Benign prostatic hyperplasia: antecedents and natural history.

Epidemiologic Reviews Copyright © 1992 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved

Vol. 14,1992 Printed in U.S.A.

Benign Prostatic Hyperplasia: Antecedents and Natural History

Harry A. Guess

history of the untreated disease. A recent World Health Organization conference identified lack of information on the natural history of untreated benign prostatic hyperplasia as one of the reasons for controversies about indications for treatment (5). Epidemiologic information about the onset and progression of the disease is useful not only in deciding on treatment approaches but also in planning studies to evaluate new forms of therapy. Finally, a review of available information provides a useful starting point for etiologic research into its pathogenesis and progression. We will first review prostate anatomy as it relates to the pathologic process by which benign prostatic hyperplasia develops. Next, we will summarize epidemiologic and biologic evidence concerning predisposing factors. Finally, we will review the natural history of the untreated disease and its complications. The primary emphasis will be on the disease itself, with only a brief mention of treatment outcomes. Because of the rapidly evolving changes in modes of therapy and the many studies in progress, it would be premature to attempt a review.

INTRODUCTION

Benign prostatic hyperplasia is a disease of men characterized histologically by the formation of nonmalignant prostatic nodules and clinically by signs and symptoms of urinary obstruction caused by the abnormal growth. The first anatomically accurate description of prostatic enlargement as a cause of urinary retention is attributed to Morgagni (1769) (1). Treatments in the 18th and early 19th centuries involved catheterization and, if that failed, percutaneous bladder puncture to relieve the obstruction. Currently the mainstay of treatment is (subtotal) prostatectomy, which in the United States is usually performed transurethrally. In the United States benign prostatic hyperplasia accounts for an estimated 1.7 million physician office visits and 379,000 prostatectomies annually, making this the most common form of major surgery in men over 55 years of age (2, 3). It has been estimated that a 40-year-old man in the United States who lives to age 80 years would have a 29 percent chance of having a prostatectomy for benign prostatic hyperplasia if current rates prevail (4). Despite the high prevalence and public health impact of benign prostatic hyperplasia, only recently has there been much interest in its epidemiology or in the natural

PATHOLOGIC PROCESS

To understand the origin of benign prostatic hyperplasia and its progression, it is helpful to review normal prostatic anatomy. In the adult prostate, four distinct regions of differing tissue composition have been described (6, 7) (figure 1). Each region contacts the prostatic urethra, which is divided into proximal and distal segments by a sharp bend in the middle. The anterior fibromuscular stroma surrounds the proximal urethra

Received for publication November 26, 1991, and in final form May 26, 1992. From the Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, and Merck Research Laboratories, Blue Bell, PA. Reprint requests to Dr. Harry A. Guess, Department of Epidemiology, School of Public Health, University of North Carolina, McGavran-Greenberg Hall, CB #7400, Chapel Hill, NC 27599-7400.

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FIGURE 1. Sagittal diagram of the distal prostatic urethral segment (UD), proximal urethral segment (UP), and ejaculatory ducts (E) showing their relations to a sagittal section of the anteromedial nonglandular tissues (bladder neck (bn), anterior fibromuscular stroma (fm), preprostatic sphincter (s), and distal striated sphincter (s)). These structures are shown in relation to the glandular prostate (central zone (CZ), peripheral zone (PZ), and transitional zone (TZ)). (From McNeal (7). Reproduced with permission.)

at the bladder neck, comprises about onethird of the mass of the prostate, and contains no glandular elements. The peripheral zone is a flat disk of secretory tissue whose ducts branch out from the distal prostatic urethra; it comprises about 70 percent of the glandular prostatic tissue, is the site of origin of most carcinomas (8), and is the region most susceptible to inflammation (9). The central zone comprises about 25 percent of the glandular tissue and is resistant to both inflammation and carcinoma (7). The fourth and smallest region, the preprostatic tissue, contains both glandular and nonglandular elements and is considered to be the exclusive site of origin of benign prostatic hyperplasia (6, 7, 10). The main nonglandular element is the preprostatic sphincter, a sleeve of smooth muscle surrounding the proximal prostatic urethra. The two glandular elements are the peri-

urethral gland region, which lies just inside the preprostatic sphincter, and the transition zone, which lies just outside the sphincter and has ducts penetrating into it. In the absence of benign prostatic hyperplasia the transition zone and periurethral gland region together comprise about 5 percent of the glandular tissue and 2 percent of the total mass of the prostate. When benign prostatic hyperplasia develops, the transition zone becomes greatly enlarged and compresses the peripheral zone into a thin elastic shell, called the "surgical capsule", which contributes to mechanical compression of the urethra caused by the disease (11). Three separate pathologic processes have been identified in the development of benign prostatic hyperplasia (7, 12): 1) nodule formation, 2) diffuse transition zone enlargement, and 3) nodule enlargement. In a detailed microscopic examination of prostates from autopsies of 63 men with the disease, McNeal (10) found that in the 36 men under the age of 70 years the number of nodules increased steadily with age but each nodule remained small, so that the total nodular mass remained small. Most of the increase in prostate size with increasing age in the under 70 years age range was caused by diffuse enlargement of the transition zone. In about half of the 27 patients aged 70 years and older there was a sharp increase in nodule size without much increase in number. Based on this and other work, McNeal (7, 13) has hypothesized that there may be two phases in the development of the disease, the initial phase of formation of individual nodules arising from local tissue influences (e.g., spontaneous reversion of a clone of stromal cells to the embryonic state) and the second phase of development involving a synchronized enlargement of existing nodules, occurring simultaneously in many nodules, possibly as the result of endocrine effects. BIOCHEMICAL FACTORS Testosterone

The two most clearly established risk factors for benign prostatic hyperplasia are age

Benign Prostatic Hyperplasia

and normal testicular function (14). It is believed that the disease does not develop in men castrated prior to puberty (15), and there are very few reports in the medical literature of the disease developing in men castrated after puberty (16, 17). However, benign prostatic hyperplasia in a phenotypic man with an XX karyotype and castrate levels of testosterone has been reported (18). Peters and Walsh (19) demonstrated that, in men with established disease, a regression in prostate size could be produced by pharmacologically reducing testosterone levels to castrate levels. Dihydrotestosterone

Within the prostate testosterone can undergo irreversible 5-a-reduction to dihydrotestosterone, which has been shown to be the major intracellular metabolite within the prostate (15, 20). Testosterone and dihydrotestosterone bind to the same androgen receptor; however, the prostate androgen receptor has a fivefold higher affinity for dihydrotestosterone than for testosterone (21). Although the dihydrotestosterone contents of normal and benign hyperplastic tissue obtained at open prostatectomy have been shown to be similar (22), the nuclear androgen receptor content of benign prostatic hyperplasia tissue is higher than in peripheral prostatic tissue (23). Wilson (15) proposed that dihydrotestosterone is the primary hormonal mediator of benign prostatic hyperplasia in both dog and man. Administration of dihydrotestosterone to beagle dogs has been shown to produce both histologic and gross anatomic evidence of benign prostatic hyperplasia (24, 25). Recent data from randomized double-blind, placebo-controlled human clinical trials show that regression in established benign prostatic hyperplasia and reduction in prostate volume occurs following treatment with a specific inhibitor of 5a-reductase which markedly reduces levels of dihydrotestosterone but does not reduce testosterone levels (26). Imperato-McGinley et al. (27, 28) described an autosomal recessive form of human male pseudohermaphroditism caused

