Association Between Cigarette Smoking andProstatism in a Japanese Community

Rosebud O. Roberts,1 Taiji Tsukamoto,3 Yoshiaki Kumamoto,3Thomas Rhodes,5 Naoya Masumori,3 Hirotsugu Miyake,4

Cynthia J. Girman,1,5 Steven J. Jacobsen,1* and Michael M. Lieber2

1Section of Clinical Epidemiology, Mayo Clinic and Mayo Foundation,Rochester, Minnesota

2Department of Urology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota3Department of Urology, Sapporo Medical University, School of Medicine, Sapporo, Japan

4Department of Public Health, Sapporo Medical University, School of Medicine,Sapporo, Japan

5Merck Research Laboratories, Blue Bell, Pennsylvania

BACKGROUND. The purpose of this study was to examine the association between ciga-rette smoking and prostatism among Japanese men.METHODS. Male residents of Shimamaki-mura, Japan, aged 40–79 years old (n=286),completed a self-administered questionnaire that included the international prostate symp-tom score (IPSS). A detailed cigarette smoking history was also obtained. All men had atransrectal ultrasonographic estimate of prostatic volume and a peak urinary flow rate mea-surement.RESULTS. Current cigarette smoking was inversely associated with an impaired peak uri-nary flow rate (<15 mL/sec) (odds ratio [OR] = 0.39, 95% confidence interval [CI] = 0.18,0.84), and with moderate to severe symptoms (IPSS>7) (OR = 0.84, 95% CI = 0.48, 1.49),but was not significantly associated with prostatic volume. Smokers of 1 to 1.4 packs a daywere less likely and smokers of less than a pack a day or 1.5 or more packs a day were morelikely to have moderate to severe symptoms and a greater prostatic volume.CONCLUSION. These findings suggest that cigarette smoking may have a protective effecton prostatism at certain smoking intensities, but no effect or a deleterious effect at otherintensities. Prostate 30:154–159, 1997. © 1997 Wiley-Liss, Inc.

KEY WORDS: benign prostatic hypertrophy; smoking; urination disorders; epidemi-ology

INTRODUCTION

Several studies have suggested that cigarettesmoking may be protective against surgery for benignprostatic hyperplasia (BPH) [1–7]. It has been arguedthat this association may have several nonetiologicexplanations such as geographic differences in trans-urethral prostatectomy rates, smokers being poorcandidates for surgery on account of chronic obstruc-tive lung disease and coronary artery disease [8, 9], orsmokers being less likely to seek health care for agiven level of symptoms than nonsmokers [8]. In acommunity-based cohort of men from Olmsted

County, MN [10], in which these potential confound-ers were unlikely to have an influence, cigarettesmoking was found to be inversely associated withobjective measures of peak urinary flow rate and pros-

Contract Grant sponsor: National Institutes of Health; ContractGrant number: AR30582.*Correspondence to: Dr. Steven J. Jacobsen, Department of HealthSciences Research, Section of Clinical Epidemiology, Mayo Clin,200 First Street S.W., Rochester, MN 55905.Received 15 August 1995; Accepted 20 October 1995

The Prostate 30:154–159 (1997)

© 1997 Wiley-Liss, Inc.

tatic volume. However, with urinary symptom sever-ity, the results suggested a biphasic association suchthat cigarette smoking was inversely associated withsymptoms at lower smoking intensities, but was di-rectly associated with symptoms at moderate to se-vere levels of 1.5 packs or more a day. This biphasicassociation between cigarette smoking and prostat-ism had not been described by other investigators,making it important to replicate the findings in otherpopulation-based studies.

The purpose of this study then, is to investigatethe association between self-reported cigarette smok-ing status and prostatism in a community-basedstudy of Japanese men, and to compare the findingsto those observed in the community-based cohort ofmen in Olmsted County, MN.

