Obesity and Benign Prostatic Hyperplasia: Clinical Connections, Emerging Etiological Paradigms and Future Directions

J. Kellogg Parsons,*, Aruna V. Sarma, Kevin McVary and John T. Wei

From the Division of Urologic Oncology, Moores Cancer Center, University of California, San Diego and Section of Surgery, San Diego Veterans Affairs Medical Center (JKP), La Jolla, California, Departments of Epidemiology (AVS) and Urology (AVS, JTW), Ann Arbor, Michigan, and Department of Urology, Northwestern University (KM), Chicago, Illinois

Abbreviations and Acronyms BLSA Baltimore Longitudinal Study of Aging BMI body mass index BPH benign prostatic hyperplasia HPS Health Professionals Follow-up Study I-PSS International Prostate Symptom Score LUTS lower urinary tract symptoms NHANES National Health and Nutrition Examination Survey PCPT Prostate Cancer Prevention Trial
* Correspondence: Division of Urology, University of California-San Diego, 200 West Arbor Dr., No. 8897, San Diego, California 92103-8897 (telephone: 619-543-2630; FAX: 619-543-6573; e-mail: leparker@ucsd.edu). Financial interest and/or other relationship with American Medical Systems. Financial interest and/or other relationship with GlaxoSmithKline, Pzer, Lilly/ICOS, SanoAventis, Allergan and National Institute of Diabetes and Digestive and Kidney Diseases. Financial interest and/or other relationship with Sano, American Medical Systems, Envisioneering, Gen-Probe and Beckman.

Purpose: Benign prostatic hyperplasia is a highly prevalent disease in older men with substantial adverse effects on public health. Classic etiological paradigms for benign prostatic hyperplasia focus on nonmodiable risk factors. However, obesity also potentially promotes benign prostatic hyperplasia. Materials and Methods: We performed a structured, comprehensive literature review to identify studies of obesity, benign prostatic hyperplasia, lower urinary tract symptoms and physical activity. Results: A preponderance of published evidence suggests strong positive associations of obesity with benign prostatic hyperplasia and lower urinary tract symptoms. This evidence encompasses most established metrics of adiposity, including body mass index, waist circumference and waist-to-hip ratio, and falls under 3 general categories, including prostate volume, clinical benign prostatic hyperplasia and lower urinary tract symptoms. 1) Prior studies consistently showed that increased adiposity is positively associated with radiographically determined prostate volume and enlargement, suggesting that obesity promotes prostate growth. 2) Most studies revealed that obesity increases the risk of clinical benign prostatic hyperplasia by several measures, including the initiation of benign prostatic hyperplasia medical treatment, noncancer prostate surgery, physician diagnosed benign prostatic hyperplasia, histological diagnosis and urinary ow rate. 3) Prior studies demonstrated that obesity increases the risk of lower urinary tract symptoms, as measured by a validated questionnaire. Also, most studies showed that physical activity signicantly decreases the risk of benign prostatic hyperplasia. Conclusions: Obesity markedly increases the risk of benign prostatic hyperplasia. Since physical activity decreases the risk of benign prostatic hyperplasia, these observations support the development of novel prevention strategies and treatment targeted toward adiposity, weight loss and lifestyle. Key Words: prostate, prostatic hyperplasia, urination disorders, obesity, metabolic syndrome X BENIGN prostatic hyperplasia is a highly prevalent disease in older men with substantial adverse effects on public health since 3 of 4 men 60 to 69 years old in the United States are affected, 21 to 38 million hours of productivity are lost annually and more than $1 billion
0022-5347/13/1891-0102/0 THE JOURNAL OF UROLOGY 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION

per year in direct health care expenditures are consumed exclusive of outpatient medication.1 The primary clinical manifestation of BPH is the LUTS complex. As a result, BPH and LUTS remain inextricably interconnected in the contemporary study of and treathttp://dx.doi.org/10.1016/j.juro.2012.11.029 Vol. 189, S102-S106, January 2013 RESEARCH, INC. Printed in U.S.A.

