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Natural History of Prostatism: Longitudinal Changes in Voiding Symptoms in Community Dwelling Men
Vol 155.595-600. February 1996 Prrnfed 111 U.S.A.
NATURAL HISTORY OF PROSTATISM: LONGITUDINAL CHANGES IN VOIDING SYMPTOMS IN COMMUNITY DWELLING MEN S T E V E N J. JACOBSEN," CYNTHIA J. GIRMAN, HARRY A. GUESS, THOMAS RHODES, J O S E P H E. OESTERLING AND MICHAEL M. LIEBER From th~aDepartments of Health Sciences Research (Section of Clinical Epidemiology) and Urology, Mavo Clinic and Mayo Foundatcon, Rorhester, Minnesota, Merck Research Laboratories, Blue Bell, Pennsylvania, and Michigan Prostate Institute and University of Michigan, Ann Arbor, Michigan
ABSTRACT
Purpose: We report t h e results of 3 contacts during 42 months of The Olmsted County Study of U r i n a r y Symptoms a n d Health Status Among Men, a longitudinal cohort study of men 40 to 7 9 y e a r s old that w a s initiated in 1990 to describe changes in lower urinary t r a c t symptom severity. Materials a n d Methods: At baseline and followup, men completed questionnaires that elicited u r i n a r y symptom severity with questions nearly identical t o those of the American Urological Association symptom index. Results: Overall, there was a n average increase i n American Urological Association symptom index of approximately 0.18 (958 confidence interval 0.13 t o 0.24) points per year of followup. The average a n n u a l symptom score slope and variability i n slope increased with patient age at baseline from a m e a n of 0.05 t 1.06 (standard deviation) per year among men in the forties t o 0.44 t 1.35 per y e a r for m e n in the sixties, a n d decreased to 0.14 ? 1.42 p e r year for men in the seventies. T h e age-related changes i n symptom severity mirror previous estimates of prostatic growth from autopsy prevalence studies. Conclusions: These results demonstrate a slow but measurable progression in urinary symptom severity among community dwelling m e n for 42 m o n t h s of followup.
KEYWOROS:prostate, urination disorders, epidemiology formation regarding the changes in symptoms in the community is needed to understand the potential benefits of surgical and pharmacological therapies in the community ~ 0 n t e x t . I ~ The Olmsted County Study of Urinary Symptoms and Health Status Among Men was done partly to fill this void. This community based sample of more than 2,000 men was followed for 42 months with detailed assessments of lower urinary tract symptoms. We describe the natural history and clinical course of this cohort in regard to changes in summary symptom scores as well as in specific symptoms.
Benign prostatic hyperplasia (BPH), and its associated signs and symptoms pose a sizable public health problem to aging men in Western societies. In the United States in 1991 an estimated 340,000 transurethral resections of the prostate were performed' and there were more than 1.2 million office visitsz for this condition. These figures represent only the tip of the iceberg, since approximately 5.5 million men in the United States would meet diagnostic criteria for discussing treatment options for BPH" according to the United States Agency for Health Care Policy and Research Diagnostic and Treatment Guidelines if they were to seek medical care.4 Despite this prominence, relatively little is known about the natural history of BPH in the community. The autopsy prevalence of histological BPH has been shown to increase dramatically with age, reaching 60 to 80% among men in the sixties." Cross-sectionally, there is a minimal correlation between prostatic volume and lower urinary tract sympsuggesting that there are other causes of voiding symptoms. Nonetheless, there is an age-related increase in prevalence of lower urinary tract symptoms in the community.", Unfortunately, longitudinal data regarding lower urinary tract symptoms are relatively scarce for community dwelling men." Most of the longitudinal data have been described for placebo arms of clinical trials that do not provide information about untreated men,'Z, 13 among men from urology practicesl". 1s and community dwelling men with documented BPH. I(; Because these populations do not represent the entire spectrum of disease in the community and, by definition, exclude those with no symptoms a t baseline, In-
METHODS
Study subjects. Many of the details of the community based cohort have been described previo~sly.~. IH Briefly, a sampling frame was developed using the resources of the Rochester Epidemiology Project that identified male residents of Olmsted County 40 to 79 years old on January 1,1990. A 16% stratified random sample was drawn, and the community
Round 1 229 replacements
Round 2
Round 3 103 replacements
I
Accepted for publication August 18, 1995. Supported in part by Grant AR30582 from the United States Public Health Service, National Institutes of Health and a grant from Merck Research Laboratories. * Requests for reprints: Department of Health Sciences Research, Mayo Clinic, 200 First St., s. W., Rochester, Minnesota 55905.
19 dead
33 dead
FIG. 1. Design of Olmsted County Study of Urinary Symptoms and Health Status Among Men.
595
NATURAL HISTORY OF PROSTATISM TABLE1. Chonge in AUA s p p t o m indrr by uge ~
.
Pt
Age lyrs
I
ACA S>mptom Index Baseline 12.115 pts 1
5.314 6 W5 736
40-49 50-59 60-69 70-79
40-79 -~ Differs from 0 . p + Differs from 0. p
7.R17
c
218 219
3/10 3/12
___
1 R Mas.-Baseline (2.060 pts.1
.- 0.7”1-
- 0 310 0.210
0.m
~
~~
1
Followup --
1 8 4 2 Mas. 11.931 pts.)
~
~
~
-
311 312 5!3 213
__
-
~
~~
~
0.9”iO 0.9-11 1.3-11 0.410
~
1/2 113 114 213
4‘2 Mas -Baseline (1.935 pts
0.110 0 6’11 l.S‘/l 0.510
1
2/12 2/3 11.1 214
6.315 219 0 001 hy signed rank test. 0.01 by signed rank test.
