INTRODUCTION

Benign prostatic hyperplasia (BPH) or enlarged prostate refers to changes in the prostate that involve an overgrowth of cells (hyperplasia), which results in nodules that enlarge the gland. It is a disorder that afflicts only humans and dogs. The term benign in this context means no cancer, although general usage, according to the Oxford Dictionary, benign describes a gentle, mild or kindly condition. BPH frequently causes problems that are far from gentle or mild and in fact can be responsible for a number of Lower Urinary Tract Symptoms (LUTS) that range from merely bothersome to critical emergency situations involving urinary blockage. In simple terms, the urinary problems arise from the tissue of the enlarged prostate pressing against the urethra and limiting or even completely cutting off the flow. But what is taking place as BPH develops is somewhat more complex. First the bladder tries to overcome the flow restriction by building more muscle, which over time thickens the bladder wall that influences its capacity to expand and store urine. The result is more frequent urination. Eventually the bladder becomes worn out and weak, a condition known as bladder decompensation [1]. Symptoms now include increased urinary urge and frequency, decreased voiding volume and flow rate, nocturia (frequent need to urinate at night), post-voiding dribbling and urine retention. This is an important concern for men as they age because the disorder is highly prevalent and its incidence and severity generally increases with age, ultimately requiring surgery or other invasive interventions in a significant number of older individuals. BPH also has a negative psychological impact associated with worry over urinary symptoms, prostate cancer, and the possibility of total blockage [2]. Preventing or slowing its progression so as to avoid surgery is thus a topic of great interest.

Recorded accounts of men's urinary problems can be traced back to the fifteenth century BC. Hippocrates (fifth century BC) described the urinary obstruction as a condition with poor prognosis and no hope for permanent relief. No significant progress in treating BPH occurred prior to the twentieth century [3]. In Victorian times men with severe urinary symptoms were known to carry catheters in hollow shafts of their walking sticks or umbrellas in order to be able to quickly deal with what has become known as Acute Urinary Retention (AUR). Even some cowboys were said to carry catheters in their hats [3]. By the turn of the last century surgical techniques were being used to open the urinary channel but these procedures were crude compared to modern invasive therapy, and no doubt accompanied by a high incidence of morbidity since postoperative infections were common in that era. As will be discussed below, rapid and significant progress has been made in the last few decades with regard to both surgical and non-surgical treatments of BPH. Much of what has been learned regarding the natural history of this disease has in fact come from the placebo arm of drug intervention studies which allowed the close observation of untreated individuals over a number of years.

BPH is a highly prevalent disease. According to autopsy studies tissue evidence of BPH is present in 20% of men age forty, 60% of age 60 and 90% of men in their 80s [4], although some studies find lower percentages [5]. Disease progression appears to slow after age of 80 [6]. The severity of the problem can be judged by the observation [1] that in about 25% of all men, BPH causes urinary symptoms that are sufficiently disturbing to seek medical advice. In a recent study it was found that there is a 45% risk of developing LUTS/BPH in a symptom-free 45 year-old man over a period of 30 years [7]. It is estimated that by 2020 over 11 million American men each year will require treatment for the symptoms of BPH and the annual cost just in the US now exceeds $8 billion [8]. An aging population is driving a rapid increase in prevalence and underlines the importance of the challenge to diagnose the disease and slow its progression at an early stage and prevent or postpone the situation where surgical intervention is required.

CAUSES OF BPH

It is a commonly held view that BPH is in part a hormone dependent disease, but the details remain unclear. In fact, the etiology of BPH is not well understood and appears multifactorial [1]. Prostate growth occurs during childhood development, but the size of the prostate remains relatively stable from puberty to middle age, after which the growth frequently resumes. Men castrated before puberty never develop BPH. Three hormones (the so-called sex steroids), testosterone (T), dihydrotestosterone (DHT) and the estrogen hormone estradiol (E2) are thought to play a role in the etiology of BPH [9]. Both T and DHT are so-called androgens which are hormones that stimulate the activity of male sex organs or control the development of male sex characteristics. All three of these hormones appear to be involved in cell growth within the prostate. Testosterone is converted into the more powerful and active form DHT by the action of the enzyme 5-a-reductase (there are actually two enzyme isoforms). Individuals lacking this enzyme fail to develop male sexual characteristics including a normal prostate gland, an observation which has focused attention on DHT, as has the success of the 5-a-reductase inhibitors in reducing prostate size and improving symptoms. However, studies to date seem merely to underscore the complexity of the relationship of the androgens and estrogen to the etiology of BPH.