MATERIALS AND METHODS

This study was part of the Japanese component ofa multinational effort to investigate the natural his-tory of BPH. The study design and participant selec-tion were very similar to those used in OlmstedCounty, MN [11, 12], and the details of patient selec-tion and eligibility have previously been published[13, 14]. Briefly, between December 1990 and March1992, all men aged 40–79 years residing in Shima-maki-mura, a small fishing village on the island ofHokkaido, Japan, were invited to participate in thestudy. Men were excluded if they had a history ofsurgery or cancer of the prostate or bladder, urethralstricture, or other neurological conditions that couldaffect normal voiding. Of the 682 men residing in thevillage, 334 (49%) agreed to participate, and com-pleted a questionnaire that elicited information oncurrent health status, urinary symptoms and their as-sociated bother, a detailed smoking history, and de-mographic information. The English version of thequestionnaire used in the Olmsted County study wastranslated from English to Japanese, then back-trans-lated into English by two English-speaking Japanesephysicians who had no knowledge of the English ver-sion. Questions in Japanese with meanings inconsis-tent with the original English version were identifiedand rewritten to produce a Japanese questionnairealmost identical to that used in the Olmsted Countrystudy [13]. All men underwent a detailed clinical ex-amination which included a serum prostate-specificantigen determination, a digital rectal examination,and a transrectal ultrasound using a 7.5 MHz biplanarendorectal transducer to estimate prostatic volume[14, 15]. Peak urinary flow rates were measured by astandard uroflowmeter (Dantec 1000). A total of 286men met inclusion criteria and completed both thequestionnaire and the clinical examination.

The questionnaire assessed the frequency of occur-rence of 12 specific urinary symptoms in the previousmonth: daytime frequency, nocturia, small or weakstream, stopping and starting, straining, sensation ofincomplete emptying of bladder, urgency, dribbling,hesitancy, dysuria, repeat urination within 10 min,and wet clothing. A symptom frequency score wascalculated from 7 of the 12 items to approximate theinternational prostate symptom score (IPSS) [11, 12],and men were classified as having mild, moderate, orsevere symptoms on the basis of their symptom fre-quency score [16]. Based on smoking habits reportedin the questionnaire, men were classified as neversmokers if they had never smoked more than 100cigarettes in their lifetime, as former smokers if theyhad smoked more than 100 cigarettes but did not cur-rently smoke cigarettes, and as current smokers ifthey currently smoked cigarettes. Current smokerswere further categorized as smokers of less than apack a day (light smokers), 1 to less than 1.5 packs aday (moderate smokers), and 1.5 or more packs a day(heavy smokers) [17]. Body mass index was assessedfrom self-reported weight and height.

Statistical Analysis

For analysis, the outcome measures were dichoto-mized, symptom frequency scores as moderate to se-vere (>7) vs. mild (#7), peak urinary flow rates asless than 15 mL/sec vs. 15 mL/sec or more [18], andprostatic volume as more than 30 mL vs. 30 mL orless. Although the cutpoint chosen for prostatic vol-ume was based on the median in American men [19],it was used as the cutpoint in this study to determinewhether the association betweeen cigarette smokingand prostatic volume is independent of racial or ge-netic background. However, cutpoints of 20, 25, 40,and 50 mL were also investigated. Age-adjusted oddsratios (OR) for the comparison of former and currentsmokers to never smokers were estimated. A dose-response relationship with smoking was assessed bycomparing smokers with never smokers on the basisof their smoking intensity (light, moderate, orheavy). Multivariable logistic regression models wereused to control for the possible confounding effects ofage (as a continuous variable), of body mass index onprostatic volume, and of voided volume on peak uri-nary flow rate. Interaction terms were tested for in-clusion in the models, but no significant interactionwas observed. The raw data for Japanese and Olm-sted County men were combined and the analysisrepeated, with the inclusion of a term to control forsite (Japan or Olmsted County) and two-factor inter-action terms for site and smoking (by smoking statusand by packs per day), and for site and age were

Cigarette Smoking and Prostatism 155

tested. Subjects were excluded from the analyses forwhich they had missing information. All the statisti-cal analyses were performed using SAS (SAS Insti-tute, Cary, NC).