FIG.2. Movement of baseline cohort across categories of lower urinary tract symptom severity. Round 2o-mild in round 1. Round Ph-moderate to severe in round 1. Round 3c and e-mild in round 2. Round 3d and f-moderate to severe in round 2. Median interval was 18 months between rounds 1 and 2, and 42 months between rounds 1 and 3 .
medical records of all men were screened for a history of prostatectomy, prostate cancer or any of a number of other medical conditions known to interfere with voiding function (other than BPH). Following these exclusions, 3,658 men were identified as potentially eligible for study. A total of 2,115 men (55%) completed the study protocol, which included a personal interview to elicit a family history of urological disease and current medications; completion of a selfadministered questionnaire that elicited lower urinary tract symptoms, basic demographic information and psychological well-being, and measurement of urinary flow rates with a portable uroflowmeter. A comparison of the medical records of responders and nonresponders suggested mostly that there were no differences except for history of urological diagnoses, and responders were slightly more likely to have had stones, urinary tract infections or BPH than nonresponders.19 Followup. Our study was designed to incorporate elements of a dynamic cohort, representing the true nature of the community a s well a s a traditional cohort. Men who moved from Olmsted County, died, refused to participate or whose age advanced out of the original cohort were replaced by men randomly selected from the community (fig. 1). Persons who
migrated from the community were also included in followup attempts. At a median of 18 months (25th percentile 16, 75th percentile 21) and 42 months (25th percentile 40, 75th percentile 45) following baseline, men were recontacted by mail and asked to complete a questionnaire with identical symptom questions. Of the 2,115 men in the cohort a t baseline 2,062 (97%1 provided followup responses at 18 months. Of the 2,259 members of the cohort at 18 months 2,157 (94%) participated in the 42-month followup. Overall, 1,930 of the original 2,115 men (91%)in t h e cohort provided responses a t all 3 contacts. The study protocol for baseline and followup was approved by the Mayo Clinic institutional review board. Measurements. The previously validated”’ self-administered questionnaire included 134 elements about the severity and bother of urinary symptoms, health status and sociodemographic characteristics. A total of 12 questions elicited information about the frequency of specific urinary symptoms during the last month. Symptom frequency questions were measured on a 7-point ordinal scale from 0 (“I do not have symptoms”) to 6 (“I always have symptoms”).A composite score for symptom severity was calculated to approximate the American Urological Association (AUA)symptom indexz1 by collapsing t h e 2 highest categories (almost always and
NATURAL HISTORY OF PROSTATISh!
597
FIG. 3 . Notch plot depicting distribution of individual estimates of annual change (slopel in AUA symptom index for 42 months of followup by patient age a t baseline. Limits of box represent 25th and 75th percentiles, limits of whiskers represent It_ 1.5 times interquartile range and points of diamonds represent mean 5 1 standard deviation.
a l w a y s ) t o t h e highest AUA symptom index category (almost a l w a y s ) for t h e 7 symptoms included i n t h e AUA symptom index. At each contact men were queried about t r e a t m e n t s for urological conditions, including pharmacological (finasteride, terazosin a n d doxazosin) a n d surgical (prostatectomy, t r a n s u r e t h r a l needle ablation, laser thera p y a n d microwave t h e r a p y ) . Analyses. For each m a n enrolled in the cohort, differences between baseline a n d followup symptom scores were calculated a n d tabulated. The signed rank test was used to test t h e null hypothesis t h a t the mean difference was 0, with a Bonferroni correction for multiple comparisons. Followup AUA symptom index scores were regressed on baseline scores t o quantify the degree a n d magnitude of association. A linear least squares model was estimated, and point a n d 95% confidence interval estimates of the slope and intercept were calculated. T o estimate change in symptom scores, a least squares regression line was estimated for each man based upon t h e n u m b e r of points measured.rl.':$ For men with 2 or 3 measurements a n estimate of annual symptom score slope a n d intercept was obtained by regressing AUA symptom index on time since baseline. For men with a single determination t h e r e was only a n estimate of intercept. The distributions of symptom score slopes were determined for t h e study cohort overall, a n d stratified by age and symptom score a t baseline. Mixed effects regression models were used to corroborate t h i s 2-step analysis."J RESULTS
At baseline there was a linear increase in AUA symptom index with patient age (table 1). This cross-sectional association h a s been described in detail p r e v i ~ u s l y . ~With . ~ " each year of patient age the AUA symptom index increased 0.10 units ( s t a n d a r d error 0.01). At followup there was much movement, across catemries of svmDtom seventy (fig.2). For
example, of the 1,288 men with mild symptoms a t baseline 1,105 (86%) reported mild symptoms at 18 months a n d 935 (73%) also reported mild symptoms a t 42 months. At 18 months 183 of the 1,288 men (14% with mild symptoms a t baseline reported moderate to severe symptoms and at 42 months 282 of the 1,288 (22Q I with mild symptoms a t baseline reported moderate to severe symptoms. Overall. there was a slight decrease in symptom severity as measured by the AUA symptom index among the cohort at 18 months. At 42 months of followup, by contrast, there was a n increase in symptom seventy across all age groups. The net change in AUA symptom index with time indicated a n increase in symptom severity across all ages. Nonetheless, there was much variability in these changes a t all ages. The regression analysis of t h e symptom score slope within each m a n demonstrated similar results. Overall, the average symptom score slope was 0.18 i_ 1.22 points (standard deviation, fig. 3 ) . This finding was slightly more pronounced among t h e 1,864 men with no treatment during followup (0.19 5 1.201 but opposite to t h a t observed among 66 with treatment (-0.21 t 1.76, p = 0.06). The change in AUA symptom index also was not consistent across patient age. The symptom score slope generally increased with patient age from 0.05 point per year for men in t h e forties to 0.44 point per year for men in t h e sixties. For men i n t h e seventies, however, the average symptom score slope was 0.14. Across all ages there was much variability in t h e estimates of slope. For example, t h e 5 t h a n d 95th percentiles were - 1.52 and 1.84, respectively, for men in the forties a n d -2.24 a n d 2.46, respectively, for men in t h e seventies. When symptom score slope was plotted against baseline AUA symptom index there was evidence of a regression to the mean phenomenon (fig. 4). The least squares regression model of symptom score slope on baseline AUA symptom index had a slope estimate of -0.06 (standard error 0.005) with a coefficient of determina-
598
NATURAL HISTORY OF PROSTATISM
0
5
10
15
20
25
30
Baseline AUASl FIG.4. Scatterplot of slope estimates for annual change in AUA symptom index (AUASZ) by baseline AUA symptom index. Solid line represents no change (slope 0). Dashed line represents least squares regression line of annual change on baseline AUA symptom index (slope 0.06, standard error 0.005 and intercept 0.52, standard error 0.04,F = 0.06, p <0.001).