Neuhouser et al [10] recently reviewed six studies examining the connection between serum steroid hormones with BPH. The results from these studies failed to present a clear or consistent picture of a relationship with comparisons between the lowest and highest quintiles generally not achieving statistical significance. However, one result was of statistical significance—a 3-fold increase in BPH risk for men in the highest vs. the lowest quintile of serum estradiol concentration. Unfortunately, serum levels are not directly correlatable to prostate tissue levels.

Shibata et al [9] found from prostate tissue analysis as a function of increasing age that intraprostatic DHT decreased with age. Intraprostatic tissue levels of T and E2 tissue levels remained constant. However, Walsh et al earlier found no decrease of DHT prostate tissue levels with age, merely a large scatter of results, and in addition, they found that the DHT levels were the same in BPH and non-BPH tissue [11]. The BPH model of Shibata et al involves the decreasing DHT and constant E2 tissue levels producing a "relatively estrogen- dominant status" which induces cell proliferation by some mechanism and thus yields BPH. In a recent study Roberts et al [12] found that in older men, there is an association between serum E2 and surrogate measures of BPH that depend on serum levels of bioavailable T. Among men with serum bioavailable T at levels above the median, E2 levels had a dose dependent positive relationship with prostate size. They point out, however, that while androgens and estrogens may act synergistically in BPH as it relates to prostate size, the precise mechanisms that underlie their effects on the maximum flow rate and other symptoms are neither simple nor clear.

Studies that implicate estradiol in the etiology of BPH have stimulated interest in intervening with aromatase enzyme inhibition which decreases the production of E2. The results have been reviewed by Sciarra and Toscano [13]. The drug Atamestane was used in both an open label and randomized, controlled studies. This drug has demonstrated ability to dramatically reduce estradiol levels (40-60%). No improvement in obstructive symptoms was found in one open label and two randomized trials. A possible explanation is that the estrogen reduction is counterbalanced by the observed parallel increase in T and DHT.

This short summary of the hormone connection underscores the present uncertain state of knowledge, the probable complexity of the hormone related mechanisms, and the need for additional research, especially studies that examine the complex biochemistry in the prostate itself rather than attempting to make associations with serum levels. However, this in no way decreases the importance of the observation that 5-a-reductase inhibitors decrease the prostate volume and have beneficial effects on the symptoms of BPH. Finally, as will be discussed below, there is evidence that a damaged prostate vascular system may play an important role in the development of BPH [14].

POSITIVE AND NEGATIVE RISK FACTORS FOR BPH

In this context, reduction of risk is akin to protective or preventive intervention. Risk factors over which one has no control include ethnic background, age and family history. Studies conducted in a number of countries find a high prevalence of moderate to severe urinary problems and while the absolute prevalence varies widely among countries, there are remarkably consistent age-related increases found in prostate volume at autopsy [5]. Based on data collected in the US, a recent study found that Asian men had the lowest risks for nocturia, physician-diagnosed BPH and surgical treatment for severe BPH. The risks for Caucasians and African Americans were similar for most measures of BPH [15]. These results are consistent with an earlier study of the influence of race and ethnicity on BPH in the Health Professionals Follow-Up [16]. The much lower incidence found for those of Asian background is not clear, but may be due to dietary habits such as the consumption of low-fat high-fiber diets which provide an enhanced supply of weak phytoestrogens [17].

Evidence for a genetic contribution to BPH appears quite consistent. Previous family history of either an enlarged prostate or early-onset BPH increases the risk of this disease in descendents by two to four times [18]. However, a family history of prostate cancer does not appear to confer an enhanced risk of BPH, although a family history of bladder cancer was found in to increase the risk by a factor of over two [19]. The connection with bladder cancer may in part be an artifact, since surgery for this cancer can reveal unsuspected prostate cancer.