RESULTS

The overall prevalence of smoking among Japa-nese men was higher than that among men in Olm-sted County, MN (51% vs. 16%, P < 0.001). Of the280 Japanese men who provided complete informa-tion on smoking habits, about half (n=142) were cur-rent smokers, 79 (28%) had never smoked more than100 cigarettes in their lifetime, and 59 (21%) no longersmoked (Table I). Among smokers the proportion ofmen who were light, moderate, or heavy smokerswas similar in the two populations: Japan vs. Olm-sted County (light smokers, 39% vs. 38%; moderatesmokers, 35% vs. 32%; and heavy smokers, 28% vs.27%). The Japanese men were slightly older than menin Olmsted County (mean age 61 years vs. 55 years,P < 0.001).

In Japanese men, current smokers were less likelyto have an impaired peak flow rate compared tonever smokers (OR = 0.39, 95% confidence interval[CI] = 0.18, 0.84). Similar results were seen with acutpoint of 10 mL/sec. Although the point estimateshowed current smokers to be 0.84 times as likely tohave moderate to severe urinary symptoms com-pared with never smokers, this was not statisticallysignificant. There was no difference in the proportionof men with an enlarged prostate in current smokerswhen compared to never smokers. Sample sizes wereinadequate to estimate the smoking/prostatic volumeassociation using 40 or 50 mL cutpoints. No dose-

response relationship was observed across levels ofincreasing smoking intensity. Whereas moderatesmokers were less likely to have any of the three out-come measures (half as likely to have moderate tosevere urinary symptoms and about 0.4 times aslikely to have an impaired peak urinary flow rate oran enlarged prostate compared to never smokers),light and heavy smokers were no different fromnever smokers in the prevalence of moderate to se-vere symptoms, and were more likely to have an en-larged prostate compared to never smokers (OR =2.40 for light smokers and 1.61 for heavy smokers),but the CIs were quite wide. Former smokers were nodifferent from never smokers in the proportion withmoderate to severe symptoms and an enlarged pros-tate, but were slightly less likely to have an impairedpeak urinary flow rate (OR = 0.71, 95% CI = 0.28,1.76) (Table II).

There were no significant two-factor interactionsbetween site and smoking with regard to urinarysymptoms, prostatic volume, or peak urinary flowrates, but power was limited due to small cell sizes.

The associaton between urinary symptoms anddifferent smoking intensities showed a biphasic asso-ciation similar to that seen in American men, but Jap-anese light smokers were no different from neversmokers whereas American light smokers were lesslikely to have moderate to severe urinary symptomscompared to never smokers (Fig. 1a). At all smokingintensities, smokers were less likely to have an im-paired peak flow rate, although the inverse associa-tion between smoking and peak flow rate was greaterfor Japanese than for American men (Fig. 1b). Japa-nese men had lower prostatic volumes than OlmstedCounty men. The mean (SD) of prostatic volume for

TABLE I. Frequency and Percentage of Men With Mild and Moderate/ SevereUrinary Symptoms by Smoking Status in Japanese and American Men

Japan Olmsted County, MN

Mild symptomsn (%)

Moderate/severesymptoms

n (%)

Mildsymptoms

n (%)

Moderate/severesymptoms

n (%)

Smoking statusNever smoker 37 (46.8) 42 (53.2) 483 (66.0) 249 (34.0)Former smoker 27 (45.8) 32 (54.2) 669 (65.1) 358 (34.9)Current smoker 73 (51.4) 69 (48.6) 242 (71.6) 96 (28.4)

Smoking intensity0 packs/daya 64 (46.4) 74 (53.6) 1152 (65.5) 607 (34.5)0–<1 pack/day 24 (43.6) 31 (56.4) 102 (79.1) 27 (20.9)1–<1.5 packs/day 31 (62.0) 19 (38.0) 77 (70.6) 32 (29.4)1.5+ packs/day 18 (46.2) 21 (53.9) 57 (62.0) 35 (38.0)

aNever and former smokers.

156 Roberts et al.

Japanese men was 20.3 (10.6), compared to 29.6 (13.4)in the Olmsted County men, and the median pros-tatic volume in Japanese men was 17.8 compared to26.4 in the Olmsted County men. Whereas smokingwas inversely associated with an enlarged prostatevolume for all three levels of smoking in OlmstedCounty men, Japanese smokers of less than a pack aday, or greater than 1.5 packs a day were more likelyto have an enlarged prostate (Fig. 1c). When lowercutpoints of 20 and 25 mL for prostatic volume wereexamined, current smokers and smokers at differentintensities were less likely to have a prostatic volumegreater than 20 or 25 mL in both Japanese and Olm-sted County men. This suggests that the negative as-sociation between cigarette smoking and prostaticvolume is similar in both Japanese and OlmstedCounty men, and is robust to different cutpoints.

