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Associations Between Improvements in Lower Urinary TractSymptoms and Sleep Disturbance Over Time in the CAMUS Trial
Brian T. Helfand, Jeanette Y. Lee, Victoria Sharp, Harris Foster, Michael Naslund,O. Dale Williams and Kevin T. McVary* for the CAMUS Study Group
From the Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (BTH, KTM); University ofArkansas for Medical Sciences, Little Rock, Arkansas (JYL); University of Iowa, Iowa City, Iowa (VS); Yale University School of Medicine,New Haven, Connecticut (HF); University of Maryland, Baltimore, Maryland (MN); and Department of Biostatistics, Florida InternationalUniversity, Miami, Florida (ODW)
Abbreviations
and Acronyms
BPH � benign prostatichyperplasia
LUTS � lower urinary tractsymptoms
PSA � prostate specific antigen
Submitted for publication March 7, 2012.Clinical Trial Registration NCT00603304 (www.
clinicaltrials.gov).Supported by the National Center for Comple-
mentary and Alternative Medicine and the Officeof Dietary Supplements, National Institutes ofHealth.
CAMUS is funded by cooperative agreementsfrom the National Institute of Diabetes and Di-gestive and Kidney Diseases U01 DK63795, U01DK63797, U01 DK63835, U01 DK63866, U01DK63833, U01 DK63862, U01 DK63840, U01DK63833, U01 DK63831, U01 DK63778 and U01DK63788.
Supplementary material can be obtained atwww.jurology.com.
* Correspondence: 303 E. Chicago Ave., Chicago,Illinois 60611 (telephone: 312-695-4471; FAX: 312-695-1144; e-mail: [email protected]).
See Editorial on page 2041.
Purpose: We recently reported an association between the bother and severity oflower urinary tract symptoms secondary to benign prostatic hyperplasia and theseverity of sleep disturbance. However, few studies have examined whetheralterations in the severity of urinary symptoms influence the degree of sleepproblems over time.Materials and Methods: The severity of lower urinary tract symptoms in menenrolled in CAMUS (Complementary and Alternative Medicine for UrologicalSymptoms), a clinical trial of saw palmetto (Serenoa repens), was evaluated usingAUASI (American Urological Association symptom index) and quality of lifescores. Sleep disturbance was evaluated by the Jenkins sleep scale at 0, 24, 48and 72 weeks. Statistical analyses were used to assess the relationship(s) be-tween changes in lower urinary tract symptoms and sleep disturbance.Results: The baseline characteristics of the 339 men (172 placebo arm and 167saw palmetto arm) enrolled in the CAMUS trial with assessment of sleep distur-bance and urinary symptoms were similar. There were no differences betweenimprovements in the severity of sleep disturbance or urinary symptoms betweenthe 2 experimental arms. Combined analyses of the entire cohort revealed sig-nificant associations (p �0.001) between the AUASI score and sleep disturbanceseverity with time. Multivariate analyses demonstrated that improvements inlower urinary tract symptoms other than nocturia were the most significantpredictors of improvements in sleep disturbance. Specific analyses adjusting forother baseline characteristics demonstrated that a 3-point improvement inAUASI score was associated with a 0.73-point improvement in the Jenkins sleepscale with time.Conclusions: Improvements in lower urinary tract symptoms correlate withchanges in sleeping abilities with time in men with benign prostatic hyperplasia.While nocturia is significantly associated with sleep disturbance, other changesin overall lower urinary tract symptoms are better predictors of changes in sleepdysfunction.
Key Words: prostatic hyperplasia, lower urinary tract symptoms, sleep
disorders, prostate2288 www.jurology.com
LOWER urinary tract symptoms are com-monly associated with benign prostatic
hyperplasia and represent significant0022-5347/12/1886-2288/0THE JOURNAL OF UROLOGY®
© 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RES
bother among aging men. While thesesymptoms are generalized to many uro-
logical disorders, they have historicallyhttp://dx.doi.org/10.1016/j.juro.2012.07.104Vol. 188, 2288-2293, December 2012
EARCH, INC. Printed in U.S.A.