DIET
Although limited in number, recent studies support a role, albeit relatively minor, of diet in the risk of BPH. In a recent large study, Suzuki et al [20] report the results of examining the intake of energy and macronutrients (protein, carbohydrate and various fats) on the risk of BPH based on food frequency questionnaires. Cases were drawn from a cohort of over 51,000 individuals in the Health Professionals Follow-up Study. Four categories of BPH were used: (1) surgery for BPH; (2) high to moderate LUT symptoms; (3) total BPH consisting of the above two categories; and (4) enlarged prostate as detected by DRE. Non-cases were defined as men who had no BPH surgery and those with a low score in a test of urinary tract symptoms. Risk, as measured by odds ratios, rose with increasing total energy intake and in a comparison of highest to lowest quintiles yielded ORs of 1.29 for category (3) and 1.43 for category (2). Total protein intake (energy-adjusted) was positively associated with total BPH (OR = 1.18) and BPH surgery (OR = 1.26). Moderate increased risk was found for eicosapentaenoic (EPA), docosahexaenoic (DHA), and arachidonic (AA) polyunsaturated fatty acids (PUFAs). All other macronutrients failed to show statistically significant associations. Food groups were not studied. The authors comment that the association with the fatty acids should be explored further (the ORs were only marginally above 1.00) because these polyunsaturated fatty acids (PUFA) have been found beneficial in preventing heart disease. The n-3 fatty acids are also implicated in preventing sudden death during a heart attack. The authors also suggest that since these PUFAs are easily oxidized, the findings also suggest a possible role of oxidative stress in the etiology of BPH. The association with total calorie intake was not found in another large study reported in 2001, and in that study there was also no connection between total fat intake and BPH [21]. Additional research will be necessary to resolve these inconsistencies.

In 1999, Yang et al [22] reported a comparison between normal controls and patients with BPH, where the parameters studied included serum levels of omega-3 (n-3) and omega-6 (n-6) PUFAs. They found that the n-3 levels were significantly decreased and the n-3/n-6 PUFA ratio was lower for BPH patients relative to controls. This would be consistent with an inflammatory component to the etiology of BPH, but is inconsistent with the results of Suzuki et al [20] discussed above which was based on the PUFA content of foods reported in a food frequency questionnaire. The use of serum levels would appear to be a more direct approach to the question, but blood samples were either not available or not studied by Suzuki et al.

In a case control study of BPH patients in Athens, Greece, Lagiou et al [23] examined both food groups and some individual foods. They found that among the food groups, only fruits were significantly inversely associated with BPH risk. Increased consumption of both butter and margarine was positively associated with risk, but olive oil was neutral. Among the micronutrients studied, only zinc consumption was found to be associated with BPH risk, in this case increased risk. This is important because of the frequently seen recommendation to take zinc supplements for prostate health.

The connection between alcohol consumption and BPH has been the subject of several recent studies, and in one the combined effect of alcohol and coffee was examined. Neuhouser et al [10] have summarized the alcohol consumption studies that occurred between 1992 and 2001. Four studies found significant inverse associations with odds ratios or relative risks ranging from 0.46 to 0.72, i.e. significant protection. One study reported an OR of 0.86 that was not significant, and one found no association. In a study reported in 2004 [24], a significant beneficial trend with alcohol consumption was found with an OR of 0.71 for 3-4 drinks/day, 0.79 for 5-6, and 0.65 for = 7 drinks/day. When the results were stratified according to wine, beer or liquor, the patterns of risk were similar but only marginally significant. The authors also found that the inverse relationship between alcohol and BPH was stronger in subjects with lower body mass index. They suggest an interaction between androgen levels and alcohol.

In a very recently published case control study [15] involving approximately 35,000 male participants ranging in age from 55 to 74, it was also found that alcohol consumption offered significant protection from BPH. Three levels of BPH were used: (1) nocturia—10756 cases; (2) physician diagnosed BPH—526 cases; (3) surgery for BPH—973 cases. Alcohol consumption ranged from < 20 g/day (reference) to = 60 g/day (a glass of table wine contains between 17 and 20 g of alcohol). ORs for low to high consumption for categories (2) and (3) were from 0.8 to 0.6 and 0.7 to 0.4 respectively, with highly significant trends and individual ORs. These ORs indicate a moderate protective effect. Stratification by type of alcoholic beverage produced similar results, but not all ORs were statistically significant.

