Epidemiology and Natural History of Benign Prostatic Hyperplasia

Transcription

1 ~~ - Review Article Int J Urol 1997;4: Epidemiology and Natural History of Benign Prostatic Hyperplasia Taiji Tsukamoto* and Naoya Masumori Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan Key words: benign prostatic hyperplasia, lower urinary tract symptom, epidemiology, natural history I NTROD UCTl ON Lower urinary tract symptoms (LUTSs), often associated with an enlargement of the prostate, are common in men over 50 years old. At least 300,000 patients with LUTSs are treated annually by physicians in Japan, and this figure is expected to increase in the coming years. It is unlikely that all of these patients have clinical benign prostatic hyperplasia (BPH). BPH is a very complex, heterogeneous disease condition, in which urinary symptoms, prostate size, and urinary flow are not always interdependent. In addition to the heterogeneous nature of the disease, the causes of this disease may be multiple and heterogeneous. Hormonal factors, growth factors, stromalepithelial interaction, and aging are likely involved in the disease development.' The last decade has been fruitful for improving the understanding of the biology and pathophysiology of BPH, as well as the diagnosis and treatment of clinical BPH. Many experimental and clinical studies, although still incomplete, have clarified some aspects of the biology, which had been veiled in the past. However, more questions relating to basic and clinical issues have been raised concerning the diagnosis and treatment of BPH. In addition, clinical profiles of patients with BPH have dramatically changed over the last decade in Japan. Two decades ago, diagnosis and treatment for BPH was simple and straightforward. Most patients had typical, severe LUTSs, markedly impaired urinary flow, enlargement of the prostate, and a significant volume of residual urine. Treatment was by either of 2 surgical procedures that were the only effective treatment modality clinically proven at that time. These procedures, transurethral resection of the prostate (TURP) or (subcapsular) prostatectomy, yielded favorable outcomes in most patients. Currently, patients who visit urologists for LUTSs tend to have a widely distributed severity of symptoms, ranging from very mild to severe.2 They may have a prostate of normal size and a urinary flow rate Received for publication in revised form Mar. 5, *Correspondence and requests for reprints to: Department of Urology, Sapporo Medical University School of Medicine, Sapporo 060, japan. corresponding to that expected for their age, in spite of LUTSs. Moreover, we now have several medical and surgical treatment options, including watchfulwaiting, for treating BPH. Unfortunately, the indications and effectiveness of each treatment have not been necessarily defined.' This situation makes therapeutic decision making difficult in the evaluation of men with LUTSs. These unfavorable aspects for the diagnosis and treatment of BPH are partly derived from 2 facts. First, there is no widely accepted, standardized definition or diagnostic criteria for clinical BPH.' The estimates of the prevalence of BPH depend on the definition Indeed, some studies have estimated a prevalence of clinical BPH based only on the size of the prostate, as determined by digital rectal examination (DRE), while others base diagnosis on prostate size and consideration of LUTSs. These discrepancies may bias the diagnosis of BPH and selection of treatments. Secondly, our understanding of the natural history of clinical BPH is still limited. We cannot predict the clinical course for the next 5 years of a 65-year-old patient who has moderate LUTSs, a maximum urinary flow rate < 15 mljs, and a moderately enlarged prostate. He could have several different treatments; he may receive TURP, or take medication for relief of symptoms, or use Watchfulwaiting, or various combinations of these therapie~.~ In this article, we review the prevalence and natural history of BPH, which we hope will result in a better understanding of this disease and the treatment of men with urinary symptoms. PREVALENCE Pathologic Benign Prostatic Hyperplasia Pathologic BPH is defined as a proliferation of heterogeneous components in the prostate, resulting in micronodule formation. While a limited clinical implication is noticed, pathologic BPH can be divided into 5 nodular types. They are the adenomyofibromatous type (the most common), and the fibromuscular, muscular, fibroadenomatous and stromal types. However, these nodules in tissues with BPH are heterogeneously mixed, consisting of varying proportions of epithelium, fibrous tissue, and smooth muscle.6 In /97/ /US$ JUA/CLJ