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by 5-a-reductase deficiency resulting in a marked decrease in plasma dihydrotestosterone levels. The affected males are born with ambiguous genitalia but, at the time of puberty, develop into a typical male phenotype with normal male levels of testosterone, normal spermatogenesis, and typical male external genitalia. The prostate remains small, however, and benign prostatic hyperplasia does not develop. Recently, it has been shown that there are two different human 5a-reductases (29), designated 5-a-reductase1 and 5-a-reductase-2, with 5-a-reductase-2 appearing to be the major form in prostatic tissue. Individuals with the male pseudohermaphrodite syndrome described above have been found to be deficient in 5-a-reductase2 and to have normal levels of 5-a-reductase1. Estrogen

In the castrated dog, administration of estradiol and dihydrotestosterone have been shown to act synergistically in inducing prostatic hyperplasia (25). In human benign prostatic hyperplasia the role of estrogen is less clear. Ekman et al. (30) found that the concentration of high-affinity estrogen receptors was lower in benign prostatic hyperplasia tissue than in normal peripheral prostate tissue, and Hulka et al. (31) found that serum levels of estradiol in benign prostatic hyperplasia patients were lower than in male general medical clinic controls of comparable age. However, Partain et al. (32) showed that when benign prostatic hyperplasia volume and hormonal levels were corrected for age, the volume correlated positively with free testosterone, estradiol, and estriol in 64 men who had undergone radical prostatectomies for low-volume prostate cancer. Also, the transformation of unconjugated estrogenic steroids into their glucuronide derivatives appears to be inhibited in men with benign prostatic hyperplasia (33). Other hormonal effects

Brochu and Belanger (33) found that plasma levels of 17-OH-pregnenolone, dehydroepiandrosterone, and endrost-5-ene-3-

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/3,17-/3-diol were higher in men with benign prostatic hyperplasia as compared with men of comparable age without this disease, while the plasma pregnenolone levels were not significantly different. They noted that dehydroepiandrosterone has been shown to be metabolized to a number of compounds, including dihydrotestosterone (34), in the human prostate and suggested that there may be an increase in adrenal 17-hydroxylase activity in benign prostatic hyperplasia. Prolactin receptors have been found in human benign prostatic hyperplasia specimens as well as in prostate cancer (35); the clinical significance of this is as yet unclear. a-Adrenergic effects

a-Adrenergic and cholinergic receptors have been identified in prostatic smooth muscle, surgical capsule, and bladder neck (36, 37). Stimson and Fihn (38) listed a number of medications (e.g., decongestants) that can exacerbate symptoms of benign prostatic hyperplasia through a-adrenergic or anticholinergic effects. The prostatic aadrenergic receptors have been subtyped into a-\ and a-2 receptors, with the a-l receptors being considered mainly responsible for the contractile properties of human prostate adenomas (39). Evidence from clinical trials suggests that treatment with aantagonists may be useful in relieving symptoms of benign prostatic hyperplasia (40). Randomized double-blind placebocontrolled clinical trials are in progress. Human prostatic growth factors

Several investigators have studied the role of growth factors in the initiation of benign prostatic hyperplasia (41-44). Nishi et al. (43) showed that the total content of growth factors was higher in benign prostatic hyperplasia tissue than in tissue from prostatic cancer patients and from normal controls. Lawson (44) hypothesized that basic fibroblast growth factor may be involved in the stromal hyperplasia, and that a second growth factor elaborated by stromal tissue may stimulate the epithelial component of

the disease. This work is at a much earlier stage of investigation than the evaluation of hormonal and a-adrenergic effects. Summary of biochemical factors

Although the etiology and pathogenesis of benign prostatic hyperplasia are not yet fully understood at a molecular level, it is clear that dihydrotestosterone plays a central role both in fetal prostatic development and in the maintenance of established disease. The increasing growth of the disease with age in spite of an age-related decrease in androgen production and increase in estrogen production raises the possibility that estrogen may be acting synergistically with dihydrotestosterone to stimulate growth of human benign prostatic hyperplasia, as has been shown to occur in the canine type of this disease. Triggering events in the initiation of the disease are not yet known. The compressive effect of the surgical capsule mediated through a-1-adrenergic receptors adds a dynamic component to the bladder outflow obstruction caused by the disease and contributes to variability in the clinical spectrum. Thus, the etiology of benign prostatic hyperplasia is still incompletely understood, but prostatic molecular biology and genetics are being actively investigated. STUDIES OF POTENTIAL RISK FACTORS Multiple risk-factor studies

There have been four large studies which examined multiple factors in relation to benign prostatic hyperplasia. In a case-control study of 219 men who underwent surgery for this disease and 4,669 male hospital controls, Morrison (45) found elevated risks for Jewish men compared with those of other religions, and for use of antihypertensive medications containing rauwolfia relative to no antihypertensive medications. Current cigarette smokers had a reduced risk relative to nonsmokers. In a prospective cohort study of 2,036 male volunteers (the Normative Aging Study), Glynn et al. (4) used Cox regression to examine potential predic-


tors of prostatectomy for benign prostatic hyperplasia, and of a clinical diagnosis of this disease, while controlling for age. (The "clinical diagnosis of benign prostatic hyperplasia" in this study means the recorded finding of "diffuse enlargement" of the prostate on manual rectal examination (46).) Elevated risks of prostatectomy were associated with prior clinical diagnosis of enlarged prostate, Jewish religion, lower socioeconomic status, and not currently smoking cigarettes. Low body mass index was associated with the clinical diagnosis. Sidney et al. (47) reported results of a prospective cohort study of 16,219 male members of the Kaiser Permanente Health Maintenance Organization who received multiphasic health examinations (including questionnaires) during 1971-1972 and were followed until membership termination or the end of 1987. Cox regression was used to examine the risk of prostatectomy for benign prostatic hyperplasia in relation to a number of potential risk factors, while controlling for age. Elevated risks of prostatectomy were independently associated with low body mass index, nonsmoking, a urine pH of 6 or more, and a history of any of the following: kidney or bladder infection, kidney radiography (intravenous pyelogram), regular medication during the past year, surgical operations other than prostate, and tuberculosis. Alcohol consumption of three or more drinks per day was associated with reduced risk of prostatectomy, as was the highest quartile of blood glucose measured 1 hour after an oral glucose load (> 233 mg/ dl). Religion was not recorded. Recently, Morrison (47a) studied risk factors for surgically treated benign prostatic hyperplasia in a telephone interview-based case-control study in which the cases were 910 Rhode Island residents who had prostatectomy not related to cancer in the years 1985-1987. Elevated risks were found for Jewish men and for blacks, however, the latter result was based on small numbers and was not statistically significant. Lower risks were found in men who were married or widowed, as compared with those who were never married. A weak and not statis-