In one of the studies included in the summary of Neuhouser et al [10], the combined effects of coffee and alcohol were examined [25]. Coffee consumption was found to be rather strongly and significantly positively associated with BPH risk. When controls having no BPH were used, the ORs for BPH among coffee users was 2.20 for 1-4 cups and 2.74 for > 4 cups/day. The combined intake of one or more glasses of an alcoholic drink and 1,2 or 3 cups of coffee/day resulted in ORs will below 1.00, but only the results for one cup of coffee/day were statistically significant (OR = 0.13). Other studies that have examined the connection between coffee and BPH are inconsistent and the mechanism whereby coffee increases the BPH risk is unknown. Also, filtered coffee has a different lipid composition than non-filtered coffee, which confuses the issue. The authors suggest that men drinking more than four cups of unfiltered coffee daily should also drink some alcohol. However, no data in this context appears available regarding the relative risks of filtered vs. unfiltered coffee.

In connection with cardiovascular disease risk, it is common to see the recommendation of up to three glasses of wine or the equivalent per day as a preventive measure for men. In fact, a recently published study found that the risk of extensive coronary calcification, a measure of atherosclerosis, was 50% lower in individuals who consumed one to two alcoholic drinks per day as compared to non-drinkers [26]. However, more than two drinks a day eliminated the benefit. Although "more than three" was not included in the data workup, three drinks a day may still be protective in this context. The studies discussed above would appear indicate that two or three alcoholic drinks such as beer or wine might also reduce the risk of BPH by around 30-50%.

MICRONUTRIENTS
The relationship between micronutrient intake and BPH risk has been the subject of only a limited number of studies. One of the most recent [27], which examined the connection with a number of micronutrients, involved men who participated in the Third National Health and Nutrition Examination Survey. In this case control study the cases had three of the following four LUT symptoms, as ascertained by an interview: nocturia, hesitancy, incomplete emptying of the bladder and a weak stream. Controls were men without symptoms. Serum levels of vitamins A, C and E, a- and ß-carotene, ß-cryptoxanthin, lutein/zeaxanthin, lycopene and selenium were determined and compared in cases and controls. The only statistically significant lower serum levels in cases vs. controls were found for vitamin E, lycopene and selenium. When the data was examined in terms of quintiles of micronutrient concentration, there were no statistically significant trends with serum level but the odds ratios for these three micronutrients clustered around 0.5 to 0.75, suggesting that men with higher levels of circulating vitamin E, selenium and lycopene had a reduced risk of LUTS and thus presumably BPH. High serum levels of vitamin C appeared to be highly protective for current smokers (OR = 0.1, 95% confidence limits 0.02-0.67). On the other hand, for individuals who had never smoked, comparison of the highest with the lowest vitamin C quintile yielded an OR of 3.61 with 95% confidence limits of 1.10 and 11.85. No significant associations were found with the other micronutrients studies. The authors suggest that the mechanism of action of lycopene may be associated with its ability to quench singlet oxygen and thus reduce oxidative damage. They hypothesized that the inverse association with selenium may be due to its being a constituent of glutathione peroxidase, which is a potent free radical quencher and is also know to inhibit cell growth. The positive association in non-smokers with high intakes of vitamin C was attributed to the possibility of this vitamin becoming pro-oxidative at high concentrations. No theory was offered for the protective effect observed for current smokers. It is interesting that the three micronutrients identified as possibly important in the context of LUTS and BPH have also been implicated as protective for prostate cancer.

A number of epidemiologic, clinical and in vitro data suggest that phytoestrogens are involved in the pathogenesis of BPH [28]. Dietary sources include tea, fruits and vegetables and in particular soy and soy products. High phytoestrogen intake has been suggested by many observers as an explanation for the difference in incidence of BPH between Far East and Western countries. The results of a recent study [28] address this matter. Prostate tissue levels of two phytoestrogens, enterolactone and genistein, were determined in a series of men undergoing surgery to relieve the symptoms of BPH. It was found that genistein tissue levels were significantly greater in men with small prostate volumes as compared to those with large volumes. No significant correlation was found for enterolactone. Genistein is thought to be biologically the most active isoflavone in soy products. The authors suggest that a possible mechanism for the influence of genistein on the incidence of BPH is that it inhibits the degradation of vitamin D which is implicated in prostate health. While these results do not prove a cause and effect relationship, they carry an implication of benefit in the context of BPH. A number of mechanisms have been proposed for the action of phytoestrogens in the prostate but what is clear is that there is still a lack of detained knowledge regarding the interplay of hormones, enzymes and weak estrogen-like compounds in this gland [29]. There may also be a risks associated with disturbing the hormone balance with substances having estrogenic properties.

