleep problems. Individuals with baseline sleep problems but no LUTS were more likely to experience LUTS at 5 years. However, baseline LUTS was not associated with the development of sleep problems. Study limitations included the lack of clinical measures (PSA and prostate volume in men), absent interim measurements between baseline and 5
years, men and women as participants (if the goal was to analyze LUTS related to BPH) and a lack of information regarding worsening LUTS in those with baseline LUTS. While CAMUS elucidated the significance of LUTS improvement in men with improved sleep habits and BACH highlighted LUTS development, there is a lack of consolidation of findings. As to our knowledge no prior studies have combined the analysis of LUTS development, LUTS progression and sleep disturbance, we used the REDUCE study to address this gap. We performed a post hoc analysis of REDUCE, a prospective, randomized trial of dutasteride vs placebo for prostate cancer prevention in men with elevated PSA and negative biopsy. Men were administered the 6-item MOS-Sleep survey10 at baseline to assess sleep and they were followed every 6 months to monitor LUTS. Based on CAMUS and BACH results, we hypothesized that men with higher baseline sleep problems would be at higher risk for LUTS than those without LUTS and greater LUTS progression than those with LUTS.
METHODS Study Cohort The REDUCE study design was previously described.11 The study was approved by the institutional review board at each site and all participants provided informed consent. The men were 50 to 75 years old. PSA was 2.5 to 10.0 ng/ml in those 50 to 60 years old and 3.0 to 10.0 ng/ml in those 61 to 75 years old. These men also had a negative 6 to 12 core prostate biopsy within 6 months of study enrollment, prostate volume less than 80 ml, no prior prostate surgery or prostate cancer diagnosis and I-PSS less than 25 or less than 20 if on a-blockers.12,13 Men were excluded from analysis if they had a history of prostate cancer, high grade intraepithelial neoplasia or atypical small acinar proliferation. A total of 8,122 men were randomized to receive placebo or dutasteride 0.5 mg per day. In this post hoc analysis we limited our analysis to 4,063 men in the placebo arm. We excluded from study 266 men with missing MOS-Sleep data at baseline, 184 missing covariates for multivariable analysis, 725 who received a-blockers or 5a-reductase inhibitors at baseline,
538
SLEEP PROBLEMS AND LOWER URINARY TRACT SYMPTOMS
38 with LUTS progression within 30 days of baseline and 272 missing followup information on LUTS. This resulted in a study of 2,588 men (see figure).
Medical Outcomes Study Sleep Scale Score At baseline men completed the 6-item standard version of MOS-Sleep to assess sleep quality (see Appendix).10 The MOS-Sleep 6-item questionnaire is a reliable and validated subset of the MOS-Sleep 12-item version.14 It covers 4 sleep dimensions, including sleep disturbance (2 items), awakening due to shortness of breath or with headache (1 item), sleep adequacy (2 items) and somnolence (1 item). Subjects were asked to recall sleep quality from the previous 4 weeks and respond on a 6-tier scale ranging from none of the time to all of the time. A scaled average of the scores on a 0 to 100 scale was used to calculate a composite sleep score to measure overall sleep quality.15 A higher sleep score indicated greater sleep disturbance.
Study Design I-PSS was obtained at baseline and every 6 months for 4 years. We stratified men into 2 groups based on baseline I-PSS. Men with I-PSS less than 8 were followed to determine LUTS development and men with I-PSS 8 or greater were followed to determine LUTS progression. LUTS development was defined as 2 I-PSS values greater than 14, any surgical procedure for BPH (including transurethral or open prostatectomy, urethral balloon dilation and laser prostatectomy) or initiation of a BPH drug (including any uroselective a-blocker such as tamsulosin or alfuzosin, any 5a-reductase inhibitor such as finasteride or any nonuroselective a-blocker in addition to a single I-PSS value greater than 14 or 2 I-PSS values of 12 or greater before the start of medication). LUTS progression was defined as an I-PSS increase of 4 points or
greater from baseline, any surgical procedure for BPH or the start of a new BPH drug.
Statistical Analysis Our a priori approach was to treat sleep score as continuous to minimize biases due to arbitrary cutoffs. However, when testing for proportional hazards assumptions, the continuous sleep score failed proportionality to predict LUTS development. Therefore, we also categorized sleep score into quartiles for the 2 analyses but kept the continuous scoring for LUTS progression as our primary approach. Kaplan-Meier estimates are reported for quartiles of sleep score. Cox proportional hazards models were used to test the association between baseline sleep score and LUTS development among those with baseline I-PSS less than 8. Similarly Cox models were used to test the association between baseline sleep score and LUTS progression among those with baseline LUTS (I-PSS 8 or greater). Beyond the composite sleep score each individual question was assessed separately as a continuous variable and modeled per 10-unit increase. To determine whether our results were influenced by nocturia, we repeated the analysis, excluding nocturia from the I-PSS score used to calculate LUTS development and progression. Models were adjusted for baseline age (continuous), race (white or nonwhite), BMI (continuous), diabetes (yes or no), smoking status (current, former or never smoker), prostate volume (continuous), PSA (continuous), digital rectal examination (abnormal or normal) and baseline I-PSS (continuous). Analyses were performed with StataÔ, version 13.1 with p <0.05 considered statistically significant.
RESULTS Baseline Characteristics Median age was 62 years (IQR 58e67) and 90% of the subjects were white (table 1). The median MOSSleep score was 16.7 (IQR 6.7e23.3), median BMI was 26.8 kg/m2 (IQR 24.7e29.1), 8% of the men had diabetes and 15% were current smokers. Of the 2,588 men 1,452 (56%) were asymptomatic for urinary symptoms and 1,136 (44%) had LUTS at baseline, defined as I-PSS 8 or greater. Lower Urinary Tract Symptoms Development. During followup LUTS developed dur-
CONSORT diagram shows 5a-reductase inhibitors.
patient
selection.
