Lower urinary tract symptoms (LUTS) are very common in both sexes, especially in aged population and negatively affect health-related quality of life of afflicted individuals. The prevalence of benign prostatic hyperplasia is strongly related to age, ranging from 8% in men in their 50s to roughly 90% in men older than 80 years. The prevalence of LUTS/BPE depends on the age of the patients. In fact the disease is present in about 8% of men between 31 and 40 years old, and it reaches 90% within 90 years old. Moreover, the presence of LUTS is also associated with more complications like acute urine retention, showing 6.8 episodes per 1000 patients per year in the general population, reaching 34.7 episodes in patients over 70s. The odds of developing moderate to severe LUTS also increased gradually after age 50 and were 3.5 and 2.4 times more frequent in men with a prostate volume greater than 50 mL and less than 50 mL, respectively. The exact etiology of LUTS/BPE is not entirely known. Among several risk factors, metabolic syndrome, diabetes mellitus, obesity, race, and cardiovascular disease represent the most important.
KeywordsBenign prostatic hyperplasia, LUTS, Age, Risk factors, Metabolic syndrome
Lower urinary tract symptoms (LUTS) are very common in both sexes, especially in aged population and negatively affect health-related quality of life (QOL) of afflicted individuals. They are also associated with high-health care costs. The etiology is multifactorial. One of the most important causes of LUTS in men is benign prostatic hyperplasia (BPH). BPH is a histological diagnosis defined by the presence of abnormal proliferation of smooth muscle and epithelial cells in prostatic tissues that clinically translates into benign prostatic enlargement (BPE) or obstruction (BPO). Left untreated, serious complications can occur in men with BPH, including acute urinary retention (AUR), renal insufficiency and failure, urinary tract infection, and bladder stones. The prevalence of BPH is strongly related to age, ranging from 8% in men in their 50s to roughly 90% in men older than 80 years [ ]. Although aging represents the strongest risk factor for this, chronic progressive disease, obesity, and metabolic syndrome (MS) have been recently shown to be associated with an increased risk of BPH. Not all men with histologic BPH develop LUTS that requires intervention. Several population-based studies evaluated the prevalence of LUTS using validated questionnaires. Particularly the International Prostate Symptoms Score (IPSS) questionnaire is a useful tool to stratify patients according to symptom severity of seven common LUTS. Indeed, patients can be classified in those with no or mild (IPSS ≤ 7), moderate (IPSS from 8 to 20), and greater-severe symptoms (IPSS ≥ 21). It is very difficult to compare different studies about LUTS, due to the varying disease definitions and assessment methods used (e.g., mail and telephone surveys, face to face interview). In addition, IPSS lacks questions on incontinence and pain that are reported in several subjects affected by LUTS. The impact of BPH on QOL can be significant and should not be underestimated. A self-administered questionnaire completed by 117 patients reported sleep, anxiety/worry over the condition, mobility, leisure, activities of daily living, and, to a larger extent, the effect on sexual activities as the most important concerns among patients with prostate symptoms (IPSS > 7) [ ]. The impact of BPH-associated LUTS has also been studied in a community-based population in the United Kingdom. A total of 1500 individuals aged 50 years or older were assessed for BPH symptoms and their impact on QOL using a self-administered survey. Moderate-to-severe LUTS was seen in 41% of the patients (as assessed by an IPSS of 8). Respondents experienced decrements in both QOL and health status as symptomatic severity increased, with most men experiencing problems with ability, self-care, activities of daily living, pain or discomfort, and anxiety or depression. Despite the high prevalence of LUTS reported in this survey, only 11% were aware of the pharmacologic or surgical interventions available to treat BPH; watchful waiting was the most common primary treatment (34%). The findings of this study underscore the need for better education about BPH and its treatments [ ]. In a Japanese study, nocturia twice at night doubled the risk of fractures and mortality [ ]. Its association with daytime fatigue, reduced work productivity, and reduced vitality is also recognized [ ].