A natural conclusion based on the above results would be that supplementation with vitamin E, selenium and lycopene and perhaps consuming modest quantities of soy containing foods might be worth considering. Unfortunately, there appear to be no randomized intervention studies that address this issue, and it may be decades before such studies are conducted, if ever. Furthermore the amounts in the form of supplements that might be effective are unknown and the doses safety of some supplemental forms has never been investigated. Lycopene can be obtained from cooked tomato products, the best being tomato paste, whereas raw tomatoes are a poor source. Genistein can of course be obtained by eating soy products such as tofu (bean curd). For these two phytochemicals, food sources appear attractive and may in fact contain other beneficial substances. The selenium content of foods is highly variable since it depends on soil concentrations. Only small amounts of vitamin E are available in food compared to the amounts many individuals take in the form of supplements. Guidance regarding supplementation with these two micronutrients can perhaps be obtained from the fact that an ongoing, multicenter clinical study of vitamin E and selenium as protective agents for prostate cancer is using supplementation of 200 micrograms of selenomethionine and 400 IU of synthetic vitamin E a day, amounts deemed safe for a study involving over 30,000 participants.

A recent review concerning the safety of vitamins E and C should reassure individuals worried by recent media coverage of the "dangers" of taking these supplements. In this review of the scientific literature, no consistent evidence was found for adverse events among healthy individuals or those with a range of diseases for daily intakes of up to 1600 IU (equivalent to about 1000 mg of natural vitamin E) or up to 2000 mg of vitamin C [30].

BPH, DIABETES, CARDIOVASCULAR DISEASE AND THE METABOLIC SYNDROME
The hypothesis that there is an association between BPH and diabetes has been around for over 30 years but still no consensus exists. Diabetes can eventually produce bladder dysfunction which involves neuropathy. Impaired detrusor (muscle involved in bladder emptying) function results in lower flow rates and can increase residual (postvoid) urine. But BPH can also cause the same lower urinary tract symptoms even though the underlying pathology is different since BPH does not directly impair detrusor function but rather enhances bladder outlet resistance by mechanisms that are both static and dynamic. In addition, both diabetes and BPH increase with age and a fraction of patients with BPH also suffer from diabetes and vice versa. The question then is whether the incidence of comorbidity of these two diseases is greater than would be expected by chance, i.e. is diabetes an independent risk factor for BPH.

Hammarsten and Högstedt have examined this question in a direct manner by examining the correlation between the rate of prostate volume change in both non-insulin dependent diabetes mellitus (NIDDM) and in individuals with the metabolic syndrome, a condition closely related to diabetes, and also in individuals with elevated insulin levels [31,32]. Since gland growth in BPH occurs in the transition zone (TZ), the authors used transrectal ultrasound to determine the TZ volume. They established that there was a linear and highly significant correlation between the total prostate volume and the TZ volume, and thus the former was a valid measure of BPH. Prostate growth rates were calculated assuming that the prostate had a volume of 20 mL at age 40. Prostate growth rates were obtained for 307 patients. Those with metabolic disease, NIDDM, treated- hypertension, obesity and dyslipidemia all had prostate growth rates significantly greater than controls. When the fasting insulin was stratified by quartiles, those in the first quartile (< 7 mU/L) had an annual growth rate of 0.84 mL whereas in the highest quartile of plasma insulin (>13 mU/L), the growth rate was 1.49 mL/year, and this difference was statistically significant. The authors regard these results as supporting the hypothesis of a relationship between BPH and diabetes, the metabolic syndrome, and hyperinsulinemia. This hypothesis is further supported by the observation that diabetes is associated with greater BPH symptom severity even after age adjustment [33]. It is also clear from these and other studies [34] that BPH and cardiovascular disease(CVD) share a common set of risk factors, it also appears that CVD is a risk factor for BPH [21,35]. In fact, when studies segregated age-matched patient populations according to clinical signs of CVD, atherosclerosis and hypertension vs. those without [35] , patients with overt vascular pathology were at a much higher risk for BPH than those where this pathology was absent, independent of age.