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tically significant inverse relation was found for coffee drinking. Cigarette smoking also shower a weak and not statistically inverse relation, with no evidence of any relation between risk and average smoking intensity. Daily alcohol consumption was inversely related to risk. The rate ratio per 12 ounces of beer (or alcoholic equivalent in other forms of alcohol) per day was 0.96 (95 percent confidence interval 0.92-1.00, p = 0.06). Only for beer was the inverse relation strong. All four studies found smoking to be negatively associated with prostatectomy for benign prostatic hyperplasia. However, the recent study of Morrison (47a) clearly argues against causality. It is possible that the association may be confounded with smokingrelated factors (e.g., chronic obstructive pulmonary disease) having to do with fitness for elective surgery, although with transurethral prostatectomies medical disqualification is said to be rare (47). A negative effect of smoking on progression of the disease seems difficult to rationalize with findings that smoking is associated with elevated testosterone levels in humans (48) and that nicotine has been shown to promote accumulation of dihydrotestosterone in the canine prostate (49). The association of low body mass index with a clinical diagnosis of enlarged prostate in one study, and with prostatectomy for benign prostatic hyperplasia in another, is biologically plausible, since lower body mass index has been associated with higher testosterone levels (50). The decreased risk of prostatectomy associated with high alcohol intake could reflect effects of alcohol on testosterone metabolism. High alcohol consumption has been shown to decrease plasma testosterone levels, decrease testosterone production, and increase testosterone clearance in humans (51, 52). A major weakness of these studies is the case definition of benign prostatic hyperplasia. As discussed in a later section of this paper, there is no well-accepted clinical case definition of this disease suitable for use in epidemiologic studies. Hence, associations between potential etiologic factors and benign prostatic hyperplasia as defined in these

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and other clinical studies must be interpreted with caution. There is insufficient evidence to regard any of these associations as causal. Cirrhosis

Men with cirrhosis have decreased plasma levels of testosterone and dihydrotestosterone and decreased testosterone production (53, 54). Hence, it is biologically plausible that cirrhosis could retard progression of benign prostatic hyperplasia (55, 56). Several authors (57-61) have examined the relation between hepatic cirrhosis and benign prostatic hyperplasia based on autopsy studies (table 1). Four studies found a somewhat lower autopsy prevalence among men with cirrhosis. The one study in which a higher prevalence was found (61) used controls from an earlier autopsy study (62). It is not clear if the same examination procedures (e.g., number of sections examined) were used in the two studies. Also, it was stated that two of the 13 cases in the study were excluded because the only sections available for analysis were from parts of the prostate in which benign prostatic hyperplasia would not be expected; it is not clear whether comparable exclusions had been carried out in the controls. The findings from the two stud-

TABLE 1. Histologically defined benign prostatic hyperplasia in autopsies of patients with and without cirrhosis

Study (reference no.)

Bennett et al. (57) Frea et al. (58) Robson (59) Stumpf and Wilens (60)

Relative risk (cirrhosis/ controls)* Crude

adjusted

0.57 0.75 0.83 0.85 1.8

0.81 —t 0.83 0.85 —t

95o/o confidence interval

0.51-1.28 0.58-0.94 0.65-1.05 0.77-0.94 1.22-2.14

* Calculated from data in the referenced articles. The 95% confidence intervals were calculated on the age-adjusted relative risks, except for the two studies in which the age-adjusted data were insufficient. t Insufficient data. t Wu (61) cited as controls the published results of an earlier autopsy study of Moore (62); see the text for a discussion of how this may have affected the results.

ies which used age-matched controls (59, 60) were consistent with each other and with an age-adjusted analysis of the published data from an earlier study (57); all three showed relative risks in the range 0.8-0.9 with confidence intervals from two of the studies compatible with no effect. Most of the cirrhosis cases in these studies involved alcoholic cirrhosis, so that any effects of alcoholism cannot be separated from effects of cirrhosis. As noted above, Sidney et al. (47) found an alcohol intake of three or more drinks per day to be associated with a reduced risk of prostatectomy for benign prostatic hyperplasia; the age-adjusted relative risk (0.75, 95 percent confidence interval 0.60-0.94) was roughly similar to the age-adjusted risk ratios for cirrhosis shown in table 1. Despite the obvious limitations of these studies, it appears that if cirrhosis or alcoholism has any inhibitory effect on progression of benign prostatic hyperplasia, that effect is likely to be modest.

Hypertension

Bourke and Griffin (63) found that the diastolic and systolic blood pressures of men admitted for elective prostatectomies were higher than those of comparably aged men admitted for non-genitourinary elective surgery, and hypothesized that hypertension was a risk factor for benign prostatic hyperplasia. Two cohort studies found no association between elevated blood pressure and prostatectomy for benign prostatic hyperplasia (4, 47). One explanation for the results of Bourke and Griffin is that benign prostatic hyperplasia with high-pressure chronic retention of urine can be a cause, rather than a consequence of hypertension (64-66). This bias would be likely in a study where the blood pressure measurements were from men being admitted for prostatectomy. The clinical implication is that benign prostatic hyperplasia with high pressure chronic urinary retention should be considered in the evaluation of hypertension of recent onset in men aged 50 years and older.


Diabetes mellitus

Diabetes mellitus has been hypothesized to be a risk factor for benign prostatic hyperplasia, based in part on a finding of a higher age-adjusted prevalence of diabetes mellitus among men presenting for prostatectomy than would be expected in the general male population (63) and in part on uncontrolled clinical observations (67, 68). One cohort study (4) found no association between fasting blood glucose and either the clinical diagnosis of benign prostatic hyperplasia or prostatectomy for benign prostatic hyperplasia, and another study (47) found a negative association between the highest quartile of blood glucose 1 hour after an oral glucose load and prostatectomy for benign prostatic hyperplasia. The most likely explanation for the increase seen in the surgical series of Bourke and Griffin (63) is detection bias. Vasectomy

Jakobsen et al. (69) used transrectal ultrasonography to examine the prostates of 56 men with vasectomies and 56 age-matched controls. Total prostate volume, volume of the periurethral area (where benign prostatic hyperplasia would be expected), and volume of the peripheral zone were similar in the two groups. The percentages of the men in whom the prostates were considered to be adenomatous was 19.6 percent in the vasectomized group and 30.3 percent in the control group, the difference was stated not to have been statistically significant. Sidney (70) examined the relation between vasectomy and benign prostatic hyperplasia in an earlier publication from the cohort study discussed above. The relative risk of a hospital diagnosis of benign prostatic hyperplasia among men with vasectomy was 1.2 (95 percent confidence interval 0.7-1.8). In a subsequent (unpublished) analysis of data from Sidney et al. (47), the relative risk was 0.97 (95 percent confidence interval 0.751.25) (S. Sidney, Kaiser Permanente Medical Care Program, Oakland, California, personal communication, 1991). These results