2 Int J Urol 1997;4: deed, BPH has different proportions of epithelialstromal ratio that varies substantially from 1 :3 to 4: 1.7 Proportions of cellular components in BPH may be different among different nationalities and races. Lepor et a1.* demonstrated in their comparative histologic study of BPH in Chinese and white American men that Chinese BPH samples contained significantly more glandular lumens and less smooth muscle and connective tissue. They suggested that this result may explain the differences in estimated prevalence of clinical BPH between these nationalities, since a higher proportion of the stroma has been suggested to be more frequently associated with symptomatic BPH.9 However, in our preliminary study of 18 clinical BPH tissue samples from Japanese men examined by using an image analyzer, we found that the smooth-muscle component occupied 47% of the total area of the prostate, and that connective tissue occupied 20% of the area. O These values nearly correspond with those of BPH samples from the white Americans studied by Lepor et a1.8 This issue will need further investigation. Data from various autopsy studies have revealed that the age-specific prevalence of pathologic BPH is similar among different nationalities, 1-13 as is the prevalence of latent prostate carcinoma. For example, the data from the 4 autopsy studies of Japanese men indicate that pathologic BPH starts to develop as early as the third or fourth decade (in their 20s and ~OS), and the prevalence increases in a linear fashion with age, as shown in Fig. l More than half of men aged 60 years or older have pathologic nodule formation in the prostate. This is the case for white American and Chinese men, in which autopsy studies revealed a similar trend in prevalence. These findings for age-specific prevalence suggest that pathologic BPH development starts in the early years of adult men, and that a common factor(s) inducing this disorder may be present in all men. Because men in Western countries have been suggested to have a higher prevalence of clinical or symptomatic BPH than those in Asian countries, progression from pathologic BPH to clinical or symptomatic BPH may be influenced by unknown promoting factor(s). Clinical Benign Prostatic Hyperplasia The age-specific prevalence of clinical BPH depends on how BPH is defined. Men with BPH who participated in mass screening studies for prostate diseases, including carcinoma, composed a group having a mixture of presenting symptoms. Even in a clinical setting, not all men have typical clinical features of BPH characterized by significant LUTSs, markedly decreased urinary flow rate, and prostate enlargement. Thus, it may be impossible to regard clinical BPH as a homogeneous disease; rather, it may be a kind of syndrome.2 In addition, how men are enrolled in the study is another crucial point for an estimation of clinical BPH prevalence. l8 If men voluntarily participate in a study, it will likely include those comparatively symptomatic, so that the prevalence will be a - On - - A0 - n A. h Y 0 0 Ic) I I I I I a NO. of autopsies (0) (8.3: (20.5: (32.1 : (58.5: (71.8: (77.1: (average, range of ) ) ) ) ) ) % prevalence of pathologic BPH) 0 (0) (1.5: (21.7: (42.1 : (67.4: (82.8: (85.0: 0-3.6) ) ) ) ) ) Fig. 1. Age-specific prevalence of pathologic benign prostatic hyperplasia (BPH) in autopsy samples of prostate glands. Solid circle, the average BPH prevalence of open circle, the average BPH prevalence of England, Austria, Norway, Denmark and the USA, adapted from the data by Bostwick et ai.l3; open triangle, the prevalence of BPH in China. 234

3 Epidemiology and Natural History of BPH overestimated unless participation or response rate is high. Thus, we should consider study design, as well as the definition of clinical BPH, when we try to estimate the prevalence of clinical BPH based on results in clinical settings, or in community- or population-based studies. In this section we will estimate the prevalence of various indices of BPH in studies freely enrolling voluntary participants, and community- and population-based studies. Enlarged prostate in studies enrolling voluntary participants When findings on DRE alone were evaluated in 6975 American men who received life insurance examinations, the prevalence of enlargement of the prostate was 8.8% for those in their forties, 20.0% for those in their fifties, 35.0% for those in their sixties and 42.9% for those in their seventies. In another American study of the prevalence of enlarged prostate as determined by DRE, where the participants were volunteers, these figures were similar, but somewhat higher, in all age decades.20 Irrespective of the minor difference in the prevalence of enlarged prostate between the 2 American studies, it is interesting that the prevalence increases at a rate almost equal to that of pathologic BPH found in autopsy studies, when enlargement of prostate size and/or LUTSs (obstructive symptoms) are considered.20 We do not have data from such studies in Japan, but in our experience of mass screening for prostate diseases, which freely enrolled 1764 men 50 years old or older, we found that a definitely enlarged prostate (moderate or marked enlargement), determined by DRE, was found in 4.4% of men in their fifties, 10.1% of those in their sixties and 15.9% of those in their seventies.2 Symptoms in participants of community- or population-based studies It is crucial to the determination of the prevalence of a disease or disease condition to enroll participants who are representative of the population from which the inference will be drawn. There are many methods to achieve this, but 2 are commonly used. * The first is to freely invite all eligible persons to join a study (community-based study), in which a high participation or response rate is mandatory. This study protocol is most easily implemented when eligible persons live in a small community and a primary care medical facility is provided. The second protocol is to randomly select participants according to a proportion of general population in the area (population-based study). This study design is typically used for larger population areas. In either of these protocols, and in the absence of nonresponse bias, the measured prevalence could be extrapolated to that in the general population. T. Tsukamoto and N. Masumori In this section, we will mainly focus on urinary symptoms, