Campbell-Walsh Urology

Complications

Many of the complications of progressive BPH are rare, and much of the knowledge comes from studies of men presenting with such complications for treatment (i.e., cases) rather than observing cohorts of men for the development of complications.

Mortality

Between 1950 and 1954, 17 of 24 countries reported mortality rates of greater than 10 per 100,000, whereas between 1985 and 1989 data were available for 61 countries, only one reporting a greater than 10/100,000 mortality rate (Boyle et al, 1996). If the mortality rates from 1950 were applied to 1990, 13,681 fewer deaths occurred in the United States alone than expected, a major but unheralded health care achievement.

Bladder Stones

In a large autopsy study the prevalence of bladder stones was 8 times higher in men with a histologic diagnosis of BPH (3.4%) compared with controls (0.4%) but no increased incidence of ureteral or kidney stones was found (Grosse, 1990). In a study comparing watchful waiting and TURP in men with moderate symptoms, only 1 of 276 patients assigned to watchful waiting developed a bladder stone in 3 years of follow-up (Wasson et al, 1995). The self-reported rate of a bladder stone in a cross-sectional study in 2002 Spanish men was 0.7% (Hunter et al, 1996).

In clinical practice the risk of bladder stone development is small and screening only indicated if clinical circumstances warrant it (e.g., hematuria, stuttering of urination).

In older surgical series UTIs constitute the main indication for surgical intervention in about 12% (Holtgrewe et al, 1989; Mebust et al, 1989). Although one might intuitively assume that increased amounts of residual urine would predispose to the development of UTIs, clear evidence is lacking. Hunter and colleagues (1996) quoted a rate of 5.2% self-reported episodes of UTI in a cross-sectional survey of 2002 men in Madrid, Spain. The best data to date come from the MTOPS study, in which the incidence of UTIs in the placebo-treated patients was only 0.1/100 patient-years (McConnell et al, 2003).

Bladder Decompensation

Urologists search for a progression from a normal mucosa to advancing trabeculation, development of cellules, and diverticula with ultimate detrusor muscle failure in mind when evaluating the bladder in men with BPH endoscopically. However, when the process starts, whether it really is related to BPH and obstruction, and when an intervention is necessary to prevent decompensation with resultant inability to void is unclear.

Biopsy samples from trabeculated, obstructed bladders show dense connective tissue deposition, a finding similar to that seen in animals experimentally obstructed (Gosling and Dixon, 1980; Levin et al, 1990, 2000; Chapple et al, 1991). However, bladder fibrosis is seen in both sexes with advancing age and may be a normal consequence of aging (Lepor et al, 1992a).

The critical question is whether delayed intervention might lead to progressive irreversible loss of bladder function and misses a window for cure. There is no direct evidence for this from longitudinal population or clinic patient studies. However, in the Veterans Affairs cooperative study comparing watchful waiting with TURP, those patients who crossed over from the conservative arm to TURP later in the trial had not as significant an improvement in symptoms and flow rate compared with those who underwent TURP at the beginning after randomization (Flanigan et al, 1998).

Urinary Incontinence

Incontinence is one of the most feared complications from surgical intervention for BPH. Although it may be the result of BPH secondary to overdistention of the bladder (overflow incontinence) or to detrusor instability estimated to affect up to one half or more of all obstructed patients (urge incontinence) (McConnell et al, 1994), it also is associated with aging; and in a community study an incidence of incontinence of 24% and 49% of incontinence in men and women older than 50 years was reported (Roberts et al, 1998). In the Veterans Affairs cooperative study a 4% incidence of incontinence in both the surgical and conservative treatment arms was reported (Wasson et al, 1995). The self-reported rate of incontinence in a cross-sectional study in 2002 Spanish men was 6.1% (Hunter et al, 1996). In MTOPS the rate of socially unacceptable incontinence was 0.3/100 patient-years (McConnell et al, 2003).