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do not suggest an effect of vasectomy on the development of benign prostatic hyperplasia. Sexual activity

Several authors have studied sexual activity in relation to benign prostatic hyperplasia (62, 71, 72). While some positive associations were found in one study testing a number of hypotheses (71), there is no consistent evidence of a relation between sexual activity and benign prostatic hyperplasia (73), except in the extreme case that castration inhibits both. RACIAL, SOCIAL, AND GEOGRAPHIC VARIATION

Early in this century several influential publications served to establish the incorrect impression that benign prostatic hyperplasia was rare among blacks, both in the United States and in Africa (74, 75). Randall (76) reported an autopsy prevalence of 13 percent (41 of 314) among blacks as compared with 20 percent (179 of 883) among whites, even though the proportion of the two races aged 50 years and older was much higher in whites than in blacks (63 percent vs. 34 percent). D'Aunoy et al. (77) and Derbes et al. (78) reviewed the early literature, compared the frequency of benign prostatic hyperplasia among black and white patients treated at Charity Hospital in New Orleans, Louisiana, and concluded that the incidence among blacks was either the same as or greater than in whites, but that the disease may occur at an earlier age in blacks. Kambal (79) reported that benign prostatic hyperplasia was common in the racially mixed population of northern Sudan but rare among pure Africans in southern Sudan. However, six patients came from a small group of pure Africans who had been living in central and northern Sudan for a number of years. The deficit of cases presenting to Khartoum for surgery from southern Sudan (which was hundreds of miles away) was speculated to be caused by dietary and sexual habits. Movsas (80) concluded

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that Indians are twice as likely as Africans to develop benign prostatic hyperplasia, however, as he noted, the Africans in his study were much younger than the Indians. Several authors reviewed benign prostatic hyperplasia in the Bantu (81-83) and in Nigeria (84) and concluded that the disease was not rare, although no interracial comparative data were given. Sidney et al. (85) compared the incidence of surgically treated benign prostatic hyperplasia among 2,175 blacks and 12,722 whites who received multiphasic health examinations in the Kaiser Permanente Medical Care Program in northern California during 1971 -1972 and were followed through 1987. The age-adjusted relative risk for blacks relative to whites was 1.0 (95 percent confidence interval 0.8-1.2). By contrast, the ageadjusted relative risk for prostate cancer among blacks as compared with whites was 1.8 (95 percent confidence interval 1.4-2.3). In this study, as in one conducted more than 50 years ago (78), the incidence of treated benign prostatic hyperplasia tended to be slightly higher in blacks until age 65 years, after which it was higher in whites. Assumpcao (86) found similar ageadjusted incidences of surgically treated benign prostatic hyperplasia among aboriginals and non-aboriginals in 1980 at an Australian hospital with a geographically defined catchment area. Barss (87) found the disease to be the most common prostatic disease resulting in hospitalization among rural Melanesians in the mid-1980s, although many men died without seeking treatment since urinary obstruction was attributed to sorcery in rural New Guinea. In an autopsy study from Thailand (88), the disease was judged to have caused about 5 percent (42 of 767) of the autopsied deaths among men aged 51 years and older; 32 of the deaths were postoperative. In a study of 1,900 consecutive autopsies in Peiping, China during 1921-1935, benign prostatic hyperplasia in men aged 41 years and older was found in 6.6 percent (10 of 152) of the Chinese cases and in 47 percent (17 of 36) of the foreign (mostly Caucasian) cases. The respective age-specific percentages for dec-

ades five through eight were 2 percent, 12 percent, 10 percent, and 20 percent, respectively, for the Chinese cases and 33 percent, 56 percent, 53 percent, and 33 percent, respectively, for the foreign cases. The authors concluded that benign prostatic hyperplasia was relatively rare in Chinese (89). A more recent pathologic study of the disease in China examined findings in 175 prostates classified according to type of hyperplasia (90). Watanabe et al. (91) conducted a mass screening program with transrectal ultrasound and concluded that there was a high prevalence of benign prostatic hyperplasia in Japanese men in whom the disease had not been suspected. The overall age-specific prevalence of the disease in decades five through eight were 9.1 percent, 15.5 percent, 24.7 percent, and 25.4 percent, respectively. Isaacs and Coffey (92) plotted autopsy studies of benign prostatic hyperplasia in different parts of the world and showed that the age specific prevalence was similar in many different countries. This work has recently been updated by Bostwick et al. (93) (figure 2). Age-specific mortality statistics for benign prostatic hyperplasia for 30 countries have been compiled and analyzed (94). Several European countries (in particular, east European countries) had the highest agespecific mortality rates, while countries with the lowest rates included not only countries such as Japan and Thailand, but also the United States and Canada. As the author noted, it is not possible to separate differences in record-keeping and coding practices from actual clinical differences in outcomes. Birkhoff (95) concluded that mortality from benign prostatic hyperplasia should come mainly from three sources: uremia, sepsis, and complications of surgery. He noted that reliable data on the incidence of uremia and sepsis in association with benign prostatic hyperplasia are not available and listed 0.31.8 percent as the range of surgical mortality rates, although higher rates have been reported in some series (96, table VIII). Increased hospitalization rates and mortality rates for benign prostatic hyperplasia

Benign Prostatic Hyperplasia 139

100

80

C 0 O

60

4

I ° 20 > ' y

20-29

30-39

/

....••••••

40-49

50-59

60-69

70-79

80-89

Age Austria India

China Jaoan

— — -

Denmark Norway

England USA

FIGURE 2. Age-specific autopsy prevalence of pathologically defined benign prostatic hyperplasia in several countries. (From Bostwick et al. (93). Reproduced with permission.)

have been found in higher social classes in Scotland (97). It was not possible to determine whether the higher hospitalization rates were the result of greater willingness to seek treatment (or access to care), greater degree of bothersomeness from symptoms, more severe disease, or a combination of these. The higher mortality rates likewise had several possible explanations. An ecologic analysis of benign prostatic hyperplasia mortality and surgery rates in Wales suggested that deaths attributed to this disease, and surgery for it, were more common among people of Welsh descent than among people of English descent (98). In summary, information on racial, social, and geographic variability in benign prostatic hyperplasia is fragmentary, partly based on anecdotal reports, and limited by lack of standard diagnostic criteria and modes of case ascertainment. Comparisons of disease prevalence are confounded by such factors as access to medical care. Nonetheless, it appears that the age-specific autopsy prevalence is similar in many countries, and that within the United States the age-specific incidence of clinically diagnosed and treated

disease should be roughly as common in blacks as in whites in settings where there is equal access to health care. NATURAL HISTORY Anatomic prevalence and progression