5ARIs,
ing the 4-year study in 209 of the 1,452 men (14%) who were asymptomatic at baseline, including in 80 due to increased I-PSS, in 110 due to medication and in 19 due to surgery. The proportion of men free of LUTS at 4 years was 82%, 83%, 78% and 77% for ascending quartiles of sleep score. Among men without baseline LUTS (I-PSS less than 8) those in the highest sleep score quartile were at increased risk for LUTS on univariable analysis (HR 1.41, 95% CI 0.92e2.16, p ¼ 0.11, table 2), although this did not reach statistical significance. Results were similar on multivariable analysis (HR 1.41, 95% CI 0.92e2.17, p ¼ 0.12).
SLEEP PROBLEMS AND LOWER URINARY TRACT SYMPTOMS
CI 1.01e1.13, p ¼ 0.020) and awakening during sleep time and having trouble falling back asleep (HR 1.08, 95% CI 1.02e1.14, p ¼ 0.010) were associated with an increased risk of LUTS on multivariable analysis. Results were similar after excluding nocturia from the calculation of LUTS development (supplementary table 1, http://jurology.com/).
Table 1. Baseline characteristics of 2,588 patients Median age (IQR) No. race (%): White Nonwhite Median kg/m2 BMI (IQR) No. smoking status (%): Never Former Current No. diabetes (%): No Yes Median ml prostate vol (IQR) Median ng/ml PSA (IQR) No. abnormal DRE (%) No. I-PSS (%): Asymptomatic (less than 8) Symptomatic (8 or greater) Median sleep score (IQR) Median question score range (IQR): 1dGet enough sleep to feel rested in morning 2dAwaken short of breath or with headache 3dTrouble falling asleep 4dAwaken during sleep time þ have trouble falling back asleep 5dTrouble staying awake during day 6dGet amount of sleep needed
62
(58e67)
2,333 (90) 255 (10) 26.8 (24.7e29.1) 1,164 1,042 381
(45) (40) (15)
Progression. Of the 1,136 men 580 (51%) with base-
line LUTS demonstrated LUTS progression, which was due to increased I-PSS in 442, medication in 114 and surgery in 24. The proportion free of LUTS progression at 4 years was 42%, 40%, 37% and 34% among ascending quartiles of sleep score. In men with baseline LUTS (I-PSS 8 or greater) a higher sleep score as a continuous variable was associated with increased LUTS progression on univariable analysis (HR 1.07, 95% CI 1.02e1.13, p ¼ 0.009) and on multivariable analysis (HR 1.06, 95% CI 1.01e1.12, p ¼ 0.029, table 2). After categorization men in the highest quartile of sleep score had increased LUTS progression on univariable analysis (HR 1.36, 95% CI 1.03e1.78, p ¼ 0.028) but this was not significant on multivariable analysis (HR 1.23, 95% CI 0.92e1.62, p ¼ 0.15). On multivariable analysis only 2 MOS-Sleep questions were associated with LUTS progression, including not getting enough sleep to feel rested in
2,374 (92) 214 (8) 41.3 (31.5e53.2) 5.6 (4.3e7.2) 99 (4) 7 (4e11) 1,452 (56) 1,136 (44) 16.7 (6.7e23.3) 20 0 0 0
(0e20) (0e0) (0e20) (0e20)
20 20
(0e40) (0e40)
539
When each MOS-Sleep question was examined individually, only the 2 questions on sleep disturbance were associated with the development of LUTS. Specifically more trouble falling asleep (HR 1.07, 95%
Table 2. Association of baseline sleep score with LUTS development in men with no symptomatic LUTS and LUTS progression in men with symptomatic LUTS Univariable Continuous HR/10 U Score Increase (95% CI)
Multivariable* p Value
Continuous HR/10 U Score Increase (95% CI)
p Value
Referent 1.07 (0.72e1.59) 1.36 (0.92e2.03) 1.41 (0.92e2.16)
e 0.72 0.12 0.11
Referent 1.07 (0.72e1.59) 1.25 (0.84e1.87) 1.41 (0.92e2.17)
e 0.74 0.27 0.12
1.03 1.01 1.08 1.09 1.05 1.00
0.25 0.69 0.009 0.001 0.15 0.87
1.04 1.01 1.07 1.08 1.03 1.02
(0.99e1.10) (0.93e1.08) (1.01e1.13) (1.02e1.14) (0.96e1.11) (0.97e1.07)
0.14 0.87 0.020 0.010 0.35 0.48
1.07 (1.02e1.13) Referent 1.05 (0.79e1.40) 1.16 (0.88e1.53) 1.36 (1.03e1.78)
0.009 e 0.73 0.30 0.028
1.06 (1.01e1.12) Referent 0.96 (0.73e1.29) 1.04 (0.79e1.38) 1.23 (0.93e1.62)
0.029 e 0.83 0.77 0.15
1.04 1.02 1.03 1.02 1.04 1.01
0.013 0.39 0.036 0.21 0.032 0.36
1.04 1.02 1.04 1.01 1.03 1.01
0.027 0.40 0.031 0.43 0.08 0.70
LUTS development Sleep score quartile: 1 2 3 4 Question: 1dGet enough sleep to feel rested in morning 2dAwaken short of breath or with headache 3dTrouble falling asleep 4dAwaken during sleep time þ have trouble falling back asleep 5dTrouble staying awake during day 6dGet amount of sleep needed
(0.98e1.09) (0.95e1.09) (1.02e1.14) (1.04e1.16) (0.98e1.12) (0.96e1.05)
LUTS progression Sleep score: Continuous Quartile 1 Quartile 2 Quartile 3 Quartile 4 Question: 1dGet enough sleep to feel rested in morning 2dAwaken short of breath or with headache 3dTrouble falling asleep 4dAwaken during sleep time þ have trouble falling back asleep 5dTrouble staying awake during day 6dGet amount of sleep needed
(1.01e1.07) (0.98e1.06) (1.00e1.07) (0.99e1.06) (1.00e1.07) (0.99e1.04)
* Adjusted for age, race, BMI, diabetes, smoking status, DRE, prostate volume, PSA and I-PSS.