tion o f f = 0.06. This relationship persisted after removing men who were treated sometime during followup. There was also much variability among the individual symptoms (table 2). As with the cross-sectional baseline data,9 nocturia and weak stream demonstrated a strong association with aging. However, as with overall symptom score the increases were successively greater at older baseline patient ages except for men in the seventies. Overall, repeat urination (within 10 minutes), difficulty stopping and starting, and post-void dribbling also demonstrated statistically significant increases with patient age. These increases were
found primarily among men in the sixties. The longitudinal changes in daytime frequency, dysuria, straining, urgency and sensation of incomplete emptying did not consistently show an increase with time. DISCUSSION
These results demonstrate the measurable progression of lower urinary tract symptom severity during 42 months of followup in a community based cohort of previously untreated men. The average annual increase in AUA symptom
TABLE2. Longitudinal annual change (slope) of urinary symptom scores __c____
Baseline Ages* Overall (4&79 yrs.)
4 M 9 Yrs.
50-59 Yrs.
AUA symptom index 0.18 2 1.22: 0.05 f 1.06 0.18 2 1.19: Individual symptoms:$ Day frequency5 0.01 f 0.33 -0.01 ? 0.31 0.00 i 0.34 Dysuria 0.00 t 0.18 -0.02 t- 0.15; -0.01 t 0.17 Nocturial 0.08 f 0.39* 0.04 t 0.32: 0.08 C 0.37 Weak stream§ 0.09 2 0.43' 0.06 t 0.36; 0.10 2 0.41 0.01 2 0.23 Straining§ 0.01 2 0.23 0.00 t 0.22 Repeat 0.022 0.211 0.01 i 0.19 0.02 2 0.20 stop5 0.022 0.29t 0.01 2 0.26 0.02 t- 0.28 Dribbling 0.04 f 0.36t 0.04 2 0.34; 0.02 2 0.35 Hesitancy 0 . 0 t 0.24 -0.01 2 0.23 -0.01 2 0.24 Urgency§ 0.01 C 0.30 -0.02 i 0.27 0.02 2 0.31 Not empty5 0.01 C 0.26 0.00 2 0.23 0.01 t 0.25 Dribbling-wet clothes 0.04 2 0.277 0.03 ? 0.27 0.03 2 0.26 Slope was determined by least squares regression of symptom score on interval from first assessment. * Unweighted average and standard deviation of individual slopes (per year) estimated across followup. t Statistically different than 0 (p <0.05, sign rank test with Bonfemoni correction). f Rated by respondent on 7-point scale from 0 (1 do not have symptom) to 6 (Always). 5 Component of AUA symptom index.
60-69 Yrs.
70-79 Yrs.
0.44 t- 1.35t
0.14 2 1.43
0.04 t 0.34t 0.03 2 0.20 0.14 t 0.45: 0.16 i 0.48t 0.02 2 0.25 0.04 i 0.25t 0.06 t 0.32t 0.05 t 0.38t 0.03 r 0.27 0.05 t 0.30i 0.04 t 0.30 0.06 2 0.29:
0.02 z 0.38 0.00 t 0.20 0.10 t 0.50: 0.07 t 0.55
0.00 t 0.24 0.02 r 0.25 -0.01 z 0.33 0.02 t 0.38 -0.01 i 0.23 0 01 5 0.36 0.01 5 0.30 0.03 z 0.30 -
NATURAL HISTORY OF PROSTATISM
599
index based on 3 time points was approximately 0.2 point present. In addition, responses to the AUA symptom index per year, with greater increases noted among men in the rely upon patient perception of the severity of symptoms. The sixties compared to those in the forties or seventies. This slowed progression among men in the seventies may be due finding mirrors the prostate growth curve estimated by partly to men accepting the symptoms and consequently Barry et al.5 There was much variability in progression, with underreporting the occurrence. Finally, there may be limitasome men getting worse and some improving. These results tions to the generalizability of these findings due to the are partly due to the regression to the mean phenomenon but response bias and the baseline exclusion criteria. The 55% resome probably represent the natural history of prostate dis- sponse rate at baseline may have enriched the sample with ease. men concerned about urological health19 but it is diacult to Our results provide insights into the changes in urinary know how this might affect the estimates of symptom score symptom severity in a community setting. Previous studies slope. The baseline exclusion of men who had already been have described the changes in lower urinary tract symptom treated also may further limit generalizability, since the severity in clinical cohorts and placebo arms of clinical trials. number of men being treated surgically has decreased in The populations represented by these samples by definition recent years. do not represent the community at large,17and may provide misleading information due to regression to the mean and CONCLUSIONS testing (Hawthorne and placebo) effects. Furthermore, while Our results have several implications. There is much varithese previous studies have demonstrated much variability in changes in individuals, our data provide a measure of that ability in symptom severity as reported by community dwellvariability for community dwelling men, more representative ing men. Because of this fact symptoms ideally should be assessed at several intervals to understand the trend in of those noted in a general practice. It is interesting to note that the longitudinal estimates of symptom progression (symptom score slope) in an individual. symptom progression differed from those observed cross-sec- On average, symptom seventy worsened during the 42 tionally a t baseline in this cohort.3. 9 At baseline there was a months of followup in untreated men. However, it did take a linear increase in AUA symptom index at a rate of approxi- dramatic annual change in AUA symptom index to place a By6 contrast, the longitudinal estimate man out at the 95th percentile for change in symptoms, mately 0.1 per ~ e a r . ~ was approximately twice the cross-sectional estimate (0.2 which agrees with the common knowledge that the course of versus 0.1) and differed with baseline patient age. Longitu- prostatism is generally slow and protracted. If these obserdinally, there was a suggestion of an acceleration in symptom vations are confirmed in future studies, the symptom score severity through the seventh decade of life and decreasing slope in addition to absolute symptom seventy might be used thereafter. The linearity of the increase noted cross-section- to determine which patients to treat. ally may have been due partly to the selection criteria for the Luanne Schmidt, Karen Hanson and Rebecca Nelson prostudy. Men treated surgically for BPH (presumably those vided continued followup of this cohort. with the most severe disease) had been excluded from the study cohort, which would have resulted in proportionately REFERENCES fewer older men with greater symptom severity, leading to an 1. Graves, E. J.: National Hospital Discharge Survey: h u a l Sumunderestimate of the age-related increase in symptom severmary, 1991. Vital Health Stat., series 13, number 114, 1993. ity. At followup, however, some men were observed throughS. M.: National Ambulatory Medical Care Survey: out the period in which the most severe symptoms developed. 