LOWER URINARY TRACT SYMPTOMS AND SLEEP DISTURBANCE 2289
been classified as obstructive or voiding (hesitancy,weak stream, incomplete bladder emptying andstraining), or irritative or storage (nocturia, fre-quency and urgency), with nocturia being the mostfrequently reported storage symptom. Nocturia is acommon and bothersome urological symptom thatcontributes to sleep loss, daytime fatigue and mooddisturbance.1,2 A variety of factors have been asso-ciated with nocturia, including aging, overactivebladder and LUTS suggestive of BPH,3 psychologi-cal or behavioral changes, and alterations in sleeppatterns.4–6 In fact, because of its associations withother morbidities, nocturia predicts mortality inmen and women.7,8 Additionally, nocturia itself in-creases the risk of depression, hip fractures andcardiovascular disease.2,9–12
The incidence of nocturia among men ranges from30% for those younger than age 55 years to 60% inmen older than 70 years.13 A plausible explanationfor this finding is the high rate of BPH, which in-creasingly affects aging men in a pattern that mir-rors the incidence of nocturia.13,14 Similarly, this issupported by the fact that the prevalence of nocturiaincreases more steeply among men as it is less likelyto develop as a new condition in women with in-creasing age.15
We recently analyzed the baseline characteristicdata set of men enrolled in the National Institute ofDiabetes and Digestive and Kidney Diseases spon-sored CAMUS trial, and determined that the sever-ity of LUTS at baseline, including or excluding thepresence of nocturia, predicts the degree of sleepdisturbance.3 In addition, we found that men withLUTS and smaller prostate volume, as approxi-mated by serum PSA, were at the greatest risk forsleep alterations, suggesting that systemic and/orother nonprostatic factors may contribute to prob-lems with sleep. However, while these initial obser-vations suggest a relationship between LUTS sever-ity and sleep patterns, it is unknown whetherchanges in urinary function influence sleep distur-bance with time.
To date, few studies have evaluated the efficacy ofmedical or other interventions for LUTS on sleephabits. The results of the CAMUS trial were re-cently published and revealed that saw palmettoextract had no greater effect than placebo in improv-ing LUTS or other outcomes related to BPH.16 How-ever, while saw palmetto extract did not lead tosignificant improvements in LUTS, it is unknownwhether the fruit extract influenced sleep patternscompared to placebo as a function of time. Addition-ally, it remains to be determined whether changes inurinary function are associated with corresponding
changes in sleep patterns over time.SUBJECTS AND METHODS
The CAMUS trial was an 18-month, placebo controlled,double masked, saw palmetto fruit extract dose escalationstudy designed to determine whether there was an impacton LUTS/BPH as assessed by changes in AUASI score.17
This study of moderate to severe LUTS (AUASI 8 to 24points) conducted at 11 North American clinical sitesincluded 369 consented men 45 years old or older with apeak urinary flow rate of 4 ml per second or more whowere randomized to receive increasing doses (every 6months) of saw palmetto fruit extract or placebo. Thebaseline characteristics of all participants were docu-mented and have been reported previously.3,16 In addi-tion, AUASI and quality of life scores were obtained atthe initial visit, and reassessed at 24, 48 and 72months.18
Sleep disturbances were assessed using the Jenkinssleep scale.19 As previously described, this questionnairecomprises 4 items each rated on a 6-step Likert scale, inwhich 0 corresponds to no sleep disturbance and 5 indi-cates sleep disturbance (scale score 0 to 20). The items askhow often during the last month the subject experiencedtrouble falling asleep, trouble staying asleep, waking upseveral times per night, and waking up feeling tired andworn out after a usual amount of sleep.19
Changes in AUASI score and Jenkins sleep scale weredetermined over time. Nocturia was assessed by the sev-enth question of the AUASI. A significant or meaningfulchange in AUASI score was defined as a 3-point change aspreviously described.20,21 For some analyses the totalAUASI score (questions 1 to 7) was used. To assess theeffects of urinary symptoms other than nocturia, sub-domains of the AUASI score (questions 1 to 6) were used.Because of historical nomenclature, we determined thestorage or irritative (AUASI questions 1, 2, 4 and 7 re-garding incomplete emptying, frequency, urgency andnocturia, respectively) and voiding or obstructive (ques-tions 3, 5 and 6 regarding intermittency, weak stream andstraining, respectively) urinary symptom subdomainscores separately for some analyses.
Generalized estimating equations taking into accountintra-patient variation were used to assess the effects ofthe 4 questions of the Jenkins sleep scale on change frombaseline and symptom subdomains of the AUASI score. Inaddition, for each outcome measure of each treatment arm(saw palmetto and placebo) a multivariate analysis wasperformed to assess the effect of each of the 4 componentquestions of the Jenkins sleep scale.
