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Curr Bladder Dysfunct Rep (2010) 5:212–218DOI 10.1007/s11884-010-0067-2 Benign Prostatic Hyperplasia and Male Lower Urinary TractSymptoms: Epidemiology and Risk Factors J. Kellogg Parsons Published online: 7 September 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract The epidemiology of benign prostatic hyperpla- sia (BPH) and male lower urinary tract symptoms (LUTS)has evolved considerably during the past several years. The The epidemiology of benign prostatic hyperplasia (BPH) term LUTS describes a distinct phenotype and allows for a and male lower urinary tract symptoms (LUTS) has broad epidemiologic description of urinary symptoms at a evolved considerably during the past several years. The population level. Although it is becoming the preferred incidence and prevalence of BPH and LUTS are increasing term for studying urinary symptoms in populations, LUTS rapidly as the US population ages. BPH and LUTS are remains interconnected with BPH in the literature. The associated with serious medical morbidities, an increased incidence and prevalence of BPH and LUTS are increasing risk of falls, depression, diminished health-related quality rapidly as the US population ages. BPH and LUTS are of life, and billions of dollars in annual health care costs.
associated with serious medical morbidities, an increased Although age and genetics play important roles in the risk of falls, depression, diminished health-related quality etiology of BPH and LUTS, recent insights at the of life, and billions of dollars in annual health care costs.
population level have revealed novel risk factors that Although age and genetics play important roles in the present new opportunities for treatment and prevention.
etiology of BPH and LUTS, recent insights at the population Indeed, an exciting notion is that to a large extent, BPH and level have revealed that modifiable risk factors are likely key LUTS pathogenesis may be driven by modifiable risk components as well. Serum dihydrotestosterone, obesity, factors, including serum dihydrotestosterone (DHT), obesity, elevated fasting glucose, diabetes, fat and red meat intake, glucose homeostasis, diet, exercise, and inflammation.
and inflammation increase the risk; vegetables, regularalcohol consumption, exercise, and NSAIDs decrease the Identification and Definition in Epidemiologic Studies LUTS represent a cluster of chronic urinary disorders that Keywords Benign prostatic hyperplasia .
occurs among 15% to 60% of men older than 40 years of Lower urinary tract symptoms .
age [–]. Specific symptoms associated with the LUTS American Urological Association Symptom Index . BPH .
complex include frequency, urgency, nocturia, difficulty LUTS . Epidemiology . Risk factor . Exercise .
initiating urination, sense of incomplete bladder emptying, Physical activity . Metabolic syndrome . Modifiable .
decreased force of stream, and interruption of stream.
Obesity . Diabetes The most common etiology of male LUTS is BPH. A persistent conundrum in designing and interpretingpopulation-based studies of urinary symptoms in older J. K. Parsons (*) men is case definition. In the past, chronic urinary In care of Leslie Parker, Division of Urology, symptoms in older men were uniformly ascribed to—and University of California, San Diego, defined as—BPH. There are at least two reasons why BPH 200 West Arbor Drive #8897, is a problematic outcome measure for population studies.
San Diego, CA 92103-8897, USAe-mail: leparker@ucsd.edu First, BPH has many different definitions, including Curr Bladder Dysfunct Rep (2010) 5:212–218 histologic analysis of prostate tissue, radiographically LUTS incidence among older men is also considerable.
determined prostate enlargement, decreased urinary flow In the Osteoporotic Fractures in Men cohort, a prospective rates, history of noncancer surgery of the prostate, study of 6,000 community-dwelling men older than 65 years physician-diagnosed BPH, and urinary symptoms. Hetero- of age, 29% of those without LUTS at baseline developed geneity in defining BPH makes validation across study clinically significant LUTS within 2 years of follow-up; populations difficult. Second, BPH excludes other potential among those 80 years of age or older, this proportion causes of urinary symptoms in older men, such as increased to 34% []. In the Olmsted County cohort, 14% interstitial cystitis and detrusor instability.