2. Schappert, 1989 Summary. Vital Health Stat., series 13, number 110, Thus, the longitudinal observations may be more represen1992. tative of disease progression in the community than the 3. Jacobsen, S. J.,Girman, C. J., Guess, H. A, Oesterling, J. E. and previous cross-sectional estimates. Lieber, M. M.: New diagnostic and treatment guidelines for While the summary AUA symptom index measure inbenign prostatic hyperplasia. Potential impact in the United States. Arch. Intern. Med., 155:477, 1995. creased with time, not all individual symptoms demonstrated 4. Mcconneu, J. D.: W h y pressure-flow studies should be optional the same amount of progression. The symptoms with the and not mandatory studies for evaluating men with benign strongest positive slope were nocturia and weak stream. prostatic hyperplasia. Urology, e4: 156, 1994. These same symptoms demonstrated a strong age-related 5. Berry, S.J., Coffey, D. S., Walsh, P. C. and Ewing, L. L.: The increase a t baseline.9 Of the remaining 5 symptoms that are development of human benign prostatic hyperplasia with age. part of the AUA symptom index, only difficulty with stopping J. Urol., 132 474, 1984. and starting demonstrated a statistically sigdicant increase 6.G m a n , C. J., Jacobaen, S. J., Guess, H. A, Oesterling, J. E., Chute, C. G., Panser, L. A. and Lieber, M. M.: Natural history with time, which contrasts with the cross-sectional data in of prostatism: relationship among symptoms, prostate volume which urgency and sensation of incomplete emptying also and peak urinary flow rate. J. Urol., 159: 1510, 1995. demonstrated a strong age-related increase. This finding is 7. Barry, M. J., Cockett, A. T. K, Holtgrewe, H. L., McConneU, somewhat contrary to current belief, since all of these s p p J. D., Sihelnik, S. A. and Winfield, H. N.: Relationship of toms are considered by many to coincide with obstructive symptoms of prostatism to commonly used physiological and disease. However, it could be that the 42 months of followup anatomical measures of the seventy of benign prostatic hyperand the limited ordinal scale did not provide adequate power plasia. J. Urol., 1M): 351, 1993. to detect change in these individual symptoms. Continued 8. Abrams, P.H. and Feneley, R. C. L.: The significance of the followup of this cohort could provide additional power. symptoms associated with bladder outflow obstruction. Urol. Int., 33: 171, 1978. When interpreting these data, several potential limitations 9. Chute, C. G., Panser, L. A., G m a n , C. J., Oesterling, J. E., must be considered. It is dimcult to discern how much of the Guess, H. A, Jacobsen, S. J. and Lieber, M. M.: The prevalence change was random and how much represented true change. of prostatism:a population-based survey of urinary symptoms. The demonstrable regression to the mean Suggests that, alJ. Urol., 1M):85, 1993. though test-retest reliability is high with the AUA symptom 10. Garraway, W.M., Collins, G. N. and Lee, R. J.: High prevalence index,21 the longer term reliability may not be as precise. In of benign prostatic hypertrophy in the community. Lancet, addition to variability in true symptom severity and testing 338: 469, 1991. effects, the modest change in mode of administration may 11. Guess, H. A.: Benign prostatic hyperplasia: antecedents and have contributed to the variability as ~ e l l . 2 ~ At9baseline, ~~ natural history. Epidemiol. Rev., 14: 131, 1992. study subjects completed the questionnaire in the presence of 12. Barry, M. J., Gman, C. J., O'Leary, M. P., Walker-Corkery. E. S., Binkowitz, B. S., Cockett, A. T. K, Guess,H. k and the a study assistant, whereas during followup the questiomcflre Benign Pmstatic Hyperplasia Treatment Outcomes Study was completed by the subject without a study asslatant belng
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NATURAL HISTORY O F PROSTATISM
Group: Using repeated measures of symptom more, uroflowmetry and prostate specific antigen in the clinical management of prostate disease.J . Urol., 153: 99, 1995. 13. Gormley, G. J., Stoner, E., Bmskewitz, R. C., Imperato-McGinley, J., Walsh, P. C., McConneU, J. D., Andriole, G. L,Geller, J., Bracken, B. R,Tenover, J. S., Vaughan, E. D., Pappas, F., Taylor, A., Bhko&tz, B. and Ng, J. for the Finasteride Study Group: The effect of finasteride in men with benign prostatic hyperplasia. New Engl. J. Med., a?: 1185,1992. 14. Bukhoff, J . D.,Wiederhorn, A. R., Hamilton, M. L. and Zinsser, H. H.:Natural Of Prostatic and acute urinary retention. Urology, ?: 48,1976. 15. Ball, A- J., Fenele~.R.C. and Abrams,P. H.: The natural history of untreated "prostatism." Brit. J . Urol., 63:613,1981. 16' Garraway' w' M'' Armstrongp "' Auld' s.p D' and Simpson. R. J.: Follow-up of a cohort of men with untreated benign prostatic hyperplasia. Eur. Urol., 2 4 313, 1993. 17. Guess, H. A., Jambsen, S. J., Girman, C. J., Oesterling, J. E., Chute, C. G,, panser, L. A. and Liebr, M. M,: The role of community-based longitudinal studies in evaluating treatment effects. Example: benign prostatic hyperplasia. Med. Care, suppl., 33: AS26, 1995. 18. Jacobsen, S. J., Guess, H. A., Panser, L., Girman, C. J., Chute, C. G., Oesterling, J. E. and Lieber, M. M.: A population-based study of health care-seeking behavior for treatment of urinary symptoms. The Olmsted County Study of Urinary Symptoms and Health Status Among Men. Arch. Fam. Med., 2 729,1993. 19. Panser, L. A, Chute, C. G., Guess, H. k,Larsonkeller, J. J., Girman, C. J., Oesterling, J. E., Lieber, M. M. and Jacobsen,