To determine if there were differences between thetreatment and placebo groups at the different studypoints, the t test for independent samples was used. Formeasures that were not normally distributed (PSA andpost-void residual) the Wilcoxon rank sum test was used.Linear regression analyses were performed univariatelyand multivariately (adjusting for patient characteristics).The changes in Jenkins scale and AUASI and subdomainscores were determined by calculating the difference be-tween the baseline and week 24, 48 and 72 data, and thepaired t test was used to determine if the change was
significantly different from baseline. Statistical signifi-
LOWER URINARY TRACT SYMPTOMS AND SLEEP DISTURBANCE2290
cance was assessed at the p �0.05 level and all statisticalanalyses were performed using SAS® version 9.2.
RESULTS
Of the 367 men enrolled in the CAMUS trial 339(92.3%, 172 placebo arm and 167 saw palmettotreatment arm) were eligible for this study, and hadfollowup AUASI, quality of life and Jenkins sleepscores at baseline, 24, 48 and 72 weeks. The baselinecharacteristics of the 2 experimental groups of menare shown in table 1. There were no significant dif-ferences in total AUASI score, serum PSA, post-voidresidual volume or Jenkins sleep scale score at fol-lowup visits between the 2 groups over time. There-fore, we combined the groups for subsequent analy-ses.
Analyses of the entire cohort demonstrated a sig-nificant and progressive improvement in LUTS andsleep disturbance with time as measured by thetotal AUASI and total Jenkins sleep scale, respec-tively (see figure). There were significant improve-ments in all 4 questions of the Jenkins sleep scaleduring the course of the study. We also documentedsignificant improvements in specific LUTS subtypes(ie irritative/storage vs obstructive/voiding) withtime. Because it is expected that nocturia would bethe driving force behind sleep disturbance, we ana-lyzed changes in nocturia (question 7) and theAUASS (AUA symptom score) excluding nocturia
Table 1. Clinical characteristics
Wk Visit Entire CohortSaw Palmetto
Group Placebo Groupp
Value*
Mean � SD pointstotal AUASI:
0 14.53 � 4.52 14.42 � 4.31 14.64 � 4.72 0.64924 12.56 � 6.07 12.71 � 5.89 12.41 � 6.25 0.65048 12.28 � 5.87 12.23 � 5.58 12.33 � 6.14 0.87772 11.89 � 6.13 12.23 � 5.78 11.57 � 6.44 0.329
Mean � SD pointsJenkins sleep scale:
0 7.34 � 4.63 6.95 � 4.28 7.72 � 4.93 0.11624 6.13 � 4.34 6.03 � 4.30 6.23 � 4.38 0.66748 6.67 � 4.28 6.66 � 4.30 6.67 � 4.28 0.99372 6.09 � 4.53 6.11 � 4.60 6.08 � 4.47 0.947
Mean � SD ng/mlserum PSA:
0 2.07 � 1.78 2.21 � 1.96 1.94 � 1.59 0.12324 2.12 � 1.95 2.27 � 2.09 1.97 � 1.79 0.08348 2.08 � 1.96 2.23 � 2.18 1.93 � 1.72 0.17572 2.25 � 2.14 2.45 � 2.34 2.05 � 1.92 0.060
Mean � SD cc post-void residual:
0 59.69 � 65.61 60.15 � 68.63 59.24 � 62.70 0.86024 59.81 � 71.55 66.56 � 80.35 53.09 � 61.08 0.32748 61.20 � 69.57 62.53 � 72.46 59.96 � 66.96 0.50772 70.67 � 85.45 79.60 � 94.48 62.05 � 75.00 0.250
* Comparison between saw palmetto and placebo groups.
(questions 1 to 6) separately. There were significantimprovements in the nonnocturia components of theAUASI with time.
We correlated changes in LUTS with changes insleep over time (see figure, table 2). Multivariateanalyses demonstrated that changes in totalAUASI, AUASS (questions 1 to 6) and nocturia scorewere highly correlated with changes in the Jenkinssleep scale and its component questions on sleepabilities. Interestingly, improvements in AUASS(questions 1 to 6) were more correlated with changesin the Jenkins score than nocturia alone (AUASIquestion 7). AUASI questions 1 to 6 were more cor-related with Jenkins sleep scale question 1 (troublefalling asleep) and question 4 (worn out after usualamount of sleep) than nocturia question 7.
It was previously determined that a 3-pointchange in total AUASI represents a clinically signif-icant difference.20 Therefore, we performed specificanalyses adjusting for other baseline characteristicsand demonstrated that a 3-point improvement inAUASI score was associated with a 0.73-point im-provement in Jenkins sleep scale score with time.