of men without LUTS at baseline subsequently reported LUTS describes a distinct phenotype of a group of moderate or severe symptoms within 18 months of follow- disorders affecting the prostate and bladder that share a up, and 22% reported moderate or severe symptoms within common clinical manifestation. The term LUTS allows for 42 months of follow-up [Similarly, 21% of Japanese, a broad epidemiologic description of urinary symptoms at a 26% of black American, and 20% of Austrian men with no population level without identification of organ- or disease- or mild LUTS at baseline reported worsened symptoms specific etiologies. This approach allows consideration of after 3, 4, and 5 years of follow-up, respectively [–] LUTS within a macroscopic context using a uniform The prevalence and incidence of BPH and LUTS in the definition unbiased by variable definitions of BPH and United States increased steadily between 1994 and 2000 other diseases. In recent observational studies, LUTS has Between 1998 and 2007, the become the preferred term for studying urinary symptoms in age-adjusted prevalence of BPH among hospitalized populations –]. Still, as most men with LUTS have BPH patients in the United States nearly doubled (Stroup and and most men with BPH have LUTS, the two terms remain Parsons, unpublished data). Increases in BPH and LUTS inextricably interconnected in the contemporary treatment prevalence and incidence are occurring within the context and study of urinary disorders in older men. Therefore, this of an aging population. By 2030, 20% of the US population review discusses BPH and LUTS as separate outcomes will be 65 years of age or older, a figure that will include describing the same spectrum of male urinary disorders.
more than 20 million men. Significantly, the fastest- The most commonly used measures of LUTS in growing segment of the older adult population is the oldest epidemiologic studies, and the primary instruments by age group: those older than 85 years of age. Current which BPH is diagnosed in clinical practice are the estimates indicate that the number of individuals 80 years American Urological Association Symptom Index (AUA- of age or older in the United States will rise from 9.3 SI) and its internationally validated counterpart, the million in 2000 to 19.5 million in 2030, an increase of more International Prostate Symptom Score (I-PSS). The AUA- than 100% ]. These trends portend substantial increases SI and I-PSS are robust and reliable quantitative instru- in the number of incident and prevalent LUTS and BPH ments for measuring urinary symptoms in men. As part of cases within the next few decades.
its clinical guidelines, the American Urological Associationrecommends the routine use of the AUA-SI or I-PSS in the Public Health Impact of Lower Urinary Tract Symptoms clinical evaluation of patients with suspected BPH and Benign Prostatic Hyperplasia It is important to consider the substantial adverseconsequences of LUTS and BPH for the global health Epidemiology of Lower Urinary Tract Symptoms of older men. Although it may be tempting to dismiss and Benign Prostatic Hyperplasia LUTS and BPH as relatively harmless disorders repre-senting more of an inexorable, if inconvenient, effect of Incidence and Prevalence in an Aging Population aging, this perception belies the substantial medical,psychological, and economic burdens of these conditions.
The prevalence of BPH and LUTS rises markedly with Despite widespread use of medical therapy ( increased age. BPH affects 70% of US men 60–69 years ), BPH remains associated with a substantial of age and 80% of those 70 years of age or older In prevalence of urinary infections, bladder stones, urinary the Boston Area Community Health survey, LUTS retention, and acute renal failure (Stroup and Parsons, prevalence increased from 8% in men 30–39 years of unpublished data). In addition, the adverse health effects of age to 35% in men 60–69 years [In the Rancho LUTS and BPH encompass serious nonurologic conditions.
Bernardo study, 56% of men 50–79 years of age, 70% of Men with severe LUTS have a 63% increased risk of falling at men 80–89 years of age, and 90% of men 90 years of age least twice within 1 year compared with men with no or older reported LUTS []. Other population-based symptoms ]. Falls in older adults are associated with studies have demonstrated similar trends [ debilitating morbidities, including pain and fractures. LUTS


Curr Bladder Dysfunct Rep (2010) 5:212–218 is also associated with a significantly diminished quality of tigators further estimated that 50% of men undergoing life, depression, and impairment in instrumental activities of surgery for BPH who were younger than 60 years of age daily living [, ].
had a heritable form of disease ]. These findings and Another important public health issue is the cost those of others have suggested an autosomal dominant associated with diagnosis and treatment. In 2000, the most pattern of inheritance ]. Men with inherited forms of recent year for which comprehensive data are available, BPH tend to have larger prostates and younger age at onset BPH generated 1.1 billion dollars in direct health care than men with sporadic BPH ].