During past years, many authors studied the prevalence of seven symptoms by IPSS. These studies report many differences in prevalence, from 47% to 49%. In 1997 the International Continence Society (ICS) assessed the bothersomeness of LUTS in 1271 male patients presenting at urology clinics in 12 countries by administering a questionnaire. This study showed that voiding symptoms are more common (90%–94%) than storage symptoms (66%–71%), but that the latter are the most bothersome. It also established that a postmicturition symptom, terminal dribble, is the most common symptom of all (prevalence: 96%) [ ]. Several studies confirmed a significant increase in prevalence with advancing age for both individuals LUTS and for the total LUTS reported by men. LUTS often appear in clusters. Overactive bladder (OAB) is a common symptom cluster. The ICS defines OAB as urinary urgency, with or without urinary incontinence, usually with frequency and nocturia [ ]. Most studies investigated OAB and reported a general prevalence of 10%–25% in men [ , ]. The longest follow-up study of the prevalence of symptoms has shown a significant increase in LUTS over an 11-year period with a mean annual incidence of 3.7% for OAB and 0.8% for incontinence. The prevalence of OAB increases with age, especially in the sixth and seventh decade of life. A pooled analysis of 126 studies has shown an increase in urinary incontinence prevalence with age from 21% to 32% for elderly men. The prevalence of daily urinary incontinence in this analysis was reported at 9% [ ]. Many publications focused specifically on the prevalence of urinary incontinence among community dwelling men; 11% of men over the age of 40 had experienced an incontinent episode during the prior year, and daily UI may be as high as 9% among men over the age of 60. The prevalence is near to 32% over 80 years [ ].
An estimated 15 million men in the United States over the age of 30 years are affected by BPH/LUTS [ ]. Large variations in existing prevalence rates are reported due to differences in BPH/LUTS definitions, assessment methods, and geographic regions. BPH/LUTS prevalence estimates also vary by age [ ]. Among men over the age of 50 years, 50%–75% experience BPH/LUTS [ , ]. For the majority of these men, without treatment, voiding and storage symptoms will significantly worsen with increasing age and time. Among men over the age of 70 years, 80% on average are impacted by BPH/LUTS. Prostate enlargement, peak flow rate, and LUTS have all been shown to be age-dependent conditions and are conditions that play a substantial role in BPH/LUTS development among aging men [ ]. Urinary symptoms of urgency, nocturia, weak stream, intermittency, and incomplete emptying are the most strongly correlated with age, and prevalence estimates rise to as high as 88%–90% by 81 years of age or greater [ , ].
The BPH Registry and Patient Survey, a prospective observational disease registry documenting BPH/LUTS practices and patient outcomes among 6909 men in the United States, reported that 33% of men had mild LUTS; 52% of men had moderate LUTS, and 15% of men had severe LUTS. The average IPSS at baseline was 11.6 (range 0–35) [ ]. In France 67% of men scored IPSS < 8, 13% scored IPSS < 19, and 1.2% scored IPSS > 19 [ ]. Another study supported these results. Among only men aged 40–49 years, these prevalence estimates for mild, moderate, and severe symptoms were 89%, 9%, and 2%, respectively. This increased to 55% with mild, 37% with moderate, and 8% with severe LUTS among men over the age of 70 years [ ]. Approximately 10% of men < 30 years old, 20% of men 30–40 years old, 50%–60% of men 40–60 years old, and greater than 80% of men 80 or more years old have enlarged prostates [ ]. Prostate volume generally increases with age. Men with significant prostate enlargement (> 50 cm 3 ) are 3.5 times more likely to have age-adjusted moderate-to-severe LUTS than men without prostate enlargement. About incidence of BPH/LUTS four longitudinal cohort studies are very important: The Prostate Cancer Prevention Trial, The Olmstead County study, The Health Professionals Follow-up Study, and a database review in the Netherlands. The Prostate Cancer Prevention Trial included 5667 men over the age of 55 years and reported the incidence of BPH to be 34.4 cases per 1000 person-years [ ]. The Olmstead County study, which identified men living in Olmstead County, Minnesota, review between 1987 and 1997, estimated the overall incidence of BPH to be 8.54 cases per 1000 men [ ]. The Health Professionals Follow-up Study followed 9628 men with moderate-to-severe LUTS (IPSS < 14) and 2557 men with severe LUTS (IPSS < 20) from LUTS onset for an average of 12.7 years to assess LUTS incidence and progression rates. Incidence rates of moderate and severe LUTS were 41 and 19 cases per 1000 person-years, respectively [ ]. Verhamme et al. [ ] utilized a longitudinal observational database in the Netherlands to assess incidence rates of BPH/LUTS among men over the age of 45 years who had at least 6 months of patient follow-up and reported the incidence of BPH/LUTS to be 15 cases per 1000 person-years of follow-up. The four studies with overall estimates mentioned previously also reported incidence rates by age and/or severity. The Prostate Cancer Prevention Trial reported that for every 1 year increase in patient age, the incidence of BPH increased by 4%. This corresponds to reports that an estimated 45% of urinary symptom-free men over the age of 45 will develop BPH/LUTS before the age of 75. The Health Professionals Follow-up Study reported increases in both moderate and severe LUTS incidence rates with increasing patient age. Verhamme and colleagues reported the incidence of BPH to linearly increase by an average of 6.15 cases per 1000 man-years for every 5-year increase in age increment between 45 and 79 years of age. This increase was from 3 cases per 1000 man-years at age 45–49 to 38 cases per 1000 man-years at age 75–79 years.