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Please cite this article as J Urol 2013;189: S102-S106. DOI: http://dx.doi.org/10.1016/j.juro.2012.11.029

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ment for urinary symptoms in older men. LUTS affects 15% to 60% of males older than 40 years and is associated with an increased risk of falls, signicantly decreased quality of life, sadness, depression, impaired instrumental activity of daily life and decreased SF-12 scores.25 Classic causal paradigms for BPH concentrated on relatively nonmodiable etiological stimuli, including sex steroid hormones, genetic predisposition and age related detrusor changes. However recent observations indicate that systemic metabolic disturbances may also contribute substantially to BPH pathogenesis.6 These data intimate that many of the metabolic disturbances associated with cardiovascular disease and the lifestyle factors that modulate these disturbances are associated with BPH onset and progression. In this context accumulating evidence suggests that obesity promotes BPH. We reviewed published data on obesity, BPH, LUTS and physical activity.

passes most established metrics of adiposity, including BMI, waist circumference and waist-to-hip ratio, and involves 3 general categories of outcome, that is prostate volume, BPH and LUTS (see table). Obesity and Increased Prostate Volume Prior studies consistently showed that increased adiposity, as determined by most anthropometric measures, is positively associated with ultrasound and magnetic resonance imaging measured prostate volume. The greater the adiposity, the greater the prostate volume. Increased prostate volume is clinically relevant, in that it strongly predicts adverse clinical outcomes associated with BPH, including acute urinary retention and renal failure.8,9 Body weight,10,11 BMI1115 and waist circumference11,13 were positively associated with prostate volume in multiple study populations. In the BLSA cohort each 1 kg/m2 increase in BMI corresponded to a 0.41 cc (95% CI 0.15 0.84) increase in prostate volume (p-trend 0.06).11 Moreover, obesity is associated with prostate enlargement. In BLSA obese (BMI 35 kg/m2 or greater) participants were at 3.5-fold increased risk for prostate enlargement, dened as magnetic resonance imaging determined prostate volume 40 cc or greater, compared to nonobese (BMI less than 25 kg/m2) participants.11 A recent analysis of more than 16,000 radical prostatectomy specimens validated these ndings (Parsons et al, unpublished data). Multivariate adjusted analysis revealed that each 1 kg/m2 increase in preoperative BMI was associated with a 0.45 gm (95% CI 0.35 0.55) increase in total prostate weight (p-trend 0.001). Moreover, there was a 41% increased risk of prostate enlargement, dened as total prostate weight 40 gm or greater, in obese (BMI 35 kg/m2 or greater) compared to nonobese (BMI less than 25 kg/m2) men (OR 1.41, 95% CI 1.011.95). These observations suggest that adiposity is linked to prostate growth. Obesity and BPH Most studies showed that obesity increases the risk of BPH, as dened by several measures. Of almost 26,000 male participants in HPS those with an obese waist circumference (greater than 109 cm) were 38% (OR 1.38, 95% CI 1.011.95) more likely to undergo BPH surgery than those with a nonobese waist circumference (less than 89 cm).16 In a case-control study of 500 Chinese men those with the highest waist-to-hip ratio were 41% more likely (OR 1.41, 95% CI 1.011.95) to undergo BPH surgery than those with the lowest waist-to-hip ratio.17 Finally, in 5,700 American men participating in the PCPT the incidence of BPH, dened as consistently severe urinary symptoms on the I-PSS, initiation of medical therapy or surgery, increased 10% for each 0.05 increase in the waist-to-hip ratio.18 Also, a BMI of 30

MATERIALS AND METHODS

We performed a structured, comprehensive literature review to identify studies of obesity, BPH, LUTS and physical activity. We completed separate searches of the MEDLINE database (January 1966 to April 2009), The Cochrane Library Central Search and the EMBASE database (1980 to 2009). Initial search terms were benign prostatic hyperplasia, lower urinary tract symptoms and obesity. Subsequent search terms were physical activity and exercise. To maximize inclusion of the most recent pertinent data we also examined reference sections in published articles, abstracts presented at the annual meeting of the American Urological Association (2002 to 2007) accessed on the American Urological Association website (www.auanet.org) and unpublished data to which we had access.