DISCUSSION

These results suggest that in Japanese men, ciga-rette smoking at any intensity may be protective foran impaired peak urinary flow rate (less than 15 mL/sec); that moderate smoking may be protective formoderate to severe symptoms of prostatism and foran enlarged prostate, but light or heavy smoking maybe a risk factor for moderate to severe symptoms, andfor an enlarged prostate.

With all current smokers combined, the results forJapanese men are similar to those for OlmstedCounty men, with smoking inversely associated withall three outcome measures. The differences in thetwo populations become evident when smokers werecompared to never smokers on the basis of theirsmoking intensity. With symptom severity, a bipha-sic association was demonstrated similar to the re-sults for Olmsted County men. Among OlmstedCounty men, light smokers were less likely to have

moderate to severe symptoms of prostatism, whereasin Shimamaki-mura, Japan, moderate smokers wereless likely to have moderate to severe symptoms, andlight smokers were slightly more likely to have mod-erate to severe symptoms compared to never smok-ers. The Japanese men in this study were observed toreport higher symptom scores than American men[13, 20] which could stem, in part, from differences inperception of symptoms, by a difference in interpre-tation of the questions, or may actually reflect ahigher prevalence of symptoms compared to Ameri-can men. As a result of the higher symptom scores,the level of smoking necessary to demonstrate an ef-fect on symptoms may be greater in Japanese than in

Fig. 1. Relative OR of a: moderate to severe symptoms of pros-tatism, b: an impaired peak urinary flow rate, and c: an enlargedprostate for Japanese (Shimamaki-mura, Japan) and American (Olm-sted, County, Minnesota) men comparing former smokers, smok-ers at different smoking intensities, and all current smokers tonever smokers. The error bars represent the upper and lower 95%confidence limits.

TABLE II. OR Comparing Never Smokers and Smokers With Respect to SymptomFrequency Scores, Peak Urinary Flow Rates, and Prostatic Volume in Japanese Men

No.Symptom scores

OR (95% CI)

Peak urinary flowrate <15 mL/sec

OR (95% CI)

Prostatic volume>30 mL

OR (95% CI)

Smoking statusNever smoker 79 1.00 1.00 1.00Former smoker 59 1.00 (0.5–1.95) 0.71 (0.28–1.76) 1.10 (0.34–3.88)

Current smoker (packs/day)0–1 55 1.07 (0.53–2.17) 0.37 (0.14–0.97) 2.40 (0.56–10.34)1–1.4 50 0.55 (0.27–1.13) 0.41 (0.14–1.21) 0.39 (0.04–3.49)$1.5 37 1.10 (0.50–2.43) 0.24 (0.08–0.77)* 1.61 (0.26–10.8)All current smokers 142 0.84 (0.48–1.49) 0.39 (0.18–0.84)* 1.00 (0.30–3.27)

*P < 0.05.

Cigarette Smoking and Prostatism 157

American men. The increased risk of an enlargedprostate seen in Japanese light and heavy smokers isin contrast to what was observed in Olmsted Countywhere smokers were less likely to have an enlargedprostate at all smoking intensities. The reason for thisis unclear.