In a purely anatomic sense, benign prostatic hyperplasia refers to prostatic cellular proliferation leading to an increase in prostate size, and it is in this sense that relation of this disease to age has been most clearly described in a series of autopsy studies. Berry et al. (99) analyzed data from published autopsy studies in four countries (England (100, 101), Austria (62), Norway (102), and India (103)) involving more than 1,000 prostates. These studies provide the best available estimates of the age-specific autopsy prevalence of histologically recognizable disease. By extrapolation of prostatic growth curves, the authors estimated that the earliest initiation of benign prostatic hyperplasia was sometime before age 30 years, a finding consistent with results of a more recent autopsy study (104). The average weight of the prostate among the 86 men aged 21 -30 years

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was 21 grams; none of these men had histologic evidence of the disease. The percentage of men with histologic evidence was 42 percent (81 of 191) among men aged 51-60 years and 85 percent (63 of 74) among men aged 81 years and older. The average weight of a prostate recognized at autopsy to contain benign prostatic hyperplasia was 33 grams; only 4 percent of the prostates in men over 70 years of age weighed more than 100 grams. The largest reported prostate size in benign prostatic hyperplasia appears to be 1,058 grams, in a 55 year-old Caucasian man (105). It is worth noting that autopsy studies involve a select population which may not be representative of the general population. Hence, inferences about prostate growth and development based on autopsy studies are subject not only to biases caused by treating cross-sectional age-specific measurements as if they were longitudinal, but also to autopsy selection bias. A recent community-based study of clinically diagnosed benign prostatic hyperplasia in Scotland found age-specific mean prostate weights by transrectal ultrasound (106) that agreed closely with the autopsy data analysis of Berry et al. (99). Another cross-sectional study of prostate size determined by transrectal ultrasound (107) found that the average volumetric increase in prostate size from age 30 years to age 70 years was about 0.2 ml per year, a somewhat lower rate than found in autopsy studies. While prostates with ultrasonic evidence of adenomatous growth (benign prostatic hyperplasia) had a somewhat higher mean volume than those that did not, there was considerable overlap. The authors concluded that prostate size alone is not sufficient for a diagnosis. These cross-sectional studies convey the impression of a steady increase in prostate size with increasing age. However, Ohnishi et al. (108) followed 16 patients with periodic transrectal ultrasound measurements over 7 years and concluded that some patients had very rapid periods of prostate growth during the span of a few years in the sixth decade, with little further change in prostate size.

Isaacs and Coffey (92) formulated a conceptual model of the natural history of benign prostatic hyperplasia with two phases (pathologic and clinical), where the first phase is subdivided into two stages (microscopic and macroscopic). They concluded, on the basis of autopsy studies, that nearly all men develop microscopic benign prostatic hyperplasia, half go on to develop macroscopic disease and half of the latter group develop clinically treatable disease. The conceptual model is a useful way to think about the development of benign prostatic hyperplasia. However, the probabilities of progression were based on comparing crosssectional data from various sources and, hence, must be viewed as rough approximations. While the age-specific autopsy prevalence of pathologically defined benign prostatic hyperplasia has been described with reasonable accuracy, much less is known about the age-specific prevalence of clinically diagnosed benign prostatic hyperplasia. Widely accepted clinical diagnostic criteria suitable for use in epidemiologic studies do not exist (56). Some epidemiologic studies of benign prostatic hyperplasia have taken as a case definition the presence of an enlarged prostate, as measured by manual rectal examination (4), transrectal ultrasonography (108, 109), or autopsy (76). However, manually determined prostate size has been shown not only to have a high degree of interobserver variability (110) but also to have poor accuracy when compared with prostate weights determined at surgery (111). Prostate size as measured by transrectal ultrasonography has shown good agreement with surgically defined prostate size (112), but the latter does not correlate with urodynamic measures of bladder outflow obstruction or degree of symptomatic improvement following prostatectomy, and is only weakly correlated with obstructive urologic symptoms (113, 114). The weight distribution of prostates which are pathologically normal at autopsy shows considerable overlap with the weight distribution of prostates found to contain pathologic evidence of the disease


(99, figure 3). A similar degree of overlap holds with studies based on transrectal ultrasonography (107). Thus, even when measured accurately, prostate size correlates poorly with pathologically defined benign prostatic hyperplasia or with evidence of bladder outflow obstruction (infravesical obstruction) caused by this disease. Hence, defining the disease clinically only in terms of prostatic enlargement would be neither anatomically accurate nor relevant to the clinical problem of deciding whether a patient has a condition (bladder outflow obstruction caused by benign prostatic hyperplasia) which a subtotal prostatectomy is likely to alleviate (14, p. 1258; 113). The need for making case definitions relevant to the problem of deciding who might benefit from therapy was recently identified, perhaps inappropriately, as a general criticism of epidemiologic studies in this field (115). To understand why prostate size correlates poorly with histologically diagnosed benign prostatic hyperplasia or with bladder outflow obstruction due to this disease, it is useful to consider where and how the disease develops. Because the expansile nodules originate in a highly localized periurethral region occupying less than about 2 percent of total prostate mass (10, 13), it is possible for obstruction to occur without much increase in prostate size. Alternatively, diffuse enlargement of the transition zone may produce considerable increase in prostate size without much obstruction. Bladder outflow obstruction from benign prostatic hyperplasia typically causes several characteristic urologic symptoms, including hesitancy in starting urination, diminished stream size and force, involuntary interruptions in stream, and a sensation of incomplete bladder emptying (116, pp. 45-51). The ill-defined term "prostatism" refers to the symptom complex characteristic or to disease diagnosed only on the basis of a medical history and physical examination. No combination of symptoms is diagnostic of benign prostatic hyperplasia (113, 117119), and prostate size shows at best weak correlations with symptoms (117, 120-122).

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The most widely used noninvasive measure of bladder outflow obstruction in patients with the disease is the maximum urinary flow rate, measured by a collecting device which senses volume and time and electronically calculates flow rates (123, 124). Normal values for men have been determined as a function of age and voided volume (123-129). Maximum flow rates below 10 ml per second in men with symptoms of benign prostatic hyperplasia are associated with obstruction (113, 130, 131). Prostatectomy produces substantial immediate improvements in urinary flow rate, followed by a slow annual decline from the initial postoperative values (132). While some statistically significant relations between symptoms and maximum urinary flow rates have been obtained, the correlations are weak and sensitivity and specificity are poor (117, 133, 134). Urinary flow rate alone cannot be used to diagnosis bladder outflow obstruction or to predict favorable response to prostatectomy (113, 135, 136). Invasive urodynamic procedures to measure pressure-flow parameters are not suitable for epidemiologic studies, and many urologists do not regard them as necessary for routine use in the clinical evaluation of patients for surgery (113). Cystourethroscopy is often used clinically to determine whether bladder outflow obstruction is present (14); however, cystourethroscopy.is too invasive for use in epidemiologic studies and is not recommended as a sole criteria for diagnosing bladder outflow obstruction due to benign prostatic hyperplasia or in selecting patients for surgery (113). Post voiding residual urine volumes are used to assess bladder outflow obstruction in evaluating patients for surgery, but the degree of withinpatient, within-day variation in the measurement makes its suitability for epidemiologic studies questionable (137, 138). Part of the rationale for considering residual urine is to decrease risk of urinary tract infection; however, Bruskewitz et al. (137) has observed that the association between high residual urine volumes and subsequent urinary tract infections has not been established.