(1.00e1.07) (0.98e1.06) (1.00e1.07) (0.98e1.05) (1.00e1.07) (0.98e1.04)
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SLEEP PROBLEMS AND LOWER URINARY TRACT SYMPTOMS
the morning (HR 1.04, 95% CI 1.00e1.07, p ¼ 0.027) and having trouble falling asleep (HR 1.04, 95% CI 1.00e1.07, p ¼ 0.031). Results were similar after excluding nocturia from the calculation of LUTS progression (supplementary table 2, http://jurology. com/).
DISCUSSION Although previous studies showed a relationship between sleep and LUTS, to our knowledge no study to date has combined an analysis of LUTS development and progression related to sleep. Additionally, these prior studies were limited in sample size, lacked interim analysis and only focused on LUTS development or progression. To address this, in a post hoc analysis using REDUCE we analyzed LUTS development and progression longitudinally during 4 years. Among asymptomatic men worse sleep scores were suggestively associated with LUTS development and individual questions assessing sleep disturbance were associated with increased LUTS development. Among men with baseline LUTS worse sleep scores were associated with LUTS progression. Individual questions assessing sleep disturbance and sleep adequacy were also associated with increased LUTS progression. Of note, our cohort included men with and without nocturia, indicating that sleep may influence LUTS not only at night but also during the day. It is often inferred that LUTS lead to sleep problems but the current results suggest that sleep problems may precede LUTS, although validation is needed. Our results show that sleep problems are related to LUTS development in asymptomatic men and LUTS progression in men with baseline LUTS. These findings are consistent with CAMUS, which showed a relationship between LUTS and sleep disturbance, although the secondary analysis of CAMUS focused on improvements in LUTS and sleep disturbances as opposed to increased sleep problems and worsened LUTS.8 CAMUS identified LUTS as a risk factor for sleep disturbance and did not address LUTS progression in subjects with sleep problems. Additionally, while our cohort included men with and without baseline LUTS, CAMUS only included men with moderate to severe LUTS (I-PSS 8 to 24), thus limiting analysis of asymptomatic men. Our results are also consistent with BACH in that LUTS were more likely to develop with time in asymptomatic individuals with sleep problems.9 The results of the current study expand these observations by including an analysis of LUTS every 6 months and an analysis of individual MOS-Sleep dimensions and their relation to LUTS. If validated in future studies, LUTS development
and progression may be added to the list of diseases linked to sleep disturbances such as type 2 diabetes and cardiovascular disease.4 If confirmed in future studies, there are several possible explanations of why poor sleep may lead to LUTS and/or worsening LUTS. First, poor sleep and urinary problems may be related to the codevelopment of some other comorbidity such as obesity or diabetes. While sleep problems and obesity are linked, the directionality of the relationship is debated, that is whether sleep disorders contribute to obesity or the reverse.16,17 Additionally, obesity is linked to LUTS. In a prospective analysis of 51,529 men higher total or abdominal adiposity was associated with increased LUTS development and progression.18 Moreover, increased BMI is associated with larger prostate volume and I-PSS increases.19,20 Others suggested that obesity mediates the relationship between sleep problems and LUTS.9 Importantly, our results were adjusted for BMI, suggesting that in our data obesity is unlikely to explain all observations. Alternatively, obesity related disorders such as metabolic syndrome (including diabetes) offer another explanation of the connection between sleep problems and LUTS. However, we adjusted for diabetes, implying that this also cannot explain the link between sleep and LUTS seen in our study. Poor sleep could potentially lead to disrupted circadian rhythms. Physiological processes involving urination typically show circadian functioning with urine production and voiding predominating during wakefulness while increased urine storage and less urination occur while sleeping.21,22 In 20 young, sleep deprived adults increased sleep deprivation was linked with increased diuresis and excess urinary sodium, which were more pronounced in men than in women.22 The exact molecular mechanisms underlying the circadian rhythm of urinary function are unknown. While the SCN in the hypothalamus is the main site regulating circadian rhythm in mammals,23 local circadian clocks also exist in tissues throughout the body, including renal and bladder tissues, although these peripheral clocks are still under SCN control.21,24e27 Future studies are needed to assess whether the molecular mechanism driving the connection between sleep problems and LUTS is a bladder or renal clock, SCN disruption or a prostatic problem (sleep problems impacting prostate size or growth). Our study is limited by few nonwhite participants. To our knowledge no standard MOS-Sleep questionnaire cutoff points exist, limiting clinical usefulness. The questionnaire does not include questions on nocturia or sleep medications and data were available on only the 6-item version of MOS-Sleep. Sleep data were only available from
SLEEP PROBLEMS AND LOWER URINARY TRACT SYMPTOMS
MOS-Sleep while detailed information on sleep apnea, which has been associated with nocturia, was unavailable. Also, in this study we only used the baseline sleep score. Future studies are needed to assess changes in the sleep score and how they correlate with changes in LUTS as well as whether LUTS predict changes in the sleep score. Furthermore, I-PSS and MOS-Sleep were patient reported. We lacked power to evaluate objective measures such as urinary retention or BPH related surgery. Nevertheless, from a practical perspective, clinicians use symptoms to make decisions. Our study only included men with elevated PSA and negative biopsies. To our knowledge it is unknown whether similar results would be seen in broader cohorts. Also, while the results are statistically significant, the significance was modest so that the clinical usefulness of these findings is unclear. Finally, as LUTS are not restricted to men, future studies are needed to assess whether similar associations are seen in women. Study strengths include the large sample size, the availability of interim I-PSS measurements and clinical confounding measures (PSA and prostate volume), and the use of validated questionnaires for sleep and LUTS.