expenditures and accounted for more than 4.4 million office Monozygotic twin concordance rates of 63% and 26% visits, 117,000 emergency department visits, 105,000 have been observed for LUTS and BPH, respectively, with hospitalizations, and 21 to 38 million hours in lost one study estimating that genetic factors may contribute as productivity in the United States. During the same year, much as 72% to the risk of high moderate or severe LUTS the direct costs of treatment for overactive bladder in men among older men , totaled 1.8 billion dollars, with another 3.9 billion dollarsdirected to ancillary health care expenditures, including Sex Steroid Hormones treatment for urinary tract infections. Estimated annualcosts of BPH treatment currently total 3.9 billion dollars Prostate tissue is composed of two basic elements: a glandular element composed of secretory ducts and acini, The high prevalence of LUTS in the older male and a stromal element composed primarily of collagen and population, its detrimental impact on male health, and the smooth muscle. In BPH, unregulated cellular proliferation substantial costs associated with diagnosis and treatment leads to increased prostate volume and increased stromal underscore the significance of this problem, particularly in smooth muscle tone; increased prostate volume and stromal an era of rapidly increasing male longevity.
smooth muscle tone in turn cause physical compression ofthe urethra and mechanical obstruction of the bladderoutlet. In prostatic secretory cells, the hormone 5-α Risk Factors Associated with Lower Urinary Tract reductase converts testosterone to DHT, a potent stimulator Symptoms and Benign Prostatic Hyperplasia of prostate growth that, in addition to being necessary forprostate development, appears to play a central role in BPH On a population level, there are five broad categories of risk pathogenesis. Multiple studies have explored associations factors for BPH and LUTS (Fig. Aside from age, the of endogenous sex steroid hormones with BPH and LUTS.
other categories are genetics, sex steroid hormones,modifiable lifestyle factors, and inflammation.
At least seven observational studies have reported noassociations and five inverse associations of serum testos- Evidence suggests that there are strong genetic components terone (total, bioavailable, or free) with BPH or LUTS [ to both BPH and LUTS. One case-control analysis, in •, ]. No studies to date have reported an increased risk which participants were men younger than 64 years of age of BPH or LUTS with higher serum testosterone levels. A who underwent surgery for BPH, noted fourfold and sixfold prominent but theoretical concern of testosterone replace- increased age-specific risks of BPH surgery among all male ment therapy is the potential for it to exacerbate BPH and relatives and brothers, respectively, of cases. These inves- LUTS [In this sense, these observations imply thathigher serum testosterone concentrations do not promoteBPH.
Several studies have noted an increased risk of BPH withincreased serum concentrations of DHT and its metabolites.
In one recent prospective study of community-dwellingmen, those with the highest midlife levels of DHT hadnearly three times the risk of subsequent BPH comparedwith those with the lowest levels [].
These results are consistent with those of three prior Fig. 1 Broad categories of epidemiologic risk factors for benignprostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) studies of serum concentrations of two DHT metabolites: Curr Bladder Dysfunct Rep (2010) 5:212–218 17b-diol-glucuronide and androstanediol glucuronide.
increased prevalence of LUTS compared with those with These metabolites are surrogate markers for DHT activity, no components. Other studies have shown that men with with higher concentrations indicating increased and lower heart disease are at significantly increased risk of clinical concentrations indicating decreased levels of DHT. Two BPH and LUTS [– cross-sectional studies and one prospective study haveshown direct associations of these DHT metabolites with BPH or LUTS [, ].
The 5-α reductase inhibitors (finasteride and dutasteride) Prior studies have consistently observed that increased decrease serum concentrations of DHT [and prevent adiposity is positively associated with prostate volume— progression of clinical BPH [However, it is not known that is, the greater the amount of adiposity, the greater the whether finasteride or dutasteride will prevent incident prostate volume. Body weight, body mass index (BMI), and waist circumference all have been positively associatedwith prostate volume in multiple different study populations –]. In the Baltimore Longitudinal Study of Agingcohort, for example, each 1-kg/m2 increase in BMI No clear patterns of estrogen, LUTS, and BPH have yet corresponded to a 0.41-mL increase in prostate volume.