S. J.: The natural history of prostatism: the effects of none response bias. Int. J. Epidemiol., 23: 1198,1994. 20. Epstein, R. s., Deverka, P. A., Chute, C. G., Panser, I,., &sterling, J. E., Lieber, M. M., Schwartz, s. and Patrick, D.: Validation of a new quality of life questionnaire for benign prostatic hyperplasia. J. Clin. Epidemiol., 45: 1431,1992. 21. BW, M. J., Fowler, F. J., Jr., OLeary, M. p.,Bruskewitz, R. C., Holtgrewe, H. L., Mebust, W. K., Cockett, A. T. K. and the Measurement Committee of the American Urological Association: the American Urological Association symptom index for benign prostatic hyperplasia. J. Urol., 148: 1549, 1992. 22. Feldman, H.A: Families of line random effects in linear r e gression analysis. J . Appl. Phy models for th 23,Ware, J. H,: ~i~~~~ ies. Amer. Stat., 3 9 95,1985. 24. Pearson, J. D., Morrell, C. H., Landis, P. R,Carter, H. B. and Brant, L. J.: Mixedeffects regression models for studying the natural history of prostate disease. Stat. Med., 1 3 587, 1994. 25. Jacobsen, S.J., Oesterling, J. E. and Lieber, M. M.: Communitybased population studies on the natural history of prostatism. Curr. Opin. Urol., 5 13,1995. 26. Barry, M. J., Fowler, F. J., Chang, Y.,k s , C. L., Wilson, H. and Stek, M., Jr.: The American Urological Association symptom index: does mode of administration affect its psychometric properties? J. Urol., 164: 1056,1995. 27. Rhodes, T., Girman,C. J., Jacobsen, S. J., Guess, H. A., Hanson, K. A, Oesterling, J. E. and Lieber, M. M.: Does the mode of questionnaire administration affect the reporting of urinary symptoms? Urology, 48.341, 1995.
NATURAL HISTORY OF PROSTATISM: LONGITUDINAL CHANGES IN VOIDING SYMPTOMS IN COMMUNITY DWELLING MEN S T E V E N J. JACOBSEN," CYNTHIA J. GIRMAN, HARRY A. GUESS, THOMAS RHODES, J O S E P H E. OESTERLING AND MICHAEL M. LIEBER From th~aDepartments of Health Sciences Research (Section of Clinical Epidemiology) and Urology, Mavo Clinic and Mayo Foundatcon, Rorhester, Minnesota, Merck Research Laboratories, Blue Bell, Pennsylvania, and Michigan Prostate Institute and University of Michigan, Ann Arbor, Michigan
ABSTRACT
Purpose: We report t h e results of 3 contacts during 42 months of The Olmsted County Study of U r i n a r y Symptoms a n d Health Status Among Men, a longitudinal cohort study of men 40 to 7 9 y e a r s old that w a s initiated in 1990 to describe changes in lower urinary t r a c t symptom severity. Materials a n d Methods: At baseline and followup, men completed questionnaires that elicited u r i n a r y symptom severity with questions nearly identical t o those of the American Urological Association symptom index. Results: Overall, there was a n average increase i n American Urological Association symptom index of approximately 0.18 (958 confidence interval 0.13 t o 0.24) points per year of followup. The average a n n u a l symptom score slope and variability i n slope increased with patient age at baseline from a m e a n of 0.05 t 1.06 (standard deviation) per year among men in the forties t o 0.44 t 1.35 per y e a r for m e n in the sixties, a n d decreased to 0.14 ? 1.42 p e r year for men in the seventies. T h e age-related changes i n symptom severity mirror previous estimates of prostatic growth from autopsy prevalence studies. Conclusions: These results demonstrate a slow but measurable progression in urinary symptom severity among community dwelling m e n for 42 m o n t h s of followup.
KEYWOROS:prostate, urination disorders, epidemiology formation regarding the changes in symptoms in the community is needed to understand the potential benefits of surgical and pharmacological therapies in the community ~ 0 n t e x t . I ~ The Olmsted County Study of Urinary Symptoms and Health Status Among Men was done partly to fill this void. This community based sample of more than 2,000 men was followed for 42 months with detailed assessments of lower urinary tract symptoms. We describe the natural history and clinical course of this cohort in regard to changes in summary symptom scores as well as in specific symptoms.
Benign prostatic hyperplasia (BPH), and its associated signs and symptoms pose a sizable public health problem to aging men in Western societies. In the United States in 1991 an estimated 340,000 transurethral resections of the prostate were performed' and there were more than 1.2 million office visitsz for this condition. These figures represent only the tip of the iceberg, since approximately 5.5 million men in the United States would meet diagnostic criteria for discussing treatment options for BPH" according to the United States Agency for Health Care Policy and Research Diagnostic and Treatment Guidelines if they were to seek medical care.4 Despite this prominence, relatively little is known about the natural history of BPH in the community. The autopsy prevalence of histological BPH has been shown to increase dramatically with age, reaching 60 to 80% among men in the sixties." Cross-sectionally, there is a minimal correlation between prostatic volume and lower urinary tract sympsuggesting that there are other causes of voiding symptoms. Nonetheless, there is an age-related increase in prevalence of lower urinary tract symptoms in the community.", Unfortunately, longitudinal data regarding lower urinary tract symptoms are relatively scarce for community dwelling men." Most of the longitudinal data have been described for placebo arms of clinical trials that do not provide information about untreated men,'Z, 13 among men from urology practicesl". 1s and community dwelling men with documented BPH. I(; Because these populations do not represent the entire spectrum of disease in the community and, by definition, exclude those with no symptoms a t baseline, In-
METHODS
Study subjects. Many of the details of the community based cohort have been described previo~sly.~. IH Briefly, a sampling frame was developed using the resources of the Rochester Epidemiology Project that identified male residents of Olmsted County 40 to 79 years old on January 1,1990. A 16% stratified random sample was drawn, and the community
Round 1 229 replacements
Round 2
Round 3 103 replacements
I
Accepted for publication August 18, 1995. Supported in part by Grant AR30582 from the United States Public Health Service, National Institutes of Health and a grant from Merck Research Laboratories. * Requests for reprints: Department of Health Sciences Research, Mayo Clinic, 200 First St., s. W., Rochester, Minnesota 55905.