Upper Urinary Tract Deterioration and Azotemia

The Agency for Health Care Policy and Research BPH guidelines reported a mean of 13.6% (range 0.3% to 30%) of patients presenting for TURP with evidence of renal failure based on predominantly older studies (McConnell et al, 1994). Patients in renal failure have an increased risk for complication after TURP compared with patients with normal renal function (25% vs. 17%) (Holtgrewe et al, 1989; Mebust et al, 1989) whereas the mortality increases up to 6-fold (Holtgrewe and Valk, 1962; Melchior et al, 1974a, 1974b). In the large database of patients who had upper tract imaging before surgery, 7.6% of 6102 patients in 25 series had evidence of hydronephrosis, of whom one third had renal insufficiency (McConnell et al, 1994).

The term silent obstruction or silent prostatism has been used to describe the constellation of asymptomatic patients who eventually develop renal failure resulting from bladder outlet obstruction, a case both rare and important (Mukamel et al, 1979). In the Veterans Affairs cooperative study, only 3 of 280 surgically treated patients and 1 or 276 patients in the watchful waiting arm developed renal azotemia, defined as a doubling of the serum creatinine concentration from baseline (Wasson et al, 1995). In none of the cohort or population-based studies have cases of renal failure been reported clearly attributable to BPH. However, the self-reported rate of an episode of renal failure in a cross-sectional study in 2002 Spanish men was 2.4% (Hunter et al, 1996).

In MTOPS there was not a single case of renal insufficiency due to BPH in over 3000 men observed for more than 4 years (McConnell et al, 2003). One has to be, however, careful not to overinterpret these findings. Participants in MTOPS were screened at baseline, and one might argue that some at higher risk for developing renal failure were excluded from participation.

Hematuria

It has always been recognized that patients with BPH might develop gross hematuria and form clots with no other cause being identifiable. Recent evidence suggests that in those patients predisposed to hematuria the microvessel density is higher compared with controls. Some renewed interest in the issue of BPH-related hematuria stems from the observation that finasteride appears to be a reasonable first-line therapy apparently influencing the expression of vascular endothelial growth factor (DiPaola et al, 2001). The self-reported rate of hematuria in a cross-sectional study in 2002 Spanish men was 2.5% (Hunter et al, 1996). Precise population estimates and incidence rates are not available, and the clinical management is dictated by the circumstances.

Acute Urinary Retention

AUR is for several reasons one of the most significant complications or long-term outcomes resulting from BPH. It has in the past represented an immediate indication for surgery. Between 25% and 30% of men who underwent TURP had AUR as their main indication in older series (Holtgrewe et al, 1989; Mebust et al, 1989), and today most patients failing to void after an attempt of catheter removal still undergo surgery. For this reason alone, AUR is both from an economic viewpoint as well as from the viewpoint of the patient an important and feared event. For the patient it presents as the inability to urinate with increasing pain, eventually a visit to the emergency department, catheterization, follow-up visits to the physicians, an attempt at catheter removal, and either recovery of spontaneous voiding or surgery, both painful and time-consuming processes. In older literature the risk of recurrent AUR was cited as being 56% to 64% within 1 week of the first episode and as occurring in 76% to 83% in men with diagnosed BPH (Breum et al, 1982; Klarskov et al, 1987; Hastie et al, 1990).

The etiology of AUR is poorly understood and obstructive, myogenic, and neurogenic causes all may play a role (Kaplan et al, 2008). Prostate infection, bladder overdistention (Powell et al, 1980), excessive fluid intake, alcohol consumption, sexual activity, debility, and bed rest have all been mentioned (Stimson and Fihn, 1990). Prostatic infarction has been suggested as being an underlying event causing AUR (Graversen et al, 1989). Spiro and associates (1976) found evidence for infarction in 85% of prostates removed for AUR versus 3% in prostates of men having surgery for symptoms only. In contrast, there was no evidence of infarction in six prostatectomy specimens removed from men who had surgery for AUR (Jacobsen et al, 1997). Anjum and associates (1998) found fundamentally similar rates of infarction in 35 men each in AUR versus no AUR (1.9% vs. 3.0%).