The EPIC survey was a population-based, cross-sectional, computer-assisted telephone survey conducted in five countries (Canada, Germany, Italy, Sweden, and the United Kingdom) [ ]. A total of 19,165 men and women agreed to participate (33%) of the general population in the five countries. This study performed in 2005 established that the prevalence of LUTS is similar in the two genders: 62.5% of men and 66.6% of women. Storage symptoms were less common in men than in women (51.3% vs. 59.2%), whereas the opposite was true for voiding symptoms (25.7% in men vs. 19.5% in women). Nocturia was the common storage symptom, 48.6% of men and 54.5% of women reported one episode per night, and 20.9% of men and 24% of women reported two episodes per night. Terminal dribble, classified as a voiding symptom, was reported by 14.2% of men and 9.9% of women. The prevalence of the various symptoms was similar among countries, with a few exceptions, such as more common terminal dribble in both men and women in Italy. It found also that ~ 11% of men and 13% of women in four European countries and in Canada reported OAB symptoms. Furthermore the prevalence of both urge urinary incontinence (UUI) and stress urinary incontinence (SUI) is higher in women compared with men (UUI: 13.1% vs. 4.5%; SUI 14.8% vs. 0.4%) [ ]. Similar prevalence of LUTS in men and women also was reported in The Boston Area Community Health (BACH) Survey [ ]. It studied a sample 5506 adults aged 30–79 from the city of Boston (2301 men, 3205 women, 1770 blacks, 1877 Hispanics, and 1859 whites) that assessed the prevalence of LUTS, defined as an American Urological Association symptom index (AUA-SI) > 8 in adults of both genders. The study established that the overall prevalence of LUTS was 18.7% and did not differ by sex or race/ethnicity. The prevalence increased with age from 10.5% in the fourth decade up to 26.5% in the seventh decade. Age trends were similar by sex until age 60 but the course of the increase differed in the two genders; there was a notable increase in the seventh decade in men that was not seen in women. The mean storage score was worse in women, whereas the mean voiding score in men. About voiding and storage symptoms separately, the BACH survey shows that mean voiding scores are significantly higher in men compared with women (1.53 and 1.28, respectively; P = .04), whereas the mean storage score is higher among women compared with men (3.21 vs. 2.56; P < .001). Both mean voiding score and mean storage score increased with age ( P < .001 for both).