541
CONCLUSIONS In REDUCE men with sleep problems were at higher risk for LUTS if they were asymptomatic at baseline, and experiencing LUTS progression if they were symptomatic at baseline. Further research is needed to validate these results. If validated, future studies should test whether treating sleep problems improves LUTS or prevents LUTS development.
APPENDIX MOS-Sleep Questionnaire Dimensions Awaken short of breath or headache Sleep disturbance Somnolence Sleep adequacy*
Question 2) Awaken short of breath or with headache 3) Trouble falling asleep 4) Awaken during sleep time and have trouble falling back asleep 5) Trouble staying awake during the day 1) Get enough sleep to feel rested in the morning 6) Get the amount of sleep needed
Each question was graded on scale of 1 to 6, including 1dall the time, 2dmost of time, 3dgood bit of time, 4dsome of time, 5dlittle of time and 6dnone of time with scaled average of scores on 0 to 100 scale used to calculate sleep score to measure overall sleep quality. * Scaled average of scores on 0 to 100 scale was reversed.
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EDITORIAL COMMENT The multifactorial etiologies which underlie LUTS often impair successful treatment. Sleep disturbance is an increasingly recognized comorbidity that contributes to the presence and severity of LUTS. The current analysis of men with sleep disorders in the REDUCE trial further supports this relationship. Despite common beliefs that sleep disturbances only contribute to nocturia, the authors document that sleep also influences the development and progression of daytime LUTS. This is consistent with previous data demonstrating associations between sleep disorders and daytime urinary symptoms (reference 7 in article). While the directions of these associations remain to be validated, the current results suggest that sleep disorders may precede the development of LUTS, which may provide an opportunity to prevent the development of LUTS. For example, studies have
demonstrated that LUTS improve with pressure airway treatment in men with obstructive sleep apnea.1 Therefore, it is possible these treatments could be used in men with obstructive sleep apnea. While this data set was not able to address the influence of obstructive sleep apnea on LUTS development and progression, further exploratory studies should be performed. At minimum the study results emphasize the importance of sleep assessment in men with and without LUTS to potentially curb onset and progression, respectively. Brian Helfand Division of Urology Department of Surgery Pritzker School of Medicine University of Chicago NorthShore University HealthSystem Evanston, Illinois
REFERENCE 1. Miyauchi Y, Okazoe H, Okujyo M et al: Effect of the continuous positive airway pressure on the nocturnal urine volume or night-time frequency in patients with obstructive sleep apnea syndrome. Urology 2015; 85: 333.
Abbreviations and Acronyms BACH ¼ Boston Area Community Health BMI ¼ body mass index BPH ¼ benign prostatic hyperplasia CAMUS ¼ Complementary and Alternative Medicine for Urological Symptoms DRE ¼ digital rectal examination I-PSS ¼ International Prostate Symptom Score LUTS ¼ lower urinary tract symptoms MOS-Sleep ¼ Medical Outcomes Study Sleep Scale PSA ¼ prostate specific antigen REDUCE ¼ Reduction by Dutasteride of Prostate Cancer Events SCN ¼ suprachiasmatic nucleus
Purpose: Although lower urinary tract symptoms and sleep problems often develop together, to our knowledge it is unknown whether sleep disturbances are linked to lower urinary tract symptoms development and progression. As measured by the 6-item MOS-Sleep (Medical Outcomes Study Sleep Scale) survey we examined the relationship between sleep problems, and the development and progression of lower urinary tract symptoms in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study. Materials and Methods: REDUCE was a randomized trial testing prostate cancer chemoprevention with dutasteride in men with prostate specific antigen 2.5 to 10 ng/ml and a negative biopsy. At baseline men completed MOS-Sleep and a scaled average was used to calculate the sleep score. Men were followed for 4 years and I-PSS (International Prostate Symptom Score) was completed at baseline and every 6 months. Asymptomatic men had I-PSS less than 8 while symptomatic men had I-PSS 8 or greater. In the placebo arm of 2,588 men not receiving a-blockers or 5a-reductase inhibitors at baseline we tested the association between sleep problems and lower urinary tract symptom development and progression using Cox models. Results: During followup lower urinary tract symptoms developed in 209 of 1,452 asymptomatic men (14%) and 580 of 1,136 (51%) with lower urinary tract symptoms demonstrated progression. On multivariable analysis higher sleep scores were suggestively associated with increased lower urinary tract symptoms in asymptomatic men (quartile 4 vs 1 HR 1.41, 95% CI 0.92e2.17, p ¼ 0.12) and with lower urinary tract symptom progression in symptomatic men (per 10 points of sleep score HR 1.06, 95% CI 1.01e1.12, p ¼ 0.029). Accepted for publication August 27, 2017. No direct or indirect commercial incentive associated with publishing this article. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. Supported by the Department of Veterans Affairs, GlaxoSmithKline and National Institutes of Health K24 CA160653. * Correspondence: Cedars-Sinai Medical Center, 8635 West 3rd St., Suite 1070W, Los Angeles, California 90048 (telephone: 310-423-3497; FAX: 310-423-4711; e-mail: [email protected]).