19 dead
33 dead
FIG. 1. Design of Olmsted County Study of Urinary Symptoms and Health Status Among Men.
595
NATURAL HISTORY OF PROSTATISM TABLE1. Chonge in AUA s p p t o m indrr by uge ~
.
Pt
Age lyrs
I
ACA S>mptom Index Baseline 12.115 pts 1
5.314 6 W5 736
40-49 50-59 60-69 70-79
40-79 -~ Differs from 0 . p + Differs from 0. p
7.R17
c
218 219
3/10 3/12
___
1 R Mas.-Baseline (2.060 pts.1
.- 0.7”1-
- 0 310 0.210
0.m
~
~~
1
Followup --
1 8 4 2 Mas. 11.931 pts.)
~
~
~
-
311 312 5!3 213
__
-
~
~~
~
0.9”iO 0.9-11 1.3-11 0.410
~
1/2 113 114 213
4‘2 Mas -Baseline (1.935 pts
0.110 0 6’11 l.S‘/l 0.510
1
2/12 2/3 11.1 214
6.315 219 0 001 hy signed rank test. 0.01 by signed rank test.
FIG.2. Movement of baseline cohort across categories of lower urinary tract symptom severity. Round 2o-mild in round 1. Round Ph-moderate to severe in round 1. Round 3c and e-mild in round 2. Round 3d and f-moderate to severe in round 2. Median interval was 18 months between rounds 1 and 2, and 42 months between rounds 1 and 3 .
medical records of all men were screened for a history of prostatectomy, prostate cancer or any of a number of other medical conditions known to interfere with voiding function (other than BPH). Following these exclusions, 3,658 men were identified as potentially eligible for study. A total of 2,115 men (55%) completed the study protocol, which included a personal interview to elicit a family history of urological disease and current medications; completion of a selfadministered questionnaire that elicited lower urinary tract symptoms, basic demographic information and psychological well-being, and measurement of urinary flow rates with a portable uroflowmeter. A comparison of the medical records of responders and nonresponders suggested mostly that there were no differences except for history of urological diagnoses, and responders were slightly more likely to have had stones, urinary tract infections or BPH than nonresponders.19 Followup. Our study was designed to incorporate elements of a dynamic cohort, representing the true nature of the community a s well a s a traditional cohort. Men who moved from Olmsted County, died, refused to participate or whose age advanced out of the original cohort were replaced by men randomly selected from the community (fig. 1). Persons who
migrated from the community were also included in followup attempts. At a median of 18 months (25th percentile 16, 75th percentile 21) and 42 months (25th percentile 40, 75th percentile 45) following baseline, men were recontacted by mail and asked to complete a questionnaire with identical symptom questions. Of the 2,115 men in the cohort a t baseline 2,062 (97%1 provided followup responses at 18 months. Of the 2,259 members of the cohort at 18 months 2,157 (94%) participated in the 42-month followup. Overall, 1,930 of the original 2,115 men (91%)in t h e cohort provided responses a t all 3 contacts. The study protocol for baseline and followup was approved by the Mayo Clinic institutional review board. Measurements. The previously validated”’ self-administered questionnaire included 134 elements about the severity and bother of urinary symptoms, health status and sociodemographic characteristics. A total of 12 questions elicited information about the frequency of specific urinary symptoms during the last month. Symptom frequency questions were measured on a 7-point ordinal scale from 0 (“I do not have symptoms”) to 6 (“I always have symptoms”).A composite score for symptom severity was calculated to approximate the American Urological Association (AUA)symptom indexz1 by collapsing t h e 2 highest categories (almost always and
NATURAL HISTORY OF PROSTATISh!
597
FIG. 3 . Notch plot depicting distribution of individual estimates of annual change (slopel in AUA symptom index for 42 months of followup by patient age a t baseline. Limits of box represent 25th and 75th percentiles, limits of whiskers represent It_ 1.5 times interquartile range and points of diamonds represent mean 5 1 standard deviation.