The question of the mechanism involved in the observed connection between diabetes, vascular disease and BPH was recently examined by Berger et al [14] using a novel approach. They employed computer-assisted quantification of color Doppler ultrasound to examine the patterns of blood flow in normal prostates and prostates in patients with NIDDM. The hypothesis was that diabetes-related vascular damage, a well-established phenomenon, might extent to the prostate. Such damage is known to reduce the available oxygen (hypoxia) and in prostate cell culture studies, hypoxia caused increased growth factor production [36,37] which could trigger prostate growth. The ultrasound technique permitted the examination of circulation in both the peripheral zone (PZ) and the transition zone (TZ). Significant reduced circulation was observed in the TZ of diabetic patients as compared to non-diabetic patients, whereas there were no differences in the circulation in the PZ. It will be recalled that the prostate growth in BPH occurs in the TZ. TZ circulation of patients with non-diabetic BPH as well as those with diabetes was significantly lower than controls, but no differences were found for the PZ. The authors conclude that these results indicate considerable vascular damage in the TZ of diabetic patients and this may contribute to the pathogenesis of BPH, perhaps via hypoxia. Thus action aimed at decreasing the risk of metabolic syndrome or adult-onset diabetes may be effective in reducing the risk of BPH. Obviously other health benefits would also accrue from such action.

Moyad [38] has recently reviewed the connection between obesity, physical activity and BPH. The strongest connection is with the waist-to-hip ratio (incidentally a metabolic syndrome factor), which is an indication of abdominal obesity. Abdominal fat may increase estrogen levels, providing the link to BPH. Hammarsten and Högsten in fact also observed a significant correlation between the waist-to-hip ratio and prostate growth rates [31], and Dahle et al [39] found that abdominal obesity was associated with a higher risk of BPH. In all the studies reviewed by Moyad, physical activity had a strong and significant impact on the risk of developing BPH. Even walking two to three hours a week resulted in a 25% reduction in the risk of BPH and in one study, men with the highest level of physical activity compared to the lowest had a 50% reduction in risk.

DIAGNOSIS OF BPH

The lower urinary tract symptoms (LUTS) characteristic of BPH may not in fact be due to this disease. Thus the diagnostic challenge is to differentiate between BPH and other causes of LUTS. Other causes include diabetes (LUTS by a non-BPH mechanism), Parkinson's disease, stroke, urethral stricture caused by scar tissue from catheterization or from a sexually transmitted disease such as gonorrhea, urinary tract infections, prostatitis, bladder cancer, advanced prostate cancer, and bladder stones. A recent study from the Mayo Clinic and Merck in fact identifies seventeen conditions that should be distinguished from BPH as causing LUTS. These include back surgery and stroke, as well as the conditions listed above. This study also found the following percentages of men with LUTS unrelated to BPH: age 50-59, 5.4%; age 60-69, 8.5%, and age > 70, 32.8% [40]. Thus older individuals present a significant diagnostic challenge, and an oversight during the initial evaluation would result in incorrect treatment and even misclassification of subjects in clinical trials. While mild symptoms are easy to ignore, severe symptoms of LUTS such as blood in the urine, recurrent urinary tract infections, bladder stones, or trouble emptying the bladder should not be ignored, since the risk of acute urinary retention or bladder or kidney damage is elevated [1]. Correct diagnosis is critical since it determines treatment.

The American Urology Association (AUA) recommends [41] that for all patients presenting with LUTS suggestive of BPH the initial evaluation should involve a medical history, physical exam including a digital rectal exam (DRE), and a urinalysis to screen for blood and urinary tract infection. It is further recommended that symptoms be assessed with either the AUA Symptom Index or the equivalent International Prostate Symptom Score (IPSS). More extensive testing may be suggested by the results. Similar recommendations have been recently made by the European Association of Urology (EAU) [42]. The success in eliminating non-BPH causes of LUTS will depend on the skill of the diagnostician.