RESULTS
This review revealed a number of subjective and objective clinical denitions of BPH. Some entailed validated questionnaires for LUTS combined with prostate examination and urinary ow rate, and others entailed medical or surgical treatment, patient reported history, physician diagnosis and histological diagnosis. Also, obesity is a component of metabolic syndrome, a clinical constellation of metabolic abnormalities that increases the risk of cardiovascular disease. In the several published denitions of metabolic syndrome there is no consensus about which anthropometric measures should be used to dene obesity, that is BMI, waist circumference or waistto-hip ratio.7 Overall published evidence supports strong associations of obesity with BPH. This evidence encom-

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Select studies of obesity, BPH and LUTS Study Population (outcome measure) BLSA11 (prostate vol 40 cc or greater) HPS:16 BPH surgery LUTS Nord-Trndelag Health Study 224 (LUTS) PCPT18 (incident BPH*) Shanghai case-control17 (BPH surgery) NHANES III23 (LUTS) Flint Mens Health Study26 (LUTS) Hong Kong cohort27 (LUTS) Risk Factor BMI greater than 35 mg/kg2 Waist circumference greater than 109 cm Referent BMI less than 25 kg/m2 Waist circumference less than 89 cm OR (95% CI) 3.52 (1.458.56) 2.38 (1.423.99) 2.00 (1.472.72) 1.79 (0.903.56) 1.30 (1.081.57) 1.41 (1.011.95) 1.48 (0.872.54) 1.13 (0.751.70) 1.08 (0.841.38)

BMI 40 mg/kg2 or greater BMI 3035 mg/kg2 Waist-to-hip ratio greater than 0.923 Waist circumference greater than 102 cm BMI 30 mg/kg2 or greater BMI 25 mg/kg2 or greater

BMI less than 25 mg/kg2 BMI less than 25 mg/kg2 Waist-to-hip ratio less than 0.856 Waist circumference less than 94 cm BMI less than 25 mg/kg2 BMI less than 23 mg/kg2

* Dened as consistently severe urinary symptoms on I-PSS, initiation of medical therapy or BPH surgery.

to 34 kg/m2 was associated with a 30% increased risk of BPH relative to a BMI of less than 25 kg/m2 (OR 1.30, 95% CI 1.08 1.57). Notably the PCPT tracked incident BPH for up to 7 years and to our knowledge is the largest incident analysis of obesity and BPH to date. Results in a case-control study of 3,000 Italian men also showed a link between obesity and BPH but were somewhat more equivocal.19 Men with a lowest lifelong BMI of 23.7 kg/m2 or greater were 56% more likely to have histological BPH than men with a lowest lifelong BMI of 20.7 kg/m2 or less but BMI and waist circumference at evaluation were inversely associated with BPH risk, as dened by histological diagnosis. Furthermore, 2 smaller studies showed no links between obesity and BPH. An analysis of 475 American men enrolled in the Olmsted County cohort showed no associations of obesity with peak urinary ow rate or acute urinary retention,20 while a case-control study in 870 Western Australian men revealed no associations of obesity with BPH surgery.21 Although a cohort analysis of United States Air Force veterans did not demonstrate any linear associations of BMI with physician diagnosed BPH, this study did not present data on BPH and obesity.22 Obesity and LUTS Several studies showed that obesity increases the risk of LUTS, as measured by a questionnaire. Obese men in the HPS were 100% more likely (OR 2.00, 95% CI 1.011.95) to report LUTS, dened as responses to a questionnaire encompassing storage and voiding symptoms, compared to men with a nonobese waist circumference.16 In 2,800 men in NHANES III an increase in BMI during adulthood and obese waist circumference were associated with increased LUTS, dened as at least 3 of certain symptoms, including nocturia, incomplete emptying, weak stream and hesitancy.23 In the second NordTrndelag Health Study in 21,700 Norwegian men obese BMI and an increased waist-to-hip ratio were associated with increased LUTS, as measured by