Possible reasons for inconsistencies between theresults for the two populations may be due to differ-ences in health profiles of men in the two studies,exposure levels, sample sizes, nonresponse bias, andhormone levels. First, although the exclusion criteriain the two populations were nominally similar, thecriteria may have been more rigorously applied inOlmsted County where exclusion was based on med-ical records and phone verification as compared toJapan where it was based only on questionnaire self-report. This could have resulted in a relatively health-ier older cohort in the Olmsted County study as com-pared to the Japanese study. Second, the imbalancein cigarette smoking exposure, 51% smokers and 25%never smokers in the Japanese population, comparedto 16% smokers and 35% never smokers in the Amer-ican population, may have resulted in some addi-tional confounding that could not be accounted for inthe analysis. Third, the small sample size of the Jap-anese study resulted in small cell sizes with greaterinstability of the results and decreased power to de-tect a significant difference. Fourth, nonresponsebias, a potential limitation for both studies, may havediffered for smokers and nonsmokers for the twostudies. Response rates for the Japanese and Ameri-can population were 49% and 55%, respectively.Fifth, racial differences in male sex hormone levelscould account for some of the differences. Anotherpossible reason for the differences is the fact that theJapanese cohort may be more homogeneous geneti-cally, socioeconomically, educationally, and cultur-ally than American men; thus, the association be-tween cigarette smoking and prostatism may be moredefinitively defined. Lastly, differences in the typesof cigarettes (filtered or not filtered), the nicotine con-tent of cigarettes (low yield or not) smoked by theJapanese and American men, and other unmeasuredconfounders that may have been present in one pop-ulation but not the other could account for the differ-ences. Despite the possible reasons for differences,the inability to detect a significant site by smokinginteraction suggests that although the strength of theassociation between smoking and prostatism for Jap-anese and American men may differ, the basic rela-tionship of a protective effect seen in Japanese menmay not differ from that in American men.

Mechanisms by which cigarette smoking could af-fect prostatism may operate through neurophysio-logic or neuroendocrine effects of nicotine (a major

constituent of cigarette smoke) on the bladder andthe prostate. The neurophysiologic effects of smokingon the bladder may be through the nicotinic effects ofsmoking on the autonomic nervous supply to thebladder. Both the bladder detrusor muscle and blad-der sphincter are supplied by sympathetic and para-sympathetic nerves, with a predominant parasympa-thetic tone which promotes bladder emptying [21].Nicotine has a dual effect on autonomic ganglia, act-ing as a low-dose agonist and a high-dose antagonistat nicotinic postsynaptic nerve endings [21–23]. Thus,low doses of nicotine stimulate the parasympatheticsupply to the bladder, resulting in stronger contrac-tion of the detrusor muscle and relaxation of the in-ternal sphincter, and promoting bladder emptying.This effect of nicotine on the bladder may explain theprotective effect of nicotine on both urinary symp-toms and on impaired peak urinary flow rate seen insmokers. Second, BPH is a well-documented hor-mone-dependent disease [24, 25], and dihydrotest-osterone is thought to be the primary mediator [25].Mean endogenous levels of testosterone and an-drostenedione (a metabolite of dihydrotestosterone)have been reported to be higher in smokers than innonsmokers [26, 27]. Higher estadiol levels have alsobeen reported in smokers relative to nonsmokers [27–29]. Since estrogens are believed to act synergisticallywith androgens in the development of BPH [24, 25],increased levels of these hormones in cigarette smok-ers may affect the development of prostatism in smok-ers through the effect on prostate size. However, thismay be a complex mechanism due to the low-doseagonist, high-dose antagonist effects of nicotine. Cig-arette smoking has been associated with the increasedblood levels of norepinephrine from sympatheticnerve endings [30], and from the adrenal medulla [21].Since norepinephrine is reported to enhance the pe-ripheral aromatization of testosterone to estradiol, theresulting androgen/estrogen ratio may determine theeffect of cigarette smoking on prostatic volume.

The results of this study suggest that smoking mayindeed have a protective effect on lower urinary tractsymptoms and function, most evident in the effect onpeak urinary flow rates, and less so on the effect onurinary symptoms. The effect on prostatic volume,however, remains unclear, but the analyses usinglower cutpoints of 20 and 25 mL suggest that it maywell be protective. Due to the lack of precision inmost of the estimates, these findings need to be ex-plored further in larger studies. Furthermore, this as-sociation between cigarette smoking and prostatismmay provide clues for future research into biochemi-cal factors related to the development of lower uri-nary tract symptoms, and may have potential fortreatment strategies.

158 Roberts et al.

ACKNOWLEDGMENTS

The authors wish to thank Ms. Sondra Buehler forher help in preparation of this manuscript. Thisproject was supported by research grants from thePublic Health Service, National Institutes of Health(AR30582), and Merck Research Laboratories.

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