From a clinical and prognostic point of view, spontaneous AUR should be separated from precipitated AUR, although this is by no means consistently done in the literature. Precipitated AUR refers to the inability to urinate after a triggering event such as non–prostate-related surgery, catheterization, anesthesia, ingestion of medications with sympathomimetic or anticholinergic effects or antihistamines, or others. All other AUR episodes are classified as spontaneous (Roehrborn et al, 2000a). The importance of differentiating the two types of AUR becomes clear when evaluating the ultimate outcomes of patients. After spontaneous AUR, 15% of patients had another episode of spontaneous AUR and a total of 75% underwent surgery, whereas after precipitated AUR only 9% had an episode of spontaneous AUR, and 26% underwent surgery (Roehrborn et al, 2000a).

Descriptive Epidemiology

Older estimates of occurrence of AUR range from 4 to 15 to as high as 130 per 1000 patient-years (calculated by Jacobsen et al, 1997, based on studies by Craigen et al, 1969; Birkhoff et al, 1976; Ball et al, 1981), which leads to 10-year cumulative incidence rates ranging from 4% to 73% (Table 91–15). The self-reported rate of AUR in a cross-sectional study in 2002 Spanish men was 5.1% (Hunter et al, 1996).

Table 91–15 Descriptive Studies on the Incidence of Acute Urinary Retention

More recent data from carefully controlled studies in better defined population shed additional light on the incidence rates in community-dwelling men and clinical BPH populations. AUR occurred in the Veterans Affairs cooperative study over 3 years in 1 man after TURP and in 8 of 276 men in the watchful waiting arm for an incidence rate of 9.6/1000 patient-years (Wasson et al, 1995). Barry and associates (1997a) reported outcomes of 500 men diagnosed by urologists with BPH who were candidates for prostatectomy by established criteria but elected to be followed conservatively. In 1574 patient-years 40 episodes of AUR occurred at a constant rate throughout the 4 years of follow-up for an incidence rate of 25/1000 patient-years.

During 15,851 patient-years of follow-up in the Physicians Health Study 82 men reported an episode of AUR for an incidence rate of 4.5/1000 patient-years (95% CI 3.1 to 6.2) (Meigs et al, 1999). Of the 2115 men aged 40 to 79 years in the Olmsted County study, 57 had a first episode of AUR during 8344 patient-years of follow-up (incidence 6.8/1000 patient-years, 95% CI 5.2, 8.9) (Jacobsen et al, 1997).

The first excellent data from men diagnosed with BPH stem from PLESS (McConnell et al, 1998). In PLESS, 1,376 placebo-treated men with enlarged prostates and moderate symptoms had complete follow-up over 4 years, of which 99 experienced an episode of AUR for a calculated incidence rate of 1.8/100 patient-years. The placebo treatment groups from three 2-year studies with a similar patient population were meta-analyzed by Boyle and associates (1998). Of 2109 patients, 57 experienced AUR over the 2 years with a constant hazard for an incidence rate of 14/1000 patient-years. In the MTOPS placebo group the incidence rate was 0.6/100 patient-years for a cumulative incidence of 2%.

Analytical Epidemiology

Age

Several well-controlled studies provided considerable insights into the risk factors for AUR. Perhaps the most significant of these risk factors is age. Studies from European countries and the United States demonstrate a nearly linear increase in the age-specific incidence of AUR for men ranging in age from 40 to older than 80 years (Jacobsen et al, 1997; Meigs et al, 1999; Verhamme et al, 2005; Cathcart et al, 2006) (Fig. 91–22).

Figure 91–22 Increase in incidence of acute urinary retention (AUR) with age in four large studies.

(From Kaplan SA, Wein AJ, et al. Urinary retention and post-void residual urine in men: separating truth from tradition. J Urol 2008;180[1]:47–54.)

LUTS

Increased symptom severity is associated with increased risk of AUR in several large population-based or cohort studies (Table 91–16). In the Physician’s Health Study in men with mild symptoms the incidence of AUR increased from 0.4/1000 patient-years for those 45 to 49 years old to 7.9/1000 patient-years for those 70 to 83 years old. In men with an AUASI score of 8 to 35, rates increased from 3.3/1000 patient-years for those 45 to 49 years old to 11.3/1000 patient-years for those 70 to 83 years old. Men with a clinical diagnosis of BPH and an AUASI score of 8 or greater had the highest rates (age-adjusted incidence 13.7/1000 patient-years). All seven LUTS comprising the AUASI individually predicted AUR. The sensation of incomplete bladder emptying, having to void again after less than 2 hours, and a weak urinary stream were the best independent symptom predictors. Use of medications with adrenergic or anticholinergic side effects also predicted AUR (Meigs et al, 1999).