Editor’s Note: This article is the fifth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 578 and 579.
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0022-5347/18/1992-0536/0 THE JOURNAL OF UROLOGY® Ó 2018 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
https://doi.org/10.1016/j.juro.2017.08.108 Vol. 199, 536-542, February 2018 Printed in U.S.A.
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Conclusions: Among men with lower urinary tract symptoms worse sleep scores were associated with the progression of lower urinary tract symptoms and among asymptomatic men worse sleep scores were suggestively associated with the development of lower urinary tract symptoms. If confirmed, these data suggest that sleep problems may precede such symptoms. Whether treating sleep problems would improve lower urinary tract symptoms requires further testing. Key Words: prostate, prostatic hyperplasia, lower urinary tract symptoms, sleep, patient reported outcome measures
AMONG patients with LUTS nocturia is a common complaint.1 Sleep disturbances associated with nocturia may worsen not only sleep quality but also quality of life.2,3 Additionally, the effects of sleep disturbance could have long-lasting consequences, including increased type 2 diabetes and cardiovascular disease.4 Despite the common co-development of LUTS and sleep problems, the relationship between the 2 conditions remains unclear. The CAMUS trial examined the relationship between sleep problems and LUTS in men with preexisting LUTS.5 This randomized North American trial compared saw palmetto extract vs placebo for LUTS in men with moderate to severe LUTS during 72 weeks and showed that saw palmetto was ineffective. A secondary analysis in 366 men examined baseline LUTS and sleep disturbance.6 Sleep disturbance was quantified by a 4-item Jenkins sleep scale, which assesses trouble falling asleep and staying asleep, waking up several times per night and waking up tired. Higher Jenkins scores, indicating more sleep disturbance, were associated with worse baseline LUTS.7 Another study in 339 participants from CAMUS showed a positive association between improved sleep and improved LUTS.8 LUTS improvement was more strongly associated with improved sleep than nocturia. However, these studies were limited in sample size, were done for only 72 weeks and only included men with LUTS in North America. BACH was an observational, longitudinal study of urological symptoms in 1,610 men and 2,534 women who completed data on LUTS and sleep quality, sleep restriction and sleep medications.9 Sleep symptoms and LUTS were assessed at baseline and 5 years. Outcomes included the development of incident LUTS in men with sleep problems but no baseline LUTS and the development of incident sleep problems in men with LUTS but no baseline sleep problems. Individuals with baseline sleep problems but no LUTS were more likely to experience LUTS at 5 years. However, baseline LUTS was not associated with the development of sleep problems. Study limitations included the lack of clinical measures (PSA and prostate volume in men), absent interim measurements between baseline and 5
years, men and women as participants (if the goal was to analyze LUTS related to BPH) and a lack of information regarding worsening LUTS in those with baseline LUTS. While CAMUS elucidated the significance of LUTS improvement in men with improved sleep habits and BACH highlighted LUTS development, there is a lack of consolidation of findings. As to our knowledge no prior studies have combined the analysis of LUTS development, LUTS progression and sleep disturbance, we used the REDUCE study to address this gap. We performed a post hoc analysis of REDUCE, a prospective, randomized trial of dutasteride vs placebo for prostate cancer prevention in men with elevated PSA and negative biopsy. Men were administered the 6-item MOS-Sleep survey10 at baseline to assess sleep and they were followed every 6 months to monitor LUTS. Based on CAMUS and BACH results, we hypothesized that men with higher baseline sleep problems would be at higher risk for LUTS than those without LUTS and greater LUTS progression than those with LUTS.
METHODS Study Cohort The REDUCE study design was previously described.11 The study was approved by the institutional review board at each site and all participants provided informed consent. The men were 50 to 75 years old. PSA was 2.5 to 10.0 ng/ml in those 50 to 60 years old and 3.0 to 10.0 ng/ml in those 61 to 75 years old. These men also had a negative 6 to 12 core prostate biopsy within 6 months of study enrollment, prostate volume less than 80 ml, no prior prostate surgery or prostate cancer diagnosis and I-PSS less than 25 or less than 20 if on a-blockers.12,13 Men were excluded from analysis if they had a history of prostate cancer, high grade intraepithelial neoplasia or atypical small acinar proliferation. A total of 8,122 men were randomized to receive placebo or dutasteride 0.5 mg per day. In this post hoc analysis we limited our analysis to 4,063 men in the placebo arm. We excluded from study 266 men with missing MOS-Sleep data at baseline, 184 missing covariates for multivariable analysis, 725 who received a-blockers or 5a-reductase inhibitors at baseline,
538
SLEEP PROBLEMS AND LOWER URINARY TRACT SYMPTOMS
38 with LUTS progression within 30 days of baseline and 272 missing followup information on LUTS. This resulted in a study of 2,588 men (see figure).
Medical Outcomes Study Sleep Scale Score At baseline men completed the 6-item standard version of MOS-Sleep to assess sleep quality (see Appendix).10 The MOS-Sleep 6-item questionnaire is a reliable and validated subset of the MOS-Sleep 12-item version.14 It covers 4 sleep dimensions, including sleep disturbance (2 items), awakening due to shortness of breath or with headache (1 item), sleep adequacy (2 items) and somnolence (1 item). Subjects were asked to recall sleep quality from the previous 4 weeks and respond on a 6-tier scale ranging from none of the time to all of the time. A scaled average of the scores on a 0 to 100 scale was used to calculate a composite sleep score to measure overall sleep quality.15 A higher sleep score indicated greater sleep disturbance.