The EpiLUTS study [ ] was a population-based, cross-sectional, Internet survey conducted in men and women > 40 year of age in the United States, the United Kingdom, and Sweden. A total of 30,000 subjects took part in the survey: 20,000 in the United States (participation rate: 59.6%), 7500 in the United Kingdom (participation rate: 60.6%), and 2500 in Sweden (participation rate: 52.3%). The main objective of the survey was to establish the prevalence of LUTS and to explore the association of LUTS with comorbid conditions. The prevalence of LUTS was defined by two symptom frequency thresholds: “at least sometimes,” which resulted in a prevalence of 72.3% in men and of 76.3% in women, and “at least often,” which resulted in a prevalence of 47.9% in men and of 52.5% in women. Once again, storage symptoms were more common in women; for example, nocturia defined as one episode per night was reported by 75.8% women and 69.4% men, and nocturia defined as two or more episodes per night was reported by 33.7% of women and 28.5% of men. Urgency was reported by 35.7% of women and 22.4% of men. Once again, terminal dribble was common (45.5% in men and 38.3% in women). Postmicturition symptoms were quite common. Incomplete emptying occurred in 22.7% of men and 27.4% of women, and postmicturition incontinence occurred in 29.7% of men and 14.9% of women. Multiple associations with chronic comorbidities were found also in the EpiLUTS survey [ ]. The triple combination of voiding, storage, and postmicturition symptoms was associated in both genders with arthritis, asthma, chronic anxiety, depression, heart disease, irritable bowel syndrome, neurologic conditions, recurrent urinary tract infection, and sleep disorders; in men, it was also associated with diabetes. It has been suggested that the association with heart disease, hypertension, and sexual disorders may be due to the presence of MS and that inflammation may be the common factor linking LUTS to diabetes, depression, arthritis, and prostatitis. The findings of the main epidemiologic studies show that the prevalence of LUTS does not differ by gender or race, but voiding symptoms are more common in men and storage symptoms are more common in women. Prevalence differs according to the definition used: 72.3% of men and 76.3% of women experience at least one symptom occasionally, but only 18.7% of adults have an AUA-SI score < 8. LUTS are associated with chronic diseases.
Economic Impact of BPH and LUTS
The high prevalence of BPH determines important health-care system and social costs. Indeed, the economic burden of BPH is related to direct medical costs related to diagnosis and treatment, indirect costs associated with lost work time, and intangible costs associated with reduced QOL. It has been estimated that the direct costs of medical services to diagnose and treat BPH in the United States were ~ 4 billion of USD annually [ ]. Moreover, as previously reported, BPH affects up to 50% of men in their working age. In this population, BPH-related periods of disabilities, diagnosis, and treatment procedures have been estimated to be responsible of up to 38 million hours of lost productivity [ ]. From an economic point of view, these data are crucial. Indeed, since the prevalence of BPH and LUTS increases with aging, the economic and social burden of BPH is only likely to increase in the future [ ]. The diagnosis and treatment of BPH represents the largest segment of urologic practice, representing 23% of all office visits. An analysis of BPH market reveals that 12.2 million BPH patients are managed each year, and the 54% of these are treated with medication, 35% are observed, and 1.1% are treated surgically [ ]. It is reasonable to expect that the economic costs of BPH treatment will only increase in the future, considering the aging of population.
Risk Factors for BPH Development
Analytical epidemiological studies have been undertaken to evaluate risk factors for the development of BPH. Studies by Lytton et al [ ] and Glynn et al. [ ] reported an association between the Jewish religion and higher rate of prostate surgery. However it is unclear whether these studies represent selection bias, as this patient population may seek medical care more often than others. Araki et al. [ ] and Glynn et al. found higher rates of BPH in upper income groups, but again this may be due to selection bias due to higher utilization of medical care.
As previously reported, the most well-reported risk factor found to be associated with the development of LUTS and BPH is age. So older men are at higher risk of experiencing BPH progression, such as deterioration of LUTS, decreased peak flow rate, increased prostate volume, AUR, and BPH-related surgery. The pioneering autopsy study by Berry et al. clearly showed this fact. Particularly, it has been shown that no men younger than 30 had BPH. However, the prevalence of BPH increased from 8% to 50% in individuals in their 40s and 50s, respectively. Men older than 80 years had the highest prevalence of BPH (roughly 90%) [ ]. The Baltimore Longitudinal Study suggests an increasing of prostate volume of 2.0%–2.5% per year in older men [ ]. In the Olmsted County study [ ], the prevalence of moderate to severe LUTS ranged from 26% to 46% in men aged 40–49 and 70–79 years, respectively, with a mean increase in the IPSS estimated in 0.18 points per year. Accordingly, a consistent decline in peak urinary flow rate was also observed. AUR showed an increase in the incidence from 1% in individuals aged 40–49 years to 9% among those 70–79 years old [ ]. Also the need for surgical treatment for BPH has been shown to be strongly age related (from 0.1% to 9.5% in individuals aged 40–49 years and in those 70–79 years old, respectively) [ ]. Similarly, among men enrolled in the placebo arm of the Medical Therapy of Prostatic Symptoms study (MTOPS), the need for BPH-related surgery increased with aging [ ].