Table 91–16 Incidence of AUR by Patient Age and AUASI Score in Two Population-Based Studies

AGE GROUP	No. AUR Events/1000 Men-Years (95% CI)
AGE GROUP	Health Professionals Follow-up Study*	Olmsted County Study of Urinary Symptoms and Health Status among Men^†
AUASI ≤7:
40-49		2.6 (0.8-6.0)
45-49	0.4 (0.02-1.8)
50-59	1.2 (0.4-2.6)	1.7 (0.3-4.8)
60-69	3.6 (1.9-6.1)	5.4 (2.0-11.6)
70-79		9.3 (3.4-20.3)
70-83	7.9 (4.1-13.5)
AUASI >7:
40-49		3.0 (0.4-10.8)
45-49	3.3 (0.2-14.4)
50-59	10.0 (5.4-16.8)	7.4 (2.7-16.1)
60-69	14.1 (9.4-20.2)	12.9 (6.2-23.8)
70-79		34.7 (20.2-55.5)
70-83	11.3 (6.4-18.3)

AUASI, American Urological Association Symptom Index; AUR, acute urinary retention; CI, confidence interval.

* Total of 82 AUR episodes in 6100 men with a crude incidence of 5.2/1000 patient-years (95% CI 4.1-6.4) in 15,851 patient-years of follow-up.

† Total of 57 AUR episodes in 2115 men with an overall incidence of 6.8/1000 patient-years (95% CI 5.2-8.9) in 8344 patient-years of follow-up.

From Kaplan SA, Wein AJ, et al. Urinary retention and post-void residual urine in men: separating truth from tradition. J Urol 2008;180(1):47–54.

The Olmsted County study focused on age, symptom severity, maximum flow rate, and prostate volume (Jacobsen et al, 1997). Incidence rates per 1000 patient-years increased from 2.6 to 9.3 for men in their 40s to their 70s if they had mild symptoms and from 3.0 to 34.7 if they had more than mild symptoms (see Table 91–16).

Urodynamic Parameters

The relative risk increased for older men, men with moderate to severe symptoms (3.2×), those with a flow rate under 12 mL/sec (3.9 times) and those with a prostate volume greater than 30 mL by TRUS (3.0 times), all compared with a baseline risk of 1.0 time for the corresponding groups (Fig. 91–23). The highest relative risk by proportional hazard models exists for 60- to 69-year-old men with more than mild symptoms and a flow rate of less than 12 mL/sec (10.3 times), and for 70- to 79-year-old men except if they had mild symptoms and a flow rate over 12 mL/sec. All other stratification of men older than age 70 years had a relative risk ranging from 12.9 to 14.8 times (all compared with men 40 to 49 years old with mild symptoms and a flow rate over 12 mL/sec for which the base risk is 1.0 time).

Figure 91–23 Relative risk of acute urinary retention in Olmsted County Study of Urinary Symptoms and Health Status Among Men by age, symptom severity, peak flow rate, and prostate volume. The shaded column represents the baseline and a relative risk of 1.0; the vertical line represents the 95% confidence interval. IPSS, International Prostate Symptom Score.

(Data from Jacobsen SJ, Jacobson DJ, et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997;158[2]:481–7.)

Prostate Volume and Serum PSA

Although age in community-dwelling men is an important risk factor, in the BPH trial population of men who already are diagnosed with BPH, other factors can be analyzed. In the placebo groups of three 2-year studies (Marberger et al, 2000) and a 4-year study (PLESS) (McConnell et al, 1998; Kaplan et al, 2000; Roehrborn et al, 2000a), prostate volume, serum PSA, and symptom severity all were predictors of AUR episodes.

The incidence increased from 5.6% to 7.7% in men with a serum PSA of less than 1.4 ng/mL from mild to severe symptoms and from 7.8% to 10.2% for those with a serum PSA of more than 1.4 ng/mL over 4 years in PLESS (Kaplan et al, 2000). In the 2-year studies the rate of AUR was 8-fold higher in those with a serum PSA of over 1.4 ng/mL (0.4% vs. 3.9%) and threefold higher if the prostate volume was over 40 mL (1.6% vs. 4.2%) (Marberger et al, 2000; Roehrborn et al, 2001). A detailed analysis showed a near linear increase in risk for AUR with increasing thresholds of serum PSA (Fig. 91–24) in PLESS, an observation that applies to both spontaneous and precipitated AUR (Roehrborn et al, 1999d). The risk for both types of AUR increases with increasing serum PSA as well as prostate volume stratified by tertiles (Fig. 91–25). Similar observations were made in MTOPS, in which the risk for AUR increased with increasing prostate volume as well as increasing baseline serum PSA (Fig. 91–26), as well as in the 2-year phase III studies comparing dutasteride with placebo (Roehrborn et al, 2002). An analysis of over 100 possible outcome predictors alone or in combination revealed a combination of serum PSA, urinating more than every 2 hours, symptom problem index, maximum urinary flow rate, and hesitancy as being only slightly superior to PSA alone in predicting AUR episodes (Roehrborn et al, 2001).

Figure 91–24 Incidence of spontaneous or precipitated acute urinary retention in the Proscar Long-Term Efficacy and Safety Study over 4 years stratified by increasing thresholds of serum prostate-specific antigen (PSA) at baseline.

(From Roehrborn CG, McConnell JD, Lieber M, et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group. Urology 1999;53[3]:473–80.)

Figure 91–25 Spontaneous, precipitated, or combined acute urinary retention incidence over 4 years in the Proscar Long-Term Efficacy and Safety Study stratified by tertiles of serum prostate-specific antigen or prostate volume at baseline.

Figure 91–26 Cumulative incidence of acute urinary retention in placebo-treated patients in the Medical Therapy of Prostatic Symptoms study stratified by baseline prostate volume (yellow) and baseline serum prostate-specific antigen (PSA) (orange).

Surgery for Benign Prostatic Hyperplasia

Both surgery and AUR represent distinct end points in the disease progression of BPH. There are, however, distinct differences. AUR is an outcome mandating management, and surgery is one of the commonly employed management styles. AUR is probably one of the clearer indications for surgery, leaving the treating physician little choice in a patient who failed a trial without catheterization. However, most patients undergo surgery not for AUR but for symptoms (Holtgrewe et al, 1989). Depending on local practice pattern, AUR accounts for 5% to over 30% of the indications for surgery. AUR can be compared with a bone fracture. It is impossible for the physician in his or her interaction with the patient to increase or decrease the probability for that outcome to occur. Furthermore, once it has occurred, no interaction or consultation can undo it. In contrast, it is easy to see how patients can be influenced in their decision to undergo surgery by the consultation with the physician. The interaction style, the quoted probabilities of beneficial and harmful outcomes to occur, and many other factors cause considerable variability in the incidence rates of prostate-related surgery, an observation that caused the Agency for Health Care Policy and Research to develop guidelines for the treatment of BPH (Wennberg et al, 1988). This situation is similar to myocardial infarction and coronary artery bypass grafting (CABG). The analytical epidemiology of myocardial infarctions is well understood, and risk factors are characterized. Not all myocardial infarctions result in CABG, and, in fact, CABG is frequently performed for other indications than a recent infarction. Consequently, there is abundant literature focusing on the geographic variation in the usage of CABG. From this brief discussion it becomes clear that surgery for BPH is a softer end point from an epidemiologic point of view than AUR, and data on rates of prostatectomy need to be interpreted in light of variation in its use, from provider to provider, region to region, health care plan to health care plan, and over time.