a l w a y s ) t o t h e highest AUA symptom index category (almost a l w a y s ) for t h e 7 symptoms included i n t h e AUA symptom index. At each contact men were queried about t r e a t m e n t s for urological conditions, including pharmacological (finasteride, terazosin a n d doxazosin) a n d surgical (prostatectomy, t r a n s u r e t h r a l needle ablation, laser thera p y a n d microwave t h e r a p y ) . Analyses. For each m a n enrolled in the cohort, differences between baseline a n d followup symptom scores were calculated a n d tabulated. The signed rank test was used to test t h e null hypothesis t h a t the mean difference was 0, with a Bonferroni correction for multiple comparisons. Followup AUA symptom index scores were regressed on baseline scores t o quantify the degree a n d magnitude of association. A linear least squares model was estimated, and point a n d 95% confidence interval estimates of the slope and intercept were calculated. T o estimate change in symptom scores, a least squares regression line was estimated for each man based upon t h e n u m b e r of points measured.rl.':$ For men with 2 or 3 measurements a n estimate of annual symptom score slope a n d intercept was obtained by regressing AUA symptom index on time since baseline. For men with a single determination t h e r e was only a n estimate of intercept. The distributions of symptom score slopes were determined for t h e study cohort overall, a n d stratified by age and symptom score a t baseline. Mixed effects regression models were used to corroborate t h i s 2-step analysis."J RESULTS
At baseline there was a linear increase in AUA symptom index with patient age (table 1). This cross-sectional association h a s been described in detail p r e v i ~ u s l y . ~With . ~ " each year of patient age the AUA symptom index increased 0.10 units ( s t a n d a r d error 0.01). At followup there was much movement, across catemries of svmDtom seventy (fig.2). For
example, of the 1,288 men with mild symptoms a t baseline 1,105 (86%) reported mild symptoms at 18 months a n d 935 (73%) also reported mild symptoms a t 42 months. At 18 months 183 of the 1,288 men (14% with mild symptoms a t baseline reported moderate to severe symptoms and at 42 months 282 of the 1,288 (22Q I with mild symptoms a t baseline reported moderate to severe symptoms. Overall. there was a slight decrease in symptom severity as measured by the AUA symptom index among the cohort at 18 months. At 42 months of followup, by contrast, there was a n increase in symptom seventy across all age groups. The net change in AUA symptom index with time indicated a n increase in symptom severity across all ages. Nonetheless, there was much variability in these changes a t all ages. The regression analysis of t h e symptom score slope within each m a n demonstrated similar results. Overall, the average symptom score slope was 0.18 i_ 1.22 points (standard deviation, fig. 3 ) . This finding was slightly more pronounced among t h e 1,864 men with no treatment during followup (0.19 5 1.201 but opposite to t h a t observed among 66 with treatment (-0.21 t 1.76, p = 0.06). The change in AUA symptom index also was not consistent across patient age. The symptom score slope generally increased with patient age from 0.05 point per year for men in t h e forties to 0.44 point per year for men in t h e sixties. For men i n t h e seventies, however, the average symptom score slope was 0.14. Across all ages there was much variability in t h e estimates of slope. For example, t h e 5 t h a n d 95th percentiles were - 1.52 and 1.84, respectively, for men in the forties a n d -2.24 a n d 2.46, respectively, for men in t h e seventies. When symptom score slope was plotted against baseline AUA symptom index there was evidence of a regression to the mean phenomenon (fig. 4). The least squares regression model of symptom score slope on baseline AUA symptom index had a slope estimate of -0.06 (standard error 0.005) with a coefficient of determina-
598
NATURAL HISTORY OF PROSTATISM
0
5
10
15
20
25
30
Baseline AUASl FIG.4. Scatterplot of slope estimates for annual change in AUA symptom index (AUASZ) by baseline AUA symptom index. Solid line represents no change (slope 0). Dashed line represents least squares regression line of annual change on baseline AUA symptom index (slope 0.06, standard error 0.005 and intercept 0.52, standard error 0.04,F = 0.06, p <0.001).
tion o f f = 0.06. This relationship persisted after removing men who were treated sometime during followup. There was also much variability among the individual symptoms (table 2). As with the cross-sectional baseline data,9 nocturia and weak stream demonstrated a strong association with aging. However, as with overall symptom score the increases were successively greater at older baseline patient ages except for men in the seventies. Overall, repeat urination (within 10 minutes), difficulty stopping and starting, and post-void dribbling also demonstrated statistically significant increases with patient age. These increases were
found primarily among men in the sixties. The longitudinal changes in daytime frequency, dysuria, straining, urgency and sensation of incomplete emptying did not consistently show an increase with time. DISCUSSION
These results demonstrate the measurable progression of lower urinary tract symptom severity during 42 months of followup in a community based cohort of previously untreated men. The average annual increase in AUA symptom
TABLE2. Longitudinal annual change (slope) of urinary symptom scores __c____
Baseline Ages* Overall (4&79 yrs.)
4 M 9 Yrs.
50-59 Yrs.
AUA symptom index 0.18 2 1.22: 0.05 f 1.06 0.18 2 1.19: Individual symptoms:$ Day frequency5 0.01 f 0.33 -0.01 ? 0.31 0.00 i 0.34 Dysuria 0.00 t 0.18 -0.02 t- 0.15; -0.01 t 0.17 Nocturial 0.08 f 0.39* 0.04 t 0.32: 0.08 C 0.37 Weak stream§ 0.09 2 0.43' 0.06 t 0.36; 0.10 2 0.41 0.01 2 0.23 Straining§ 0.01 2 0.23 0.00 t 0.22 Repeat 0.022 0.211 0.01 i 0.19 0.02 2 0.20 stop5 0.022 0.29t 0.01 2 0.26 0.02 t- 0.28 Dribbling 0.04 f 0.36t 0.04 2 0.34; 0.02 2 0.35 Hesitancy 0 . 0 t 0.24 -0.01 2 0.23 -0.01 2 0.24 Urgency§ 0.01 C 0.30 -0.02 i 0.27 0.02 2 0.31 Not empty5 0.01 C 0.26 0.00 2 0.23 0.01 t 0.25 Dribbling-wet clothes 0.04 2 0.277 0.03 ? 0.27 0.03 2 0.26 Slope was determined by least squares regression of symptom score on interval from first assessment. * Unweighted average and standard deviation of individual slopes (per year) estimated across followup. t Statistically different than 0 (p <0.05, sign rank test with Bonfemoni correction). f Rated by respondent on 7-point scale from 0 (1 do not have symptom) to 6 (Always). 5 Component of AUA symptom index.
60-69 Yrs.
70-79 Yrs.