DISCUSSION
We previously reported that the severity of LUTSsecondary to BPH is related to the degree of sleepdisturbance.3 However, it has been thought that thisrelationship could be explained by the presence ofnocturia.22–24 The present study suggests that thepresence of LUTS, other than nocturia, may contrib-ute to sleep disturbance as measured by the Jenkinssleep scale. In addition, our results demonstrate thatchanges in LUTS directly correlate with changes insleep habits.
Prior analyses of the baseline characteristics ofmen in the CAMUS trial suggested that while noc-turia may be a strong predictor of severe sleep dis-turbance, other LUTS also contribute to impairedsleep patterns.3 The results of the present studyexpand on this observation and suggest that moni-toring changes with time in urinary symptoms otherthan nocturia may provide improved insight into theinfluence of LUTS on sleeping habits in men. Thisissue is becoming increasingly important as it hasbeen repeatedly demonstrated that alterations insleep are associated with increased morbidity andmortality.25
BPH and its associated LUTS may appear to becompletely unrelated to sleep hygiene. However, it ispossible that a common underlying mechanism(s)may link these disorders. For example, it has beenthought that imbalances in steroid hormone action,sympathetic nervous system activity and/or immunedysfunction may contribute to the development of
symptomatic BPH and bladder outlet obstruc-
ed with
LOWER URINARY TRACT SYMPTOMS AND SLEEP DISTURBANCE 2291
tion.26,27 Certainly it is possible that these underly-ing disorders could also contribute to the develop-ment of sleep alterations, even in the absence ofnocturia.
Saw palmetto extracts have been widely usedby men with LUTS. In addition, it has also beensuggested that many herbal extracts have some
AUASI and subdomain scores compar
Table 2. Correlations between changes in AUASI and subdoma
Change in TotBaseline � (
Jenkins sleep scale 0.47 (0.58Question 1–Change in trouble falling asleep 0.91 (0.23Question 2–Change in waking up several times/night 1.00 (0.15Question 3–Change in trouble staying asleep 0.82 (0.16Question 4–Change in waking up after usual amount of sleep 0.79 (0.18
* Beta coefficient and standard error from the generalized estimating equations analysis
efficacy for treating insomnia.28 However, the re-sults of the CAMUS trial,16 including the presentstudy, demonstrate no obvious differences be-tween saw palmetto extract and placebo in theirability to influence sleep patterns over time. Be-cause there is a well recognized, profound placeboeffect in tests of efficacy for agents treating
Jenkins sleep scale scores over time
res with changes in Jenkins sleep scale scores over time
I fromlue*
Change in AUASS (6 questions)from Baseline � (SE)/p Value*
Change in Nocturia from Baseline� (SE)/p Value*
1 0.39 (0.05)/�0.001 0.07 (0.01)/�0.0011 0.76 (0.20)/�0.001 0.15 (0.06)/0.0111 0.81 (0.14)/�0.001 0.20 (0.03)/�0.0011 0.71 (0.14)/�0.001 0.11 (0.03)/�0.0011 0.70 (0.17)/�0.001 0.09 (0.04)/0.033
in sco
al AUASSE)/p Va
)/�0.00)/�0.00)/�0.00)/�0.00)/�0.00
.
LOWER URINARY TRACT SYMPTOMS AND SLEEP DISTURBANCE2292
LUTS,29 it is likely that this effect is responsiblefor the improvements in LUTS observed in theCAMUS trial. However, this is the first study toour knowledge that suggests that a similar effectmay also be responsible for the mirrored observedimprovements in sleep disturbance.
The CAMUS trial was designed to evaluatewhether saw palmetto extract would prove betterthan placebo at improving LUTS and other BPHrelated outcomes. However, the results of the studyshould be viewed within the context of its limita-tions such as the relatively small sample size. Inaddition, the data collected on sleep in the CAMUStrial were proposed as a secondary analysis. A fu-ture study designed to specifically analyze sleep asan outcome should be performed. In addition, whilethe Jenkins sleep scale has been used as a measureof sleep disturbance, other more recent question-naires that more specifically address other detailedaspects of sleep should be used. Finally, the resultsof the CAMUS trial demonstrated no difference be-tween the treatment arms. Therefore, any changesin LUTS and sleep patterns observed in this studywere spontaneous, or reflected a positive effect and
similar effect of placebo and saw palmetto. Addi-tional studies evaluating this relationship withsleep using a medication known to influence LUTSwould be interesting.