Of all prostate surgeries, TURP and laser ablation of the prostate are still clearly the most common procedures and the best studied. Cross-sectional descriptive data on incidence rates are available from the Medicare database. While in 1962 TURP constituted over 50% of all major surgeries performed by American urologists, this number had dropped to 38% by 1986 (Holtgrewe et al, 1989; Mebust et al, 1989). Although the number of TURPs performed on Medicare patients declined from an all time peak of 258,000 in 1987 to 168,000 in 1993—a reduction by 34%—it remains second only to cataract surgery on the list of Medicare’s most costly surgical procedures. A 20% sample of Medicare beneficiaries was examined to further specify rates of TURP in the United States. In 1990 the rates of TURP (including all indications) were approximately 25, 19, and 13 per 1000 for men older than the age of 75, 70 to 74, and 65 to 69, respectively. The 30-day mortality after TURP for the treatment of BPH decreased from 1.20% in 1984 to 0.77% in 1990 (Lu-Yao et al, 1994). Compared with the period 1984 to 1990, age-adjusted rates of TURP for BPH during 1991 to 1997 declined further by approximately 50% for white (14.6 to 6.72/1000) and 40% for black (11.8 to 6.58/1000) men (Wasson et al, 2000). Medicare databases are only relevant to those men older than age 65 years enrolled in Medicare and therefore are less interesting from a longitudinal epidemiologic point of view.

Older series of the natural history of BPH such as the one reported by Craigen and coworkers (1969) projected somewhat unrealistic estimates of 35% incidence of prostatectomy at 1 year and 45% at 7 years. Diokno and colleagues (1992) reported an annual incidence rate of 2.6% and 3.3% for years 1 and 2 in their cohort of men followed longitudinally (1992). Frequency, hesitancy, straining, and an interrupted stream were all associated with an increased risk.

The first study of substantial quality reporting on incidence rates and risk factors of prostate surgery was the Baltimore Longitudinal Study of Aging (BLSA) (Arrighi et al, 1990, 1991; Guess et al, 1990). Over 1000 men were observed for 30 years with yearly symptom assessments, questionnaires, and examinations. Age, incomplete emptying, change in size, and force of stream were all independently associated with the risk of prostate surgery, as was a reportedly enlarged prostate by DRE. Of 464 men without risk factors, only 3% required surgery during follow-up. For men with one risk factor the cumulative incidence was 9%, with two risk factors 16%, and with three risk factors even 37%. In a similar study, namely, the Veterans Affairs Normative Aging Study, nocturia and hesitancy emerged as independent predictors of surgery in 1868 men aged 49 to 68 observed for more than 20 years (Hindley et al, 2001). Age and five LUTS (dysuria, incontinence, trouble initiating flow, nocturia, and slow stream) were associated with the risk of surgery in 16,219 men over 40 years enrolled in the Kaiser Permanente Health Plan in California, of whom 1027 men underwent prostatectomy over 12 years of follow-up (Sidney et al, 1991a, 1991b).

In the Veterans Affairs cooperative trial comparing surgery with watchful waiting, 65 of 276 (24%) patients assigned to watchful waiting crossed over to surgery within 3 years of follow-up, of which 20 met predefined end points (azotemia, high residual urine volumes, incontinence, or high AUASI scores). High baseline bother score was a strong predictor of requiring surgery (Wasson et al, 1995).

The probability of undergoing surgery over 4 years increased from 10% in those men diagnosed with BPH who had mild symptoms to 24% in those with moderate and 39% in those with severe symptoms at baseline as reported in a natural history and observation study by Barry and colleagues (1997a).

The Olmsted County study and the placebo-treated patients from PLESS provide additional insights into the risk factors for undergoing prostate surgery in either community-dwelling men or men enrolled in a BPH treatment trial.