Study Design I-PSS was obtained at baseline and every 6 months for 4 years. We stratified men into 2 groups based on baseline I-PSS. Men with I-PSS less than 8 were followed to determine LUTS development and men with I-PSS 8 or greater were followed to determine LUTS progression. LUTS development was defined as 2 I-PSS values greater than 14, any surgical procedure for BPH (including transurethral or open prostatectomy, urethral balloon dilation and laser prostatectomy) or initiation of a BPH drug (including any uroselective a-blocker such as tamsulosin or alfuzosin, any 5a-reductase inhibitor such as finasteride or any nonuroselective a-blocker in addition to a single I-PSS value greater than 14 or 2 I-PSS values of 12 or greater before the start of medication). LUTS progression was defined as an I-PSS increase of 4 points or
greater from baseline, any surgical procedure for BPH or the start of a new BPH drug.
Statistical Analysis Our a priori approach was to treat sleep score as continuous to minimize biases due to arbitrary cutoffs. However, when testing for proportional hazards assumptions, the continuous sleep score failed proportionality to predict LUTS development. Therefore, we also categorized sleep score into quartiles for the 2 analyses but kept the continuous scoring for LUTS progression as our primary approach. Kaplan-Meier estimates are reported for quartiles of sleep score. Cox proportional hazards models were used to test the association between baseline sleep score and LUTS development among those with baseline I-PSS less than 8. Similarly Cox models were used to test the association between baseline sleep score and LUTS progression among those with baseline LUTS (I-PSS 8 or greater). Beyond the composite sleep score each individual question was assessed separately as a continuous variable and modeled per 10-unit increase. To determine whether our results were influenced by nocturia, we repeated the analysis, excluding nocturia from the I-PSS score used to calculate LUTS development and progression. Models were adjusted for baseline age (continuous), race (white or nonwhite), BMI (continuous), diabetes (yes or no), smoking status (current, former or never smoker), prostate volume (continuous), PSA (continuous), digital rectal examination (abnormal or normal) and baseline I-PSS (continuous). Analyses were performed with StataÔ, version 13.1 with p <0.05 considered statistically significant.
RESULTS Baseline Characteristics Median age was 62 years (IQR 58e67) and 90% of the subjects were white (table 1). The median MOSSleep score was 16.7 (IQR 6.7e23.3), median BMI was 26.8 kg/m2 (IQR 24.7e29.1), 8% of the men had diabetes and 15% were current smokers. Of the 2,588 men 1,452 (56%) were asymptomatic for urinary symptoms and 1,136 (44%) had LUTS at baseline, defined as I-PSS 8 or greater. Lower Urinary Tract Symptoms Development. During followup LUTS developed dur-
CONSORT diagram shows 5a-reductase inhibitors.
patient
selection.
5ARIs,
ing the 4-year study in 209 of the 1,452 men (14%) who were asymptomatic at baseline, including in 80 due to increased I-PSS, in 110 due to medication and in 19 due to surgery. The proportion of men free of LUTS at 4 years was 82%, 83%, 78% and 77% for ascending quartiles of sleep score. Among men without baseline LUTS (I-PSS less than 8) those in the highest sleep score quartile were at increased risk for LUTS on univariable analysis (HR 1.41, 95% CI 0.92e2.16, p ¼ 0.11, table 2), although this did not reach statistical significance. Results were similar on multivariable analysis (HR 1.41, 95% CI 0.92e2.17, p ¼ 0.12).
SLEEP PROBLEMS AND LOWER URINARY TRACT SYMPTOMS
CI 1.01e1.13, p ¼ 0.020) and awakening during sleep time and having trouble falling back asleep (HR 1.08, 95% CI 1.02e1.14, p ¼ 0.010) were associated with an increased risk of LUTS on multivariable analysis. Results were similar after excluding nocturia from the calculation of LUTS development (supplementary table 1, http://jurology.com/).
Table 1. Baseline characteristics of 2,588 patients Median age (IQR) No. race (%): White Nonwhite Median kg/m2 BMI (IQR) No. smoking status (%): Never Former Current No. diabetes (%): No Yes Median ml prostate vol (IQR) Median ng/ml PSA (IQR) No. abnormal DRE (%) No. I-PSS (%): Asymptomatic (less than 8) Symptomatic (8 or greater) Median sleep score (IQR) Median question score range (IQR): 1dGet enough sleep to feel rested in morning 2dAwaken short of breath or with headache 3dTrouble falling asleep 4dAwaken during sleep time þ have trouble falling back asleep 5dTrouble staying awake during day 6dGet amount of sleep needed
62
(58e67)
2,333 (90) 255 (10) 26.8 (24.7e29.1) 1,164 1,042 381
(45) (40) (15)
Progression. Of the 1,136 men 580 (51%) with base-
line LUTS demonstrated LUTS progression, which was due to increased I-PSS in 442, medication in 114 and surgery in 24. The proportion free of LUTS progression at 4 years was 42%, 40%, 37% and 34% among ascending quartiles of sleep score. In men with baseline LUTS (I-PSS 8 or greater) a higher sleep score as a continuous variable was associated with increased LUTS progression on univariable analysis (HR 1.07, 95% CI 1.02e1.13, p ¼ 0.009) and on multivariable analysis (HR 1.06, 95% CI 1.01e1.12, p ¼ 0.029, table 2). After categorization men in the highest quartile of sleep score had increased LUTS progression on univariable analysis (HR 1.36, 95% CI 1.03e1.78, p ¼ 0.028) but this was not significant on multivariable analysis (HR 1.23, 95% CI 0.92e1.62, p ¼ 0.15). On multivariable analysis only 2 MOS-Sleep questions were associated with LUTS progression, including not getting enough sleep to feel rested in
2,374 (92) 214 (8) 41.3 (31.5e53.2) 5.6 (4.3e7.2) 99 (4) 7 (4e11) 1,452 (56) 1,136 (44) 16.7 (6.7e23.3) 20 0 0 0
(0e20) (0e0) (0e20) (0e20)
20 20