CONCLUSIONS
It is important to appreciate that men who experi-ence bothersome LUTS are at increased risk forsleep disorders. While it has previously been as-sumed that nocturia is the motivating symptom forthis sleep disturbance, it appears that other urinarysymptoms are more highly associated. Based onthese findings it is reasonable to believe that a com-mon etiology underlies LUTS and sleep disturbance,and that successful treatment of urinary symptomscan improve sleep behavior and vice versa. Further-more, these data also support the concept that eval-uation of sleep should be considered in men present-ing with LUTS.
ACKNOWLEDGMENTS
Saw palmetto fruit extract and matching placebosupplied by Rottapharm/Madaus, Cologne, Ger-
many.APPENDIX
CAMUS Study GroupSteering Committee ChairMassachusetts General Hospital
Michael J. Barry, MDData Coordinating CenterUniversity of Alabama at Birmingham
O. Dale Williams, PhD (Director)Sreeletha Meleth, PhD (Associate Director)
Clinical SitesNew York University
Andrew McCullough, MD (PI through 12/3/10)Christopher Kelly, MD (PI as of 12/3/10)Brianne Goodwin, BSN, RN (Study Coordinator)Laurie Mantor (Study Coordinator)Artrit Butuci (Research Data Associate)
Northern California Kaiser PermanenteAndrew L. Avins, MD, MPHHarley Goldberg, DO (Co-I)Luisa Hamilton (Study Coordinator)Cynthia Huynh (Research Associate)
Northwestern University Feinberg School of MedicineKevin T. McVary, MD (PI)Robert Brannigan, MD (Co-I)Brian Helfand, MD, PhD (Consultant)Maria Velez (Study Coordinator)Nancy Schoenecker, RN, CCRC (Clinical Research Coordinator)
Queens UniversityJ. Curtis Nickel, MD (PI)Alvaro Morales (Co-I)D. Robert Siemens, MD (Co-I)Joe Downey, MSc, CCRP (Study Coordinator)Janet Clark-Pereira, CCRP (Study Coordinator)
University of Colorado DenverE. David Crawford, MD (PI)Shandra S. Wilson, MD (Co-I)Paul D. Maroni, MD (Co-I)Patricia DeVore, BS (Clinical Research Coordinator)Cliff Jones (Clinical Research Coordinator)
University of IowaKarl J. Kreder, MD, MBA (PI)Victoria Sharp, MD, MBA (Co-I)Diane Meyerholz, RN, BSN (Study Coordinator)Mary Eno, RN (Study Coordinator)
University of MarylandMichael J. Naslund, MD (PI)Ganine Markowitz-Chrystal, MS, CCRC (Study Coordinator)University of Texas Southwestern Medical CenterClaus G. Roehrborn, MD (PI)Brad Hornberger, PA-C (Co-I)Allison Beaver, RN (Study Coordinator)Suzie Carter (Data Manager)
Washington University School of MedicineGerald L. Andriole, MD (PI)Vivien Gardner, RN, BSN (Study Coordinator)Karen Whitmore (Supervisor Patient Services)
Weill Cornell Medical CollegeSteven A. Kaplan, MD (PI)Alexis E. Te, MD (Co-I)Noreen Buckley, NP, CCRC (Study Coordinator)Maritza Rodriquez (Medical Assistant)
Yale University School of MedicineHarris E. Foster, Jr., MD (PI)John W. Colberg, MD (Co-I)
Karen Stavris, RN, MSN, CCRC (Study Coordinator)
LOWER URINARY TRACT SYMPTOMS AND SLEEP DISTURBANCE 2293
APPENDIX (continued)
Biostatistics ConsultantUniversity of Arkansas for Medical Sciences
Jeannette Y. Lee, PhDNational Institutes of HealthNational Institute of Diabetes and Digestive and Kidney Diseases
John W. Kusek, PhDLeroy M. Nyberg, PhD (through 9/2/09)
National Center for Complementary and Alternative MedicineCatherine M. Meyers, MD
Office of Dietary SupplementsJoseph M. Betz, PhDPaul M. Coates, PhD
Data Safety Monitoring BoardUniversity of Minnesota VA Medical Center
Timothy J. Wilt, MD, MPH (Chair)University of Illinois at Chicago
Harry H.S. Fong, PhDUniversity of Chicago
REFERENCES
1115. sures in clinical research:
University of VirginiaMikel Gray, RN, PhD, CUNP, FAAN
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Alliance for Prostate Cancer PreventionCol (Ret). James E. Williams, Jr.
Hines VA Hospital Cooperative Studies Program Coordinating CenterDomenic Reda, PhD
Supplier of saw palmetto fruit extractRottapharm/Madaus
Glenn S. Gerber, MDJoseph J. Veilleux, RPH, MBA
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