The AUA Symptom Index [41] questionnaire is scored according to the following answers: not at all = 0; less than one time in five = 1; less than half the time = 2; about half the time = 3; more than half the time = 4; almost always = 5. The questions, which all relate to a one month period, are:

1. How often have you had a sensation of not emptying your bladder completely after you finish urinating?
2. How often have you had to urinate again less than two hours after you finished urinating:
3. How often have you found you stopped and started several times when you urinated?
4. How often have you found it difficult to postpone urination?
5. How often have you had a weak urinary stream?
6. How often have you had to push or strain to begin urination?
7. How many times did you most typically get up to urinated from the time you went to bed until the time you got up in the morning? Score according to the number of times with five for five or more.

Symptoms are classified as MILD if the total score is 0-7; MODERATE for 8-18, and SEVERE from 19-35. The IPSS uses the same questions and scoring system. This score is not necessarily diagnostic of BPH but merely indicates severity of LUTS.

The AUA also recommends [41] that the serum prostate-specific antigen (PSA) test be offered under the following circumstances: (1) those with at least a 10-year life expectancy and for whom knowledge of the presence of prostate cancer would change the management; or (2) those for whom the PSA measurement may change the management of their voiding symptoms. This brings up the subject of PSA testing, an area of great controversy in urology, even in the context of BPH. The use of the word offered in the AUA recommendation speaks volumes.

At issue is the detection of prostate cancer (PC) in patients presenting with LUTS and the use of PSA levels in managing the treatment of BPH. The above recommendation implies that this test will provide an answer to the question of the presence of prostate cancer. Research in the last several years has cast serious doubt on this simple view of the PSA test and highlights the difficulties associated with the exclusion of PC when evaluating patients presenting with LUTS. Most prostate cancers occur in the peripheral zone of the gland and some are palpable, but only a portion of the surface area of the prostate is accessible via the DRE. When this exam reveals abnormalities, it is normal to pursue further the question of PC. However, the common situation is a non-suspicious DRE, and a normal or elevated PSA. But "elevated" is based on a somewhat arbitrary cut-off. A lengthy discussion of the PSA debate is not appropriate for this review, but the following appears important.

If the offer of a PSA test is accepted, the result will be a number ranging from the lower limit of sensitivity of the test (˜0.2 ng/ mL) to possibly a number over 100 ng/mL. Values above 20 ng/mL are cause for alarm. The "normal" cut-off is 4 ng/mL, above which it is usual practice to suggest a biopsy. But this cut-off is not age- adjusted. However, it is now known that PC, including high-grade cancers, is not rare among men with PSA levels of less than 4.0 ng/mL. Furthermore, PSA levels between 4 and 10 ng/mL occur in men with BPH, and prostate cancer is present in only 25% of patients with PSA in this range [43]. The magnitude of the problem is illustrated by recent results reported by Thompson et al published in The New England Journal of Medicine [44]. A cohort of 2050 men with normal DRE and PSA that that had been below 4 ng/mL for seven years were enrolled and underwent biopsy at the end of the study. PC was diagnosed in 15.2% of the men and of these, 14.9% had high-grade cancer. Among those with PC, the prevalence of cancer was 6.6% for the group with PSA up to 0.5 ng/ml, 10.1% for those with values between 0.6 and 1.0, 17% for those with values from 1.1 to 2.0, 23.9% for those between 2.1 and 3.0, and 26.9% for those with values between 3.1 and 4.0 ng/mL. The prevalence of high-grade cancer was 12.5% of those with PC for PSA = 0.5 and 25% for PSA in the range 3.1- 4.0. Tumor grade is important because if one is old enough, low-grade cancer found in the majority of these cases may not pose a threat. It is well known that most men die with rather than from PC. These results point to the folly of the view that a cut-off of 4 can be used to answer the question, does this patient have cancer, and this cut-off also fails to discriminate low- from high-grade tumors. In fact, if a cut-off of 2.1 had been used, it would have, on the basis of this data, missed 33% of the cancers.