0.44 t- 1.35t
0.14 2 1.43
0.04 t 0.34t 0.03 2 0.20 0.14 t 0.45: 0.16 i 0.48t 0.02 2 0.25 0.04 i 0.25t 0.06 t 0.32t 0.05 t 0.38t 0.03 r 0.27 0.05 t 0.30i 0.04 t 0.30 0.06 2 0.29:
0.02 z 0.38 0.00 t 0.20 0.10 t 0.50: 0.07 t 0.55
0.00 t 0.24 0.02 r 0.25 -0.01 z 0.33 0.02 t 0.38 -0.01 i 0.23 0 01 5 0.36 0.01 5 0.30 0.03 z 0.30 -
NATURAL HISTORY OF PROSTATISM
599
index based on 3 time points was approximately 0.2 point present. In addition, responses to the AUA symptom index per year, with greater increases noted among men in the rely upon patient perception of the severity of symptoms. The sixties compared to those in the forties or seventies. This slowed progression among men in the seventies may be due finding mirrors the prostate growth curve estimated by partly to men accepting the symptoms and consequently Barry et al.5 There was much variability in progression, with underreporting the occurrence. Finally, there may be limitasome men getting worse and some improving. These results tions to the generalizability of these findings due to the are partly due to the regression to the mean phenomenon but response bias and the baseline exclusion criteria. The 55% resome probably represent the natural history of prostate dis- sponse rate at baseline may have enriched the sample with ease. men concerned about urological health19 but it is diacult to Our results provide insights into the changes in urinary know how this might affect the estimates of symptom score symptom severity in a community setting. Previous studies slope. The baseline exclusion of men who had already been have described the changes in lower urinary tract symptom treated also may further limit generalizability, since the severity in clinical cohorts and placebo arms of clinical trials. number of men being treated surgically has decreased in The populations represented by these samples by definition recent years. do not represent the community at large,17and may provide misleading information due to regression to the mean and CONCLUSIONS testing (Hawthorne and placebo) effects. Furthermore, while Our results have several implications. There is much varithese previous studies have demonstrated much variability in changes in individuals, our data provide a measure of that ability in symptom severity as reported by community dwellvariability for community dwelling men, more representative ing men. Because of this fact symptoms ideally should be assessed at several intervals to understand the trend in of those noted in a general practice. It is interesting to note that the longitudinal estimates of symptom progression (symptom score slope) in an individual. symptom progression differed from those observed cross-sec- On average, symptom seventy worsened during the 42 tionally a t baseline in this cohort.3. 9 At baseline there was a months of followup in untreated men. However, it did take a linear increase in AUA symptom index at a rate of approxi- dramatic annual change in AUA symptom index to place a By6 contrast, the longitudinal estimate man out at the 95th percentile for change in symptoms, mately 0.1 per ~ e a r . ~ was approximately twice the cross-sectional estimate (0.2 which agrees with the common knowledge that the course of versus 0.1) and differed with baseline patient age. Longitu- prostatism is generally slow and protracted. If these obserdinally, there was a suggestion of an acceleration in symptom vations are confirmed in future studies, the symptom score severity through the seventh decade of life and decreasing slope in addition to absolute symptom seventy might be used thereafter. The linearity of the increase noted cross-section- to determine which patients to treat. ally may have been due partly to the selection criteria for the Luanne Schmidt, Karen Hanson and Rebecca Nelson prostudy. Men treated surgically for BPH (presumably those vided continued followup of this cohort. with the most severe disease) had been excluded from the study cohort, which would have resulted in proportionately REFERENCES fewer older men with greater symptom severity, leading to an 1. Graves, E. J.: National Hospital Discharge Survey: h u a l Sumunderestimate of the age-related increase in symptom severmary, 1991. Vital Health Stat., series 13, number 114, 1993. ity. At followup, however, some men were observed throughS. M.: National Ambulatory Medical Care Survey: out the period in which the most severe symptoms developed. 2. Schappert, 1989 Summary. Vital Health Stat., series 13, number 110, Thus, the longitudinal observations may be more represen1992. tative of disease progression in the community than the 3. Jacobsen, S. J.,Girman, C. J., Guess, H. A, Oesterling, J. E. and previous cross-sectional estimates. Lieber, M. M.: New diagnostic and treatment guidelines for While the summary AUA symptom index measure inbenign prostatic hyperplasia. Potential impact in the United States. Arch. Intern. Med., 155:477, 1995. creased with time, not all individual symptoms demonstrated 4. Mcconneu, J. D.: W h y pressure-flow studies should be optional the same amount of progression. The symptoms with the and not mandatory studies for evaluating men with benign strongest positive slope were nocturia and weak stream. prostatic hyperplasia. Urology, e4: 156, 1994. These same symptoms demonstrated a strong age-related 5. Berry, S.J., Coffey, D. S., Walsh, P. C. and Ewing, L. L.: The increase a t baseline.9 Of the remaining 5 symptoms that are development of human benign prostatic hyperplasia with age. part of the AUA symptom index, only difficulty with stopping J. Urol., 132 474, 1984. and starting demonstrated a statistically sigdicant increase 6.G m a n , C. J., Jacobaen, S. J., Guess, H. A, Oesterling, J. E., Chute, C. G., Panser, L. A. and Lieber, M. M.: Natural history with time, which contrasts with the cross-sectional data in of prostatism: relationship among symptoms, prostate volume which urgency and sensation of incomplete emptying also and peak urinary flow rate. J. Urol., 159: 1510, 1995. demonstrated a strong age-related increase. This finding is 7. Barry, M. J., Cockett, A. T. K, Holtgrewe, H. L., McConneU, somewhat contrary to current belief, since all of these s p p J. D., Sihelnik, S. A. and Winfield, H. N.: Relationship of toms are considered by many to coincide with obstructive symptoms of prostatism to commonly used physiological and disease. However, it could be that the 42 months of followup anatomical measures of the seventy of benign prostatic hyperand the limited ordinal scale did not provide adequate power plasia. J. Urol., 1M): 351, 1993. to detect change in these individual symptoms. Continued 8. Abrams, P.H. and Feneley, R. C. L.: The significance of the followup of this cohort could provide additional power. symptoms associated with bladder outflow obstruction. Urol. Int., 33: 171, 1978. When interpreting these data, several potential limitations 9. Chute, C. G., Panser, L. A., G m a n , C. J., Oesterling, J. E., must be considered. It is dimcult to discern how much of the Guess, H. A, Jacobsen, S. J. and Lieber, M. M.: The prevalence change was random and how much represented true change. of prostatism:a population-based survey of urinary symptoms. The demonstrable regression to the mean Suggests that, alJ. Urol., 1M):85, 1993. though test-retest reliability is high with the AUA symptom 10. Garraway, W.M., Collins, G. N. and Lee, R. J.: High prevalence index,21 the longer term reliability may not be as precise. In of benign prostatic hypertrophy in the community. 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600
NATURAL HISTORY O F PROSTATISM
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