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Clinical studies of benign prostatic hyperplasia often do not state the specific criteria used to define the disease or else avoid the problem by studying "objectively defined" bladder outflow obstruction in men with prostatism and not giving the criteria used to make the objective definition. Some epidemiologic studies have used a case definition based on some combination of symptoms, urinary flow rates, and prostate size measurements (106). However, the lack of a well-accepted standard epidemiologic case definition makes it difficult to compare results between studies. Finally, a number of epidemiologic studies have studied either hospitalized cases or surgically treated cases of benign prostatic hyperplasia (4, 45, 47, 77, 78, 85-87, 96-98, 121, 139-142). Information on surgically operated cases is easier to identify than on other types of cases, and a tissue diagnosis is generally available only on cases who had surgery, or who undergone biopsy because of suspicion of prostate cancer, or came to autopsy. Barry (56) has cautioned against interpreting surgically treated disease as a surrogate for benign prostatic hyperplasia corresponding to a given level of objectively defined disease severity, because ageadjusted rates of surgery are influenced not only by factors related to the disease itself but also by patient and physician treatment preferences, referral thresholds of primary care physicians, accessibility of surgical care, and operating thresholds of urologists (143147). A further discussion of variability in the incidence of surgically treated disease is given in a later section of this paper. In summary, clinical and epidemiologic studies of benign prostatic hyperplasia are hampered by the lack of standardized diagnostic criteria, the poor agreement among different measures used in clinical evaluation, the small numbers of patients in most individual studies, and the lack of correlation between preoperative evaluations, and postoperative outcome. Interpretation of comparisons among population statistics in different countries are further complicated by differences in access to medical and surgical care, patient preferences and attitudes,

treatment thresholds, and variations in coding practice. These limitations have been pointed out by other authors (55, 56, 113) and must be considered when interpreting results of epidemiologic studies of benign prostatic hyperplasia and its natural history. Clinical prevalence

Estimates of the age-specific prevalence of benign prostatic hyperplasia vary widely depending on the way in which the disease is defined (figure 3). In figure 3 the first bar represents the autopsy prevalence of pathologically defined disease from a compilation of autopsies in four countries (99). This shows surprisingly close agreement with the second bar, which is age-specific prevalence of prostatism (disease diagnosed clinically on the basis of a medical history and manual rectal examination) in the Baltimore Longitudinal Study of Aging (148). The third bar is the age-specific prevalence of the disease defined as "enlarged prostate on manual rectal examination," in exactly the same population and the same examinations as were used to obtain the second bar (148). Thus, two definitions of benign prostatic hyperplasia in the same study yield very different prevalences. The fourth bar represents the same definition (enlarged prostate) as the third bar, but in a population of men having medical examinations to qualify for life insurance (149). The reasonably close agreement between the prevalence estimates provided by the third and fourth bars could be because of the use of the same case definition, despite the differences in the population groups studied and the poor accuracy and high interobserver variability of such examinations on individual patients (110, 111). The fifth and sixth bars represent the age-specific prevalence of the disease defined in the same way (using a symptom score, urinary flow rate, and prostate size by transrectal ultrasound) in a Scottish community (106) and a US community (C. Johnson and C. Chute, Mayo Clinic, Rochester, Minnesota, personal communication, 1991). The seventh bar represents the prevalence of benign pros-

Benign Prostatic Hyperplasia 143

c

2

100 80

C 0)

O i_

QL

40-49

50-59

60-69

70-79

Age ^H 1 FIGURE 3. Age-specific prevalence of benign prostatic hyperplasia. Bar 1, prevalence of pathologically defined benign prostatic hyperplasia from a compilation of five autopsy studies {n = 1,075) (99); bars 2 and 3, clinical prevalence in the Baltimore Longitudinal Study of Aging (n = 1,057) (121,140,148): bar 2 is based on history and physical examination and bar 3 is based on the presence of an enlarged prostate on manual rectal examination; bar 4, prevalence is based on an enlarged prostate on manual rectal examination from a compilation of life insurance examinations (n = 6,975) (149); bar 5, community prevalence in Bridge of Allan, Scotland, based on a case definition using symptoms, prostate size, and urinary flow rates (n = 699) (106); bar 6, community prevalence in Rochester, Minnesota, using the same case definition as in bar 5 (n = 457) (C. Johnson and C. Chute, Mayo Clinic, Rochester, Minnesota, personal communication, 1991); and bar 7, prevalence in Japan based on transrectal ultrasonography in a mass screening study (n ~ 3,000) (91,109).

tatic hyperplasia by transrectal ultrasonography in a Japanese mass screening study (109). It is evident that the disease, however defined, is prevalent in a substantial fraction of men aged 50 years and older, that prevalence increases with age, and that differences in prevalence among studies could be because of different case definitions, differences in the populations studied, or both. To describe benign prostatic hyperplasia clinically, it is necessary not only to describe physical findings and symptoms, but to relate these to patient perceptions and to interference in daily activities. The latter considerations are important for understanding how the disease affects patients and have been shown in a decision analysis to be important for deciding among treatment options (143). Two community studies now in progress in Scotland and in Minnesota (106, 150) are examining this using similar protocols. The American Urological Associa-

tion has recently developed a questionnaire which the World Health Organization has recommended for use in the diagnosis and treatment of this disease (151). Clinical progression

Most information on the clinical course of benign prostatic hyperplasia has been obtained from relatively small series of patients followed in urology clinics over various time periods for symptoms of prostatism (117, 152-154). These studies have shown that the clinical course of benign prostatic hyperplasia in individual patients is highly variable over time, whether measured by symptoms or by urinary flow rates. An appreciable fraction of patients improve spontaneously without treatment. Because of the small sample size and the high degree of intraindividual variability in the diagnostic measures used to assess the disease, most studies

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have had little statistical power to quantify what factors are relevant to long term prognosis. Three prospective studies, representing successive 10-fold multiples in size, have examined which urologic symptoms are most predictive of subsequent prostatectomy for benign prospective hyperplasia in a general male population. The first study (155) found no combination of symptoms to be predictive in a population of 115 men followed for up to 7 years. The second study (121) analyzed data from the Baltimore Longitudinal Study of Aging involving 1,057 men followed for up to 30 years with periodic general health questionnaires (including eight urologic symptoms) and physical examinations. In a multivariate Cox regression three factors were predictive, each with a relative risk of about 2: 1) weak stream, 2) sensation of incomplete emptying, and 3) enlarged prostate on manual rectal examination. Another symptom (hesitancy in starting urination) did not quite reach statistical significance as a predictor of prostatectomy but was associated with an enlarged prostate. The third study (47) used questionnaire data from 16,219 men who received multiphasic health examinations during 1971-1972 while members of the Northern California Kaiser Permanente Medical Care Program and who were followed by computer records through 1987 (47). There was no information on prostate size and the questions were somewhat different from those in the second study. The following urologic symptoms were predictive in a multivariate Cox regression: hesitancy, weak stream, painful urination, loss of bladder control, and nocturia. In both the second and third studies the urologic questions were part of general health questionnaires which were administered for research purposes and were unlikely to have been seen by the surgeons who later made the decisions to perform prostatectomies. These two studies are the only ones to quantify the extent to which prospectively ascertained symptoms and rectal examination findings predict prostatectomy for benign prostatic hyperplasia in a general male population.

Complications

Potential complications of the outflow obstruction and urinary residuals caused by benign prostatic hyperplasia include bladder wall muscular hypertrophy leading to trabeculation and formation of diverticula. When urine remains in the diverticular outpouchings of the bladder, bacterial overgrowth may ensue leading both to urinary tract infections and formation of bladder calculi. Reflux into the ureters may eventually occur, with resulting hydronephrosis, and sometimes pyelonephritis with permanent renal damage. Finally, acute episodes of complete urinary retention may develop, necessitating emergency surgical intervention. The main sources of morbidity and mortality with benign prostatic hyperplasia are renal failure, urologic infections leading to pyelonephritis and sometimes to sepsis, acute urinary retention, and mortality from complications of therapy (95). Quantitative epidemiologic information on the likelihood of these complications and on what risk factors may be most important is lacking (56). Information on the frequency of renal impairment in benign prostatic hyperplasia comes mainly from surveys of men undergoing prostatectomy for this disease and from surveys of hospital admissions for renal failure. Elevated plasma creati nines were found in 7 percent of men at the time of prostatectomy (156), and upper urinary tract dilatation has been reported in 5 percent of men being investigated in-hospital for prostatism (157, 158). In a review of communityacquired acute renal failure presenting to the Boston Veterans Administration Medical Center, 17 percent of the cases were due to urinary obstruction, of which 65 percent were considered to be caused by benign prostatic hyperplasia (159). These results imply that benign prostatic hyperplasia is responsible for an appreciable fraction of acute renal failure among older men, and at least several percent of men coming to prostatectomy for this disease have evidence of clinically significant renal impairment. However, the probability of renal impairment among


men with this disease has not been quantified, even though this is one of the major sources of serious morbidity. Estimates of the incidence of acute urinary retention among men with benign prostatic hyperplasia are based on a few studies, with estimates of risk ranging from 0.4 to 6 percent per year (38, 152, 153, 155). Acute urinary retention is unpredictable in onset and men who develop it do not tend to be among the most highly symptomatic (152, 160). Although acute urinary retention is often the presenting complaint in men with benign prostatic hyperplasia (155), it can also occur in men who do not have the disease (161). Bacteriuria has been found in about 9 percent of men with the disease without urinary tract instrumentation, increasing to 15 percent with instrumentation (162, 163). In an East German population where the proportion of all deaths coming to autopsy was about 32 percent, Grosse (164, table 6) tabulated the autopsy prevalence of bladder stones and stones of the kidney and/or ureter among 9,961 men and 9,902 women aged 60 years and older. The autopsy prevalence of bladder stones among men aged 60 years and older was more than eight times higher in men with evidence of benign prostatic hyperplasia (3.4 percent) than in men without evidence of the disease (0.4 percent) or in women (0.3 percent). Stones of the kidney and/or ureter were about equally prevalent in the three groups (6.0 percent, 5.7 percent, and 5.6 percent, respectively). This supports the clinical impression that benign prostatic hyperplasia predisposes to formation of bladder stones but not to upper tract (kidney or ureter) stones.

TREATMENT

A comprehensive discussion of treatment outcomes of benign prostatic hyperplasia research is beyond the scope of this paper. However, a brief review of the main issues is helpful in understanding how lack of knowledge of the natural history of untreated benign prostatic hyperplasia contrib-

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utes to variability in treatment approaches and outcomes. Within the United States, age-adjusted rates of prostatectomy for benign prostatic hyperplasia vary by a factor of three among local hospital service areas and by a factor of 1.7 in larger geographic areas (144-146, 165). Variation in age-adjusted rates between and within European countries is also substantial (166). In addition, postoperative mortality rates vary greatly among hospitals (167) as well as among studies (96, table VIII). Efforts to explain the high variability in rates of prostatectomy for benign prostatic hyperplasia motivated research to develop a decision-analytic model based on probabilities derived from the medical literature and from analyses of medical claims databases (143, 145). The decision which maximized quality-adjusted-life-months was particularly sensitive to how much symptoms bothered patients and interfered with their lives. Patients who experienced similar symptoms at similar levels of frequency differed considerably in how much the symptoms bothered them (168). The investigators concluded that new methods were needed to permit patients to evaluate decisions about prostatectomy based on their own preferences and results of a decision analysis applicable to their case. As an outgrowth of this work there has been an increased emphasis on development of questionnaires to assess symptoms and quality of life in men with the disease (119, 143, 151, 168). Another area of controversy concerns differences in postoperative mortality and reoperation rates between two different surgical approaches to prostatectomy in patients with benign prostatic hyperplasia. Nearly all prostatectomies for this disease in the United States are performed by the transurethral route. Other approaches (e.g., suprapubic, perineal), known as "open" prostatectomies, are typically reserved for men with prostates too large to permit transurethral resection. Several recent studies conducted using administrative databases have found consistently higher rates of postoperative mortality and higher reoperation rates

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with transurethral prostatectomies as compared with open prostatectomies (167, 169, 170). Differences in mortality persist after extensive adjustment for comorbidity (169). However, the causes of the excess deaths have differed among studies (169, 170). A recent study using medical records to obtain additional information on comorbidity found that differences in patient characteristics that were not available in the discharge diagnosis data may explain differences in the long-term mortality following these types of prostatectomies (171). This result is in keeping with a recent study which called into question the validity of comorbidity adjustments based on coded secondary discharge diagnoses (172). PROSTATE CANCER RISK AMONG MEN WITH BENIGN PROSTATIC HYPERPLASIA

The relation between benign prostatic hyperplasia and prostate cancer was investigated in two conflicting studies (173, 174) which were recently reviewed by Nomura and Kolonel (52). The study where no risk increase was found compared prostate cancer incidence among men who had undergone transurethral prostatectomies for benign prostatic hyperplasia with that in agematched male controls. The author justified his use of benign prostatic hyperplasia patients who had undergone transurethral prostatectomies by noting that prostatic cancer typically involves a part of the prostate not removed by transurethral prostatectomy (8). However, the exclusion from the benign prostatic hyperplasia cases of men with latent prostate cancer found at transurethral prostatectomy may have created a bias in this study, since no similar exclusion could be made for the controls (52, 175, 176). The study which found a positive association consisted of two parts, a follow-up study of men who had been hospitalized for benign prostatic hyperplasia and a casecontrol study in which prostate cancer cases were compared with controls with respect to a history of antecedent hospitalizations for possible benign prostatic hyperplasia (173,

177). In selecting prostate cancer cases, all those suggestive of having been discovered in latent form were excluded. Nearly all of the potential controls had received rectal examinations and those potential controls who had been found to have had an enlarged prostate were eliminated. Both studies found similar elevations in relative risk. The authors noted that both benign prostatic hyperplasia patients and controls were considered to have had similar diagnostic scrutiny for prostate cancer. The authors attributed their finding of an increased prostate cancer risk among men with benign prostatic hyperplasia to either a third (unknown) factor being causally related both to benign prostatic hyperplasia and prostate cancer or to a direct association in which benign prostatic hyperplasia either itself predisposed to prostate cancer or was an intermediate stage in the causal pathway between some other factor and prostate cancer. One of the limitations of this study was the lack of a tissue diagnosis of benign prostatic hyperplasia (52, 175, 176). Also, men with clinically diagnosed benign prostatic hyperplasia may receive more medical attention for prostate cancer, because the symptoms of this disease are similar to those of prostate cancer. This could occur in ways that would be difficult to measure in any epidemiologic study. In the 20 years since these studies were undertaken there have been a number of advances in the understanding of both benign prostatic hyperplasia and prostate cancer. It is of interest to examine the relation between benign prostatic hyperplasia and prostate cancer in light of current knowledge. Several lesions have been identified which appear on pathologic grounds to be precursors of prostate carcinoma. One of these, known as atypical adenomatous hyperplasia, has an anatomic distribution similar to benign prostatic hyperplasia (93, 178-180). In its milder forms it may sometimes be difficult to distinguish histologically from benign prostatic hyperplasia, and in its more severe forms it resembles prostatic carcinoma. Bostwick et al. (93) has suggested that benign prostatic hyperplasia could be related


to a subset of prostate cancers arising in the transition zone, perhaps in association with atypical adenomatous hyperplasia. Any epidemiologic study to evaluate histologically defined benign prostatic hyperplasia as a risk factor for prostate cancer would have to distinguish benign prostatic hyperplasia with atypical adenomatous hyperplasia from benign prostatic hyperplasia without atypical adenomatous hyperplasia. This would require a tissue diagnosis of benign prostatic hyperplasia, which would require biopsy (usually performed for suspicion of prostate cancer), subtotal prostatectomy, or autopsy. Harbitz and Haugen (102) found no relation between pathologically defined benign prostatic hyperplasia and prostate cancer in an age-stratified analysis of a consecutive series of 206 autopsies of men aged 40 years and older. The frequency of prostate cancer in men with previous prostate surgery for benign prostatic hyperplasia was similar to that in men with no prior prostate surgery. Holund (181) reported no conclusive evidence of a relation between benign prostatic hyperplasia and latent prostate cancer in a study of 223 consecutive autopsies, but did not give sufficiently detailed data to permit calculation of appropriate statistics. Billis (182) noted a number of autopsy studies giving conflicting results regarding the relation between latent prostate cancer and benign prostatic hyperplasia. McNeal et al. (183) found evidence that some stage A (nonpalpable) prostate cancers appear to have arisen within benign prostatic hyperplasia tissue. On the basis of morphometric studies he estimated that as many as half of all anterior prostatic cancers may be accounted for by malignant transformation of benign prostatic hyperplasia. This study did not provide any suggestion that a given volume of benign prostatic hyperplasia tissue was any more likely, or any less likely, to transform to prostate cancer than a given volume of other glandular tissue in the transition zone or peripheral zone. On the basis of this study and on the findings of McNeal (8), one might hypothesize that the likelihood that a given volume of transition zone or peripheral zone glandular tissue gives rise

147

to prostate cancer in a given time period is proportional to the volume of the tissue. If this were true, then benign prostatic hyperplasia would predispose to prostate cancer, roughly in proportion to the amount of excess glandular tissue, over time. An increased risk of prostate cancer in glands with benign prostatic hyperplasia would be in keeping with the observation that prostate cancers arise from active rather than atrophic epithelium (8). On the other hand, this hypothesis appears to have been considered by Greenwald et al. (174) and rejected because of lack of supporting evidence in the rather limited data available to address it. Nomura and Kolonel (52) concluded that the issue of whether benign prostatic hyperplasia could predispose to prostate cancer would be difficult to study epidemiologically because of the high prevalence of benign prostatic hyperplasia in older men; the fact that histologic confirmation of benign prostatic hyperplasia is generally available only following transurethral prostatectomy, which is only performed on men in whom benign prostatic hyperplasia is clinically suspected; and the possibility that men being followed for benign prostatic hyperplasia may have increased diagnostic surveillance for prostate cancer. They suggested a cohort study in a population of men with a prevalence of benign prostatic hyperplasia below 50 percent, screened for prostate cancer by the best available means. In view of the anatomic heterogeneity of clinically diagnosed benign prostatic hyperplasia, even a study of the type proposed would be open to several different interpretations. A recent small ecologic study (184) raised the hypothesis that racial differences in 5-areductase activity, resulting in differences in intraprostatic levels of dihydrotestosterone, may account for some of the differences in rates of prostate cancer in different racial groups. Dihydrotestosterone is necessary for normal fetal prostatic development (27) and plays a role in maintenance of established benign prostatic hyperplasia (15, 23). Inhibition of 5-a-reductase activity has been shown to result in reductions in prostate

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volume in men with benign prostatic hyperplasia (26). The hypothesized relation of 5a-reductase activity to prostate cancer merits further investigation.

search required involves not only examining disease mechanisms and etiologic factors, but also measuring patient perceptions and quality of life (143, 185).

CONCLUSIONS

REFERENCES Benign prostatic hyperplasia is heterogeneous in its etiology, pathology, and pathophysiology, so it is hardly surprising that it is similarly heterogeneous in its onset, severity, untreated natural history, and response to therapy. Adding to the natural complexity of the disease itself are lack of standardized diagnostic criteria, high degree of intraindividual variability in evaluation measures, small sample sizes and short duration of most studies, and the confounding effects of differences in patient attitudes and access to care. The lack of quantitative information on the natural history of benign prostatic hyperplasia makes it difficult for clinicians to know when, how, and in whom to intervene. This, in turn, contributes to the large amount of variability in treatment approaches from one hospital to the next. In the legislation (Public Law 101-239) establishing the Agency for Health Care Policy and Research, the US Congress listed benign prostatic hyperplasia as one of three medical conditions for which the Agency for Health Care Policy and Research is to fund development of clinical treatment guidelines, based on a formal evaluation of available scientific knowledge and professional judgment. While much of the emphasis to date in the guideline development process has centered on assessing outcomes of treatment, there has been increasing recognition that additional descriptive information on the epidemiology and natural history of benign prostatic hyperplasia is a prerequisite to a proper assessment of the risks and benefits of treatment (55, 56, 113). This view was reiterated at a recent international consultation on benign prostatic hyperplasia sponsored by the World Health Organization, and recommendations for the direction of future research were given (5). With benign prostatic hyperplasia, as with many other chronic diseases, the epidemiologic re-

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