Another problem involves intra-individual variations. A recent study examined this question over four years of annual check-ups. Among men with an abnormal PSA finding, a high proportion had a normal PSA finding at one or more subsequent visits. For those with a PSA greater than 4 ng/mL, i.e. a value that would trigger the recommendation of a biopsy, 44% had at least one normal value on subsequent visits. When a cutoff of 2.5 ng/mL was used similar results were obtained. Thus significant intra-individual variations must be added to the lack of specificity that characterizes this test. The authors suggest that an isolated elevated PSA level should be confirmed several weeks later before proceeding with other tests or to a biopsy [45].

Given that men with BPH have elevated PSA and that PSA tends to increase with age even among the cancer free, and that as Thompson et al [44] demonstrated, even a PSA cut-off of 2.1 ng/mL would miss a third of cancers, it would seem that if a definitive answer regarding PC is the goal, the only solution appears to be a biopsy, or more than one, as some urologists suggest [1]. This appears to be the position of Dr. P. C. Walsh, the well-known urologist from Johns Hopkins Medical School who is responsible for the development of the nerve- sparing radical prostatectomy procedure [46]. Commenting on the paper by Thompson et al, he states, "…if a patient really wants to know whether or not he had cancer, I guess we have to do a biopsy." In fact, based on the experience of Stanford University Urologists, Stamey et al [47] have recently taken the position that PSA is only useful in the context of estimating the size of the prostate! However, it is almost inconceivable that the recommendation would be put forward that everyone presenting with LUTS have a biopsy for PC. The term "offered" implies a discussion between patient and physician where the pros and cons and probabilities are considered, and especially what would be the next step if a certain PSA value were found. Such a discussion involves the age, health, life expectancy and attitudes of the patient and perhaps his spouse, and as well, the attitude and knowledge of the physician as regards PSA. It is important to remember that PSA is organ specific but not cancer specific.

There are other more sophisticated PSA tests that show promise for use in the differential diagnosis of BPH vs. PC. These are not routinely done and are not part of either the AUA or EAU general recommendations, but appear definitely worth considering when one is confronted with the problem of the lack of specificity of the PSA test. For example, in a recent study [48] aimed at reducing the number of biopsies in men with non-suspicious DRE and PSA between 4 and 10 ng/mL, it was found that by measuring the free PSA rather than the total PSA, and using a cut-off of = 23% as a criterion for biopsy, 94.4% of cancers would have been detected and 18% of biopsies yielding benign results would have been avoided. The researchers also found that PSA density, calculated from the prostate volume and total PSA, gave a similar specificity. However, PSA density requires the gland volume, which can only be reliably estimated from transrectal ultrasound or other more expensive imaging techniques. DRE generally underestimates the volume [49]. In the next few years these alternative PSA tests as well as others now under development will no doubt become better characterized and more commonly performed.

It appears well established that PSA has its place in the management of BPH treatment and in particular in assessing the probability of progression, an acute urinary retention episode, or the future need for surgery. A very recent consensus statement at the end of a series of papers on this subject in the British Journal of Urology International [50] outlines the current status of this application of PSA levels. The following points are of interest.

• Prostate volume (PV) consistently increases with age and in studies higher baseline PVs were associated with greater growth rates of the prostate. Men with a PV of = 30 ml are 3.5 times more likely to have moderate to severe symptoms, 2.5 times more likely to have decreased flow rates and 3 to 4 times more likely to an AUR episode than men with lower PVs. However, the accuracy of the DRE in determining PV is limited, and MRI in general too expensive. Transrectal ultrasound provides a more accurate measure of PV, but the specialized equipment is not normally used in the physician's office environment. Thus another marker would be useful.
• PSA levels have been shown to be closely related to PV in benign glands, and even low PSA is indicative of an enlarged prostate. Eighty-nine percent of a patient group studied in Holland with PSA of at least 1.5 ng/mL had PV of > 30 mL.
• When a group of patients in the placebo arm of a drug study were examined for a correlation between PSA levels, symptom severity, and risk of AUR or surgery, those in the highest PSA quartile vs. the lowest had greater symptom severity and a higher risk for surgery to treat BPH and also higher risk of an AUR episode.
• Thus PSA appears to be a satisfactory surrogate for PV and to have utility in identifying patients with higher risk of BPH progression. The consensus group [50] concluded that men with a PSA = 1.5 ng/mL should be considered at increased risk of clinically significant BPH progression and therefore should be considered for more aggressive therapy than those with PSA below this limit. For the latter, they suggest symptomatic treatment.

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