emerged. Prior studies have reported positive, negative, and Moreover, obese (BMI ≥35 kg/m2) participants had a 3.5-fold null associations of endogenous estrogens with BPH and increased risk of prostate enlargement compared with non- obese (BMI <25 kg/m2) participants ]. A preponderanceof published epidemiologic evidence also demonstrates that obesity increases the risks of BPH surgery, urinary symptomprogression, initiation of BPH medical therapy, and LUTS Other sex steroid hormones also have not demonstrated consistent links with LUTS or BPH. One study observed apositive association of DHEAS (dehydroepiandrosterone Diabetes and Disruptions in Glucose Homeostasis sulfate, a primary adrenal androgen with little intrinsicandrogenic activity) with BPH and two inverse associations Disruptions in glucose homeostasis at multiple different with LUTS [].
levels—from alterations in serum insulin growth factorconcentrations to diagnosis of clinical diabetes—are asso- ciated with higher likelihoods of prostate enlargement,BPH, and LUTS. Higher serum concentrations of insulin- A notable development in the epidemiology of BPH and like growth factor-1 and insulin-like growth factor binding LUTS is the recognition that modifiable lifestyle factors protein-3 have been associated with increased risk of substantially influence the natural history of these clinical BPH and BPH surgery ]. Physician-diagnosed conditions. Accumulating data intimate that many of the diabetes, increased serum insulin, and elevated fasting same metabolic disturbances associated with cardiovas- plasma glucose have been associated with increased cular disease—and the lifestyle factors that modulate prostate size and increased risks of prostate enlargement, these disturbances—influence the risk of BPH and clinical BPH, BPH surgery, and LUTS in multiple different LUTS. These observations are important because they cohorts cumulatively incorporating tens of thousands of suggest the existence of modifiable pathways for BPH and LUTS that may present novel targets for preventionand treatment.
The Metabolic Syndrome and Cardiovascular Disease Relatively few data are available on potential associationsof lipids (high-density lipoprotein, low-density lipoprotein, The metabolic syndrome is a clinical constellation of and triglycerides) with BPH and LUTS. At least five metabolic abnormalities—obesity, glucose intolerance, studies have been conducted, with three showing positive dyslipidemia, and hypertension—that increases the risk of and two showing null associations [, ].
cardiovascular disease and results primarily from dietaryand other lifestyle practices endemic to Westernized societies ].
In one cohort, men diagnosed with at least three There are some indications that macronutrients and components of the metabolic syndrome had an 80% micronutrients may affect the risk of BPH and LUTS, Curr Bladder Dysfunct Rep (2010) 5:212–218 although the patterns are somewhat inconsistent. For BPH represents a nonmalignant pathway of unregulated macronutrients, increased total energy intake, energy- prostate growth promoted by oxidative stress, inflamma- adjusted total protein intake, red meat, fat, milk and dairy tory mediators, and insulin growth pathways.
products, cereals, bread, poultry, and starch potentially There are strong links between BPH and histologic increase the risks of clinical BPH and BPH surgery; inflammation in surgical specimens, with the extent and vegetables, fruits, polyunsaturated fatty acids, linoleic severity of the inflammation corresponding to the magni- acid, and vitamin D potentially decrease the risks of BPH tude of prostate enlargement and BPH area –Men and LUTS [, ]. With respect to micronutrients, with LUTS are more likely to have higher serum C-reactive higher circulating concentrations of vitamin E, lycopene, protein, a robust marker of systemic inflammation [ selenium, and carotene have been inversely associated while prior gonorrheal infection or prostatitis increase the with BPH and LUTS [•, ]; zinc has been likelihood of BPH surgery and LUTS [A history of associated with increased and decreased risk , infection with gonorrhea, chlamydia, or trichomonosisincreases the risk of elevated prostate-specific antigen Physical Activity ]; high serum IgG antibody titers to cytomegalovirus,herpes virus, human papilloma virus, and hepatitis are Increased physical activity and exercise have been associated with LUTS ].
robustly and consistently linked with decreased risks of Conversely, inhibition of inflammatory pathways poten- BPH surgery, clinical BPH, histologic BPH, and LUTS tially attenuates BPH risk. In one community cohort, men . A meta-analysis of 11 published studies (n = who reported daily NSAID use experienced significantly 43,083 men) indicated that moderate to vigorous physical decreased risks of LUTS, low urinary flow rate, increased activity reduced the risk of BPH or LUTS by as much as prostate volume, and elevated prostate-specific antigen 25% relative to a sedentary lifestyle, with the magnitude of the protective effect increasing with higher levels ofactivity [].