Evidence suggests a strong genetic component to BPH. A case control study analyzed men < 64 years underwent BPH surgery showed that male parents and brothers had a fourfold and sixfold increase, respectively, of age-specific risks for BPH surgery. This study estimated that 50% of men < 60 years, undergoing surgery for BPH, had a heritable form of disease [ ]. It also observed that heritable disease was associated with larger prostate volume and younger age of onset. These findings suggest an autosomal pattern of inheritance. Data showed monozygotic twin concordance rates of 26% and a strong association in sex hormone metabolism with risks of enlarged prostate and BPH treatment [ ].
Sex Steroid Hormones
Testosterone is converted to dihydrotestosterone (DHT) in prostatic secretory cells by 5-alpha reductase enzyme. Several studies showed an increased serum concentration of DHT and its metabolism. The risk to develop BPH is nearly three times with the highest midlife of DHT, compared with those with lowest levels of DHT [ ]. A Taiwanese study shows a sevenfold increased risk of prostate enlargement in subject with the highest DHT serum concentration [ ].
The MS is characterized by the simultaneous presence of a number of risk factors for heart disease, including abdominal obesity, proatherosclerotic dyslipidemia, high-blood pressure, insulin resistance or glucose intolerance, and a prothrombotic and proinflammatory state in the blood. The prevalence of MS is believed to be on the order of 50 million individuals in the United States [ ]. Several studies showed the link between MS and BPH. Recent results from NHANES III also indicate that serum C-reactive protein level, a feature of MS, may be associated with intraprostatic inflammation in BPH [ ]. Russo et al. showed a link between MS and BPH due to severity of inflammation, typically present in this kind of pathology [ ].
Cardiovascular (CV) disease, including coronary artery disease and stroke, accounts for 25%–55% of deaths worldwide [ ]. Hypertension is a well-established risk factor for CV disease, and like BPH, the prevalence of hypertension increases with age. Although BPH and hypertension appear to involve separate disease processes, it has been postulated that age-related increases in sympathetic tone may play a role in their pathophysiology. Studies from both the United States (Third National Health and Nutrition Examination Survey [NHANES III]) and the United Kingdom suggest that about 50%–65% of people over the age of 60 years are hypertensive and ~ 25% of men 60 years and older have BPH with comorbid hypertension. It is important, therefore, for urologists and cardiologists to recognize the frequent coexistence of these conditions and to consider hypertension and BPH in patients 60 years or older when deciding on a course of treatment [ ]. A retrospective study evaluated BPH symptom severity and blood pressure in more than 9800 patients who had BPH. The authors observed an increase of 0.13 points and 1.60 points in IPSS with each year of age and measured incidence of hypertension, respectively. Similarly, in the logistic regression analysis, the risk of hypertension was increased by 5.3% and 5.0% with each year of age and each IPSS point. Findings of this study are consistent with a possible pathophysiologic relationship between BPH and hypertension, which may be related to increased sympathetic activity in the aging man [ ].
Several studies showed that increasing the adiposity is positively associated with greater prostate volume. In agreement body weight, body mass index (BMI), and waist circumference have all been positively associated in multiple different study populations. In Baltimore Longitudinal Study of aging, each 1 kg/m 2 increase in BMI corresponded to 0.41 mL increase in prostate volume. Furthermore obese participants (BMI > 35 Kg/m) had a 3.5-fold increased risk of prostate enlargement compared to nonobese (BMI < 25 Kg/m) participants. Data also showed the increasing risk of AUR, initiation of BPH medical therapy, urinary symptom progression, and BPH surgery in obese participants [ ].
Diabetes and Alterations in Glucose Homeostasis
Alterations in glucose homeostasis are associated with higher likelihoods of prostate enlargement and BPH. Higher serum concentrations of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) have been associated with an increased risk of clinical BPH and BPH surgery. Several studies showed the increasing prostate size, BPH surgery, and clinical BPH in patients affected by diabetes, increased serum insulin, and elevating fasting glucose plasma [ ].