(0e40) (0e40)
539
When each MOS-Sleep question was examined individually, only the 2 questions on sleep disturbance were associated with the development of LUTS. Specifically more trouble falling asleep (HR 1.07, 95%
Table 2. Association of baseline sleep score with LUTS development in men with no symptomatic LUTS and LUTS progression in men with symptomatic LUTS Univariable Continuous HR/10 U Score Increase (95% CI)
Multivariable* p Value
Continuous HR/10 U Score Increase (95% CI)
p Value
Referent 1.07 (0.72e1.59) 1.36 (0.92e2.03) 1.41 (0.92e2.16)
e 0.72 0.12 0.11
Referent 1.07 (0.72e1.59) 1.25 (0.84e1.87) 1.41 (0.92e2.17)
e 0.74 0.27 0.12
1.03 1.01 1.08 1.09 1.05 1.00
0.25 0.69 0.009 0.001 0.15 0.87
1.04 1.01 1.07 1.08 1.03 1.02
(0.99e1.10) (0.93e1.08) (1.01e1.13) (1.02e1.14) (0.96e1.11) (0.97e1.07)
0.14 0.87 0.020 0.010 0.35 0.48
1.07 (1.02e1.13) Referent 1.05 (0.79e1.40) 1.16 (0.88e1.53) 1.36 (1.03e1.78)
0.009 e 0.73 0.30 0.028
1.06 (1.01e1.12) Referent 0.96 (0.73e1.29) 1.04 (0.79e1.38) 1.23 (0.93e1.62)
0.029 e 0.83 0.77 0.15
1.04 1.02 1.03 1.02 1.04 1.01
0.013 0.39 0.036 0.21 0.032 0.36
1.04 1.02 1.04 1.01 1.03 1.01
0.027 0.40 0.031 0.43 0.08 0.70
LUTS development Sleep score quartile: 1 2 3 4 Question: 1dGet enough sleep to feel rested in morning 2dAwaken short of breath or with headache 3dTrouble falling asleep 4dAwaken during sleep time þ have trouble falling back asleep 5dTrouble staying awake during day 6dGet amount of sleep needed
(0.98e1.09) (0.95e1.09) (1.02e1.14) (1.04e1.16) (0.98e1.12) (0.96e1.05)
LUTS progression Sleep score: Continuous Quartile 1 Quartile 2 Quartile 3 Quartile 4 Question: 1dGet enough sleep to feel rested in morning 2dAwaken short of breath or with headache 3dTrouble falling asleep 4dAwaken during sleep time þ have trouble falling back asleep 5dTrouble staying awake during day 6dGet amount of sleep needed
(1.01e1.07) (0.98e1.06) (1.00e1.07) (0.99e1.06) (1.00e1.07) (0.99e1.04)
* Adjusted for age, race, BMI, diabetes, smoking status, DRE, prostate volume, PSA and I-PSS.
(1.00e1.07) (0.98e1.06) (1.00e1.07) (0.98e1.05) (1.00e1.07) (0.98e1.04)
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SLEEP PROBLEMS AND LOWER URINARY TRACT SYMPTOMS
the morning (HR 1.04, 95% CI 1.00e1.07, p ¼ 0.027) and having trouble falling asleep (HR 1.04, 95% CI 1.00e1.07, p ¼ 0.031). Results were similar after excluding nocturia from the calculation of LUTS progression (supplementary table 2, http://jurology. com/).
DISCUSSION Although previous studies showed a relationship between sleep and LUTS, to our knowledge no study to date has combined an analysis of LUTS development and progression related to sleep. Additionally, these prior studies were limited in sample size, lacked interim analysis and only focused on LUTS development or progression. To address this, in a post hoc analysis using REDUCE we analyzed LUTS development and progression longitudinally during 4 years. Among asymptomatic men worse sleep scores were suggestively associated with LUTS development and individual questions assessing sleep disturbance were associated with increased LUTS development. Among men with baseline LUTS worse sleep scores were associated with LUTS progression. Individual questions assessing sleep disturbance and sleep adequacy were also associated with increased LUTS progression. Of note, our cohort included men with and without nocturia, indicating that sleep may influence LUTS not only at night but also during the day. It is often inferred that LUTS lead to sleep problems but the current results suggest that sleep problems may precede LUTS, although validation is needed. Our results show that sleep problems are related to LUTS development in asymptomatic men and LUTS progression in men with baseline LUTS. These findings are consistent with CAMUS, which showed a relationship between LUTS and sleep disturbance, although the secondary analysis of CAMUS focused on improvements in LUTS and sleep disturbances as opposed to increased sleep problems and worsened LUTS.8 CAMUS identified LUTS as a risk factor for sleep disturbance and did not address LUTS progression in subjects with sleep problems. Additionally, while our cohort included men with and without baseline LUTS, CAMUS only included men with moderate to severe LUTS (I-PSS 8 to 24), thus limiting analysis of asymptomatic men. Our results are also consistent with BACH in that LUTS were more likely to develop with time in asymptomatic individuals with sleep problems.9 The results of the current study expand these observations by including an analysis of LUTS every 6 months and an analysis of individual MOS-Sleep dimensions and their relation to LUTS. If validated in future studies, LUTS development
and progression may be added to the list of diseases linked to sleep disturbances such as type 2 diabetes and cardiovascular disease.4 If confirmed in future studies, there are several possible explanations of why poor sleep may lead to LUTS and/or worsening LUTS. First, poor sleep and urinary problems may be related to the codevelopment of some other comorbidity such as obesity or diabetes. While sleep problems and obesity are linked, the directionality of the relationship is debated, that is whether sleep disorders contribute to obesity or the reverse.16,17 Additionally, obesity is linked to LUTS. In a prospective analysis of 51,529 men higher total or abdominal adiposity was associated with increased LUTS development and progression.18 Moreover, increased BMI is associated with larger prostate volume and I-PSS increases.19,20 Others suggested that obesity mediates the relationship between sleep problems and LUTS.9 Importantly, our results were adjusted for BMI, suggesting that in our data obesity is unlikely to explain all observations. Alternatively, obesity related disorders such as metabolic