In the Olmsted County study during more than 10,000 patient-years of follow-up 167 men were treated, yielding an overall incidence of 16.0/1000 patient-years. There was a strong age-related increase in risk of any treatment from 3.3/1000 patient-years for men 40 to 49 years old to more than 30/1000 patient-years for those 70 years old or older. Men with moderate to severe symptoms, depressed peak urinary flow rates (<12 mL/sec), enlarged prostate (>30 mL), or elevated serum PSA (≥1.4 ng/mL) had about four times the risk of BPH treatment than those who did not. After adjustment for all measures simultaneously an enlarged prostate (hazard ratio 2.3, 95% CI 1.1 to 4.7), depressed peak flow rate (hazard ratio 2.7, 95% CI 1.4 to 5.3), and moderate to severe symptoms (hazard ratio 5.3, 95% CI 2.5 to 11.1) at baseline each independently predicted subsequent treatment. Overall nearly 1 in 4 men received treatment in the eighth decade of life. These data suggest that men with moderate to severe LUTS, impaired flow rates, or enlarged prostates are more likely to undergo treatment, with increases in risk of similar magnitude to those associated with adverse outcomes, such as AUR (Jacobsen et al, 1999).

Over 1500 patients with moderate LUTS and enlarged prostate glands were followed in PLESS on placebo for 4 years. Of these, 10% or 2.5% per year underwent surgery for BPH (McConnell et al, 1998). Whereas the hazard of undergoing surgery was linear, that is, it remained constant throughout the duration of the study, it was different when patients were stratified by either prostate volume or serum PSA in tertiles at the beginning of the study (Fig. 91–27). Similar to the incidence of AUR, the rates of surgery increased from 6.2% to 14.6% for patients in the lowest to the highest PSA tertile and from 6.7% to 14.0% from the lowest to the highest prostate volume tertile. In MTOPS the incidence of invasive therapy for BPH in the placebo group increased equally nearly linearly when stratifying by baseline serum PSA or prostate volume (Fig. 91–28) (McConnell et al, 2003).

Figure 91–27 Incidence of surgery stratified by tertiles of serum prostate-specific antigen (PSA) and prostate volume in placebo-treated patients in the Proscar Long-Term Efficacy and Safety Study.

Figure 91–28 Cumulative incidence of invasive therapy (surgery) for benign prostatic hyperplasia in placebo-treated patients in the Medical Therapy of Prostatic Symptoms study stratified by baseline prostate volume (yellow) and baseline serum prostate-specific antigen (PSA) (orange).

Key Points: Epidemiology and Natural History

• There is no globally accepted epidemiologic definition of BPH, and thus prevalence and incidence rates must be viewed in the context of the definitions chosen by the investigator reporting the data.

• Despite the significantly different proportion of men admitting to moderate to severe symptoms, a clear trend toward an increase in symptom scores with advancing age is noticeable in all reported studies.

• In general, in all cross-sectional studies prostate volume as assessed by TRUS has been found to increase slowly but steadily with advancing age.

• Analytical epidemiologic data suggest a limited role of classical determinants of the disease such as religion, socioeconomic factors, sexual activity, alcohol intake, hypertension, dietary factors, and others. There is conflicting evidence regarding smoking and some evidence suggesting dietary factors, obesity, and increased BMI as determinants of disease severity.

• All relevant parameters such as symptom severity and frequency, bother, interference, disease-specific HRQOL, maximum flow rate, and prostate volume tend to worsen with advancing age. However, reported correlations between these parameters as well as urodynamic pressure-flow studies are in general weak, with some exceptions. Strong correlations exist between measures of symptom severity and frequency (IPSS), bother, disease-specific HRQOL, and interference scores.

• The natural history of the disease has been studied in many longitudinal population-based studies as well as in placebo and sham control groups of treatment trials of men diagnosed with the condition. These studies suggest, in general, a worsening of LUTS and BPH with time. There are several key baseline parameters allowing a stratification of patients according to the risk of progression. Age, symptom severity, flow rate, prostate size, and serum PSA are useful predictors of the risk of progression.

• Complications of LUTS and BPH such as mortality, urinary tract infections, bladder decompensation, bladder stones, hematuria, urinary incontinence, upper urinary tract deterioration with renal insufficiency, and others are, in general, rare in properly supervised patients.

• The two most significant progression events are AUR and the need for BPH-related surgery. Although not exceedingly common, there is a significant baseline incidence rate and the risk is cumulative; that is, with increasing time of observation the incidence rate increases linearly.

• The risk of AUR and need for surgery is to some degree predictable from baseline parameters with advancing age, increased prostate size, and higher serum PSA levels representing the most significant risk factors.