However, evidence is scarce and conflicting regarding their role in prostatic enlargement, and their impact on BPH and LUTS is still poorly understood. Conversely, the relationship between BPH and obesity, MS, and BMI has been widely assessed. Patients with BMI ≥ 35 kg/m 2 had higher risk of harboring large prostate volume (> 40 mL) and of developing LUTS (IPSS ≥ 15) compared to those with BMI < 25 kg/m 2 [ ]. Moreover, men with an obese waist circumference (> 109 cm) were at higher risk of being surgically treated for BPH as compared to not obese individuals. In this context, MS, diabetes, and hypertension might predispose patients to BPH and/or LUTS [ ]. From a clinical point of view, these data clearly indicate that modification of lifestyle and physical activity may be of benefit to treat or prevent LUTS. There are some indications that both macronutrients and micronutrients may affect the risk of BPH, although the patterns are somewhat inconsistent. For macronutrients, increased total energy intake, energy-adjusted total intake, red meat, fat, milk, cereals, bread, poultry, and starch all potentially increase the risks of clinical BPH and BPH surgery, while vegetables fruits, polyunsaturated fatty acid, linoleic acid, and vitamin D potentially decrease the risk of BPH. About micronutrients vitamin E, Selenium, and carotene have been inversely associated with BPH [ , ].
Increased physical activity and exercise have been robustly and consistently linked to decreased risks of BPH surgery, clinical BPH, histological BPH, and LUTS [ , ]. A metaanalysis of 11 studies (43,083 patients) indicates that moderate to vigorous physical activity reduced the risk of BPH by as much as 25% relative to a sedentary lifestyle, with the magnitude of the protective effect increasing with higher levels of activity [ ].
Moderate alcohol intake has a protective function against BPH. A metaanalysis of 19 studies (120,091 patients) showed up to 35% decreased likelihood of BPH among who drank daily [ ].
One review notes that while several studies support the existence of an inverse, protective effect of smoking on the risk of BPH, several others have reported either no or increased risk [ ]. Thus, no definitive conclusions may be drawn at this time.
Many studies showed that inflammation is linked to the development of BPH and prostate cancer. In this sense, MS promotes systemic inflammation and oxidative stress and mediates the connection of both [ ]. Oxidative stress, inflammatory mediators, and insulin growth pathway promote prostate growth in both conditions. Also infections such as gonorrhea, chlamydia, or trichomonas increase the risk of elevated prostate-specific antigene (PSA) and prostate enlargement. Inhibition of inflammation may potentially attenuate the BPH risk. In the Olmested County cohort, men who taken statin or nonsteroidal antiinflammatory drugs had significantly decreased risks of LUTS and BPH [ ].
Instead other studies do not show similar results [ ].
As concerning the influence of race on BPH severity, unfortunately there are no sufficient data about this association. Several studies showed an increase of prostate transition zone and total volume for US black men compared with white men. The PLCO study observed no differences in clinical BPH between black and white subjects. Some data suggested a decreased risk of clinical BPH in Asian compared with white men. BPH/LUTS prevalence estimates are infrequently reported by race/ethnicity. Many studies have primarily racially homogenous populations and are, therefore, unable to draw conclusions on racial or ethnic differences in disease prevalence. However, there are a few published articles of heterogeneous populations that are able to assess this difference, and these studies tend to indicate that the prevalence of BPH/LUTS may vary by race/ethnicity. The Prostate Cancer Prevention Trial reported the highest prevalence of BPH to be among Hispanic men, followed by black, white, and Asian men [ ]. This mirrored the results of the California Men’s Health Study and the Research Program in Genes, Environment and Health, which reported the highest prevalence of LUTS among Hispanic men, followed by black, white, and Asian men [ ]. Additionally, black men had an estimated moderate-to-severe LUTS prevalence of 39.6% in the Flint Men’s Health Study [ ]. Other studies reported that Japanese, Chinese, and Indian men have significantly lower prostate volumes than Australian or American men, which could contribute to BPH/LUTS prevalence differences [ , ].