syndrome (including diabetes) offer another explanation of the connection between sleep problems and LUTS. However, we adjusted for diabetes, implying that this also cannot explain the link between sleep and LUTS seen in our study. Poor sleep could potentially lead to disrupted circadian rhythms. Physiological processes involving urination typically show circadian functioning with urine production and voiding predominating during wakefulness while increased urine storage and less urination occur while sleeping.21,22 In 20 young, sleep deprived adults increased sleep deprivation was linked with increased diuresis and excess urinary sodium, which were more pronounced in men than in women.22 The exact molecular mechanisms underlying the circadian rhythm of urinary function are unknown. While the SCN in the hypothalamus is the main site regulating circadian rhythm in mammals,23 local circadian clocks also exist in tissues throughout the body, including renal and bladder tissues, although these peripheral clocks are still under SCN control.21,24e27 Future studies are needed to assess whether the molecular mechanism driving the connection between sleep problems and LUTS is a bladder or renal clock, SCN disruption or a prostatic problem (sleep problems impacting prostate size or growth). Our study is limited by few nonwhite participants. To our knowledge no standard MOS-Sleep questionnaire cutoff points exist, limiting clinical usefulness. The questionnaire does not include questions on nocturia or sleep medications and data were available on only the 6-item version of MOS-Sleep. Sleep data were only available from
SLEEP PROBLEMS AND LOWER URINARY TRACT SYMPTOMS
MOS-Sleep while detailed information on sleep apnea, which has been associated with nocturia, was unavailable. Also, in this study we only used the baseline sleep score. Future studies are needed to assess changes in the sleep score and how they correlate with changes in LUTS as well as whether LUTS predict changes in the sleep score. Furthermore, I-PSS and MOS-Sleep were patient reported. We lacked power to evaluate objective measures such as urinary retention or BPH related surgery. Nevertheless, from a practical perspective, clinicians use symptoms to make decisions. Our study only included men with elevated PSA and negative biopsies. To our knowledge it is unknown whether similar results would be seen in broader cohorts. Also, while the results are statistically significant, the significance was modest so that the clinical usefulness of these findings is unclear. Finally, as LUTS are not restricted to men, future studies are needed to assess whether similar associations are seen in women. Study strengths include the large sample size, the availability of interim I-PSS measurements and clinical confounding measures (PSA and prostate volume), and the use of validated questionnaires for sleep and LUTS.
541
CONCLUSIONS In REDUCE men with sleep problems were at higher risk for LUTS if they were asymptomatic at baseline, and experiencing LUTS progression if they were symptomatic at baseline. Further research is needed to validate these results. If validated, future studies should test whether treating sleep problems improves LUTS or prevents LUTS development.
APPENDIX MOS-Sleep Questionnaire Dimensions Awaken short of breath or headache Sleep disturbance Somnolence Sleep adequacy*
Question 2) Awaken short of breath or with headache 3) Trouble falling asleep 4) Awaken during sleep time and have trouble falling back asleep 5) Trouble staying awake during the day 1) Get enough sleep to feel rested in the morning 6) Get the amount of sleep needed
Each question was graded on scale of 1 to 6, including 1dall the time, 2dmost of time, 3dgood bit of time, 4dsome of time, 5dlittle of time and 6dnone of time with scaled average of scores on 0 to 100 scale used to calculate sleep score to measure overall sleep quality. * Scaled average of scores on 0 to 100 scale was reversed.
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EDITORIAL COMMENT The multifactorial etiologies which underlie LUTS often impair successful treatment. Sleep disturbance is an increasingly recognized comorbidity that contributes to the presence and severity of LUTS. The current analysis of men with sleep disorders in the REDUCE trial further supports this relationship. Despite common beliefs that sleep disturbances only contribute to nocturia, the authors document that sleep also influences the development and progression of daytime LUTS. This is consistent with previous data demonstrating associations between sleep disorders and daytime urinary symptoms (reference 7 in article). While the directions of these associations remain to be validated, the current results suggest that sleep disorders may precede the development of LUTS, which may provide an opportunity to prevent the development of LUTS. For example, studies have
demonstrated that LUTS improve with pressure airway treatment in men with obstructive sleep apnea.1 Therefore, it is possible these treatments could be used in men with obstructive sleep apnea. While this data set was not able to address the influence of obstructive sleep apnea on LUTS development and progression, further exploratory studies should be performed. At minimum the study results emphasize the importance of sleep assessment in men with and without LUTS to potentially curb onset and progression, respectively. Brian Helfand Division of Urology Department of Surgery Pritzker School of Medicine University of Chicago NorthShore University HealthSystem Evanston, Illinois
REFERENCE 1. Miyauchi Y, Okazoe H, Okujyo M et al: Effect of the continuous positive airway pressure on the nocturnal urine volume or night-time frequency in patients with obstructive sleep apnea syndrome. Urology 2015; 85: 333.