In summary, BPH and LUTS are of significant impor- Like exercise, moderate alcohol intake also appears to be tance to public health, affecting millions of older men protective against multiple outcomes related to BPH [].
and contributing to billions of dollars in health care cost However, unlike exercise, the same protective effect does each year. Current disease trends in the United States not appear to apply to LUTS. A meta-analysis of 19 suggest that the number of men suffering from these published studies (n = 120,091 men) observed up to a 35% conditions will swell markedly in the very near future.
decreased likelihood of BPH among men who drank daily, The rapid aging of the US population, coupled with the but an increased risk of LUTS [].
obesity and diabetes epidemics is poised to substantiallyincrease the prevalence of BPH and LUTS within the general population and place even greater burdens onfinite health care resources. Although the relatively Although several studies support the existence of an immutable consequences of age and genetics factor inverse protective effect of smoking on the risk of BPH substantially in the development of BPH and LUTS, and LUTS, several others have reported no risk or many modifiable variables contribute as well—factors increased risk [Thus, no definitive conclusions can that may be manipulated to delay onset, prevent be drawn at this time.
progression, or attenuate symptoms. Potential strategiesinclude inhibition of DHT synthesis with 5-α reductase inhibitors, modulation of metabolic risk factors withcomprehensive lifestyle interventions incorporating diet Most observational studies suggest that inflammation is change and physical activity, and suppression of inflam- intimately linked to the development of BPH and LUTS.
matory pathways with NSAIDs.
The mechanisms underpinning this relationship areunclear. One potential explanation is that the metabolic Dr. Parsons has received grant funding from the syndrome, which promotes systemic inflammation and National Institutes of Health.
oxidative stress, mediates the connection between them Dr. Parsons has served as a consultant for American Medical [Inflammation has been implicated as a primary Systems and the University of California Physician Enhancement stimulus for prostate carcinogenesis, and it is possible that Curr Bladder Dysfunct Rep (2010) 5:212–218 This article is distributed under the terms of the 18. Rohrmann S, Fallin MD, Page WF, et al.: Concordance rates and Creative Commons Attribution Noncommercial License which per- modifiable risk factors for lower urinary tract symptoms in twins.
mits any noncommercial use, distribution, and reproduction in any Epidemiology 2006, 17:419–427.
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The Right to Parenthood An Argument for a Narrow Interpretation1 ABSTRACTThe paper argues for two kinds of limitations on the right to parenthood. First, it claims that the right to parenthooddoes not entail a right to have as many children as one desires. This conclusion follows from the standard justificationsfor the right to parenthood, none of which establishes the need to grant special protection to having as many childrenas one desires. Second, with respect to the right to receive assistance from the state in IVF, it is suggested that the stateshould also be allowed to take non-medical considerations into account in determining whether or not an applicant isentitled to this service, particularly in cases where the applicant seems to lack mothering ability.

Mcr-13-0239 1279.129

Signal Transduction Minocycline Targets the NF-kB Nexus through Suppressionof TGF-b1-TAK1-IkB Signaling in Ovarian Cancer Parvin Ataie-Kachoie1, Samina Badar1,2, David L. Morris1,2, and Mohammad H. Pourgholami2 Substantial evidence supports the critical role of NF-kB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes thatoverlap significantly with the NF-kB transcriptome. Here, it was examined whether or not the molecularmechanism could be attributed to modulation of NF-kB signaling using a combination of in vitro and in vivomodels. Minocycline suppressed constitutive NF-kB activation in OVCAR-3 and SKOV-3 ovarian carci-noma cells and was correlated with attenuation of IkBa kinase (IKK) activation, IkBa phosphorylation anddegradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to beassociated with suppression of TGF-b-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-b and TAK1. Further studiesdemonstrated that minocycline downregulated TGF-b1 expression. Enforced TGF-b1 expression inducedNF-kB activity, and minocycline rescued this effect. Consistent with this finding, TGF-b1 knockdownsuppressed NF-kB activation and abrogated the inhibitory effect of minocycline on this transcription factor.These results suggest that the minocycline-induced suppression of NF-kB activity is mediated, in part,through inhibition of TGF-b1. Furthermore, the influence of minocycline on NF-kB pathway activation wasexamined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronicadministration of minocycline led to suppression of p65 phosphorylation and nuclear translocationaccompanied by downregulation of NF-kB activity and endogenous protein levels of its target gene products.These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-b–NF-kB axis in ovarian cancer.

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