I-PSS.24 In a cohort of 1500 Austrian men there was a trend toward higher I-PSS with increased waist circumference but not with increased BMI.25 There were no associations of BMI determined obesity with LUTS in a cohort of black American men26 or in a cohort of Chinese men.27 Physical Activity, BPH and LUTS Obesity is strongly associated with a lack of physical activity. Accordingly increased physical activity has been linked to a decreased risk of BPH surgery,28,29 clinical BPH,30,31 histological BPH32 and LUTS.29,33 A meta-analysis of 11 published studies indicated that moderate to vigorous physical activity decreased the risk of BPH or LUTS by as much as 25% relative to a sedentary lifestyle.34 The strength of the protective effect appeared to be greater at higher activity levels but there was a nonsignicant trend toward a protective effect with even light physical activity. Adjusting for multiple confounders underscored the independence of the protective effect of physical activity toward BPH. A decreased risk of BPH with increased physical activity provides further evidence of a link between obesity and BPH. Moreover, this observation intimates that lifestyle changes may alter the natural history of BPH.

DISCUSSION
Thus, obesity increases the risk of BPH by multiple outcome measures. The public health import of this observation is considerable. The prevalence of obesity continues to increase and obesity now affects more than a third of American men.35 BPH also affects a broad swath of the older male population, which (like obesity) grows larger each year. By 2030, 20% of the American population will be 65 years old or older, including more than 20 million men.36 The conuence of these 3 trends, that is an increased BPH risk with obesity, the obesity epidemic and the rapid aging of the population, suggests the gathering of a perfect storm that will markedly swell the

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ranks of men with BPH in the near future and place ever greater burdens on nite health care resources. These observations are also important because they intimate the existence of modiable pathways for BPH that represent novel targets for prevention and treatment by modulating adiposity. Also, the robust, signicant inverse association of physical activity with BPH justies the design and implementation of clinical trials using weight loss, exercise and lifestyle alterations. To our knowledge there are no published studies to date of the effect of such interventions on BPH or LUTS. Further studies should determine optimum physical activity levels and the relative importance of targeting adiposity vs overall body weight to achieve a therapeutic effect. These data are observational and, thus, should serve primarily as a guide to inform the design of future clinical trials. However, there is little if any negative side to promoting healthy lifestyle interventions, specically increased physical activity and weight loss, in obese older men to prevent or attenuate BPH, particularly since such interventions have proven benets to overall and cardiovascular health. To our knowledge the physiological mechanisms by which obesity promotes BPH remain to be described. A potential explanation is systemic inammation. Obesity is a component of metabolic syndrome,7 and obesity and metabolic syndrome are associated with systemic inammation and oxidative stress.37 There are multiple lines of evidence connecting BPH with inammation. 1) BPH in surgical specimens is associated with inammation,38 40 and the extent and severity of inammation correspond to the amount of prostate enlargement.41 2) In NHANES III higher serum C-reactive protein was associated with an increased risk of LUTS.42 3) In the Olmsted county cohort daily nonsteroidal anti-inammatory use was

associated with a 27%, 49% and 47% decreased risk of LUTS, low urinary ow rate and enlarged prostate, respectively.43 Thus, it is possible that BPH represents a nonmalignant pathway of unregulated prostate growth promoted by oxidative stress and inammatory mediators. The extent to which obesity may inuence BPH independent of sex steroid hormones is also unclear. Since increased adiposity promotes increased aromatization of circulating testosterone into estrogen, alterations in the balance between testosterone and estrogen in prostate tissue may possibly contribute to BPH pathogenesis. However, the BLSA controlled for serum total and free testosterone, suggesting that obesity may inuence prostate growth through mechanisms other than sex steroid growth pathways.11 While these data are compelling, they are primarily cross-sectional. Moreover, it is unclear as to how obesity interacts with other components of metabolic syndrome, including glucose insensitivity, dyslipidemia and hypertension. Additional longitudinal analyses of incident BPH and LUTS may be needed to elucidate these pathways. These analyses should explore correlations among variables and incorporate evaluations of prevalent and incident health conditions that could confound associations of obesity with BPH and LUTS. Such analyses would facilitate the development and implementation of efcacious prevention strategies.

CONCLUSIONS
Obesity substantially increases the risk of BPH. Since physical activity decreases BPH risk, these observations support the development of novel strategies for BPH prevention and treatment targeted toward adiposity, weight loss and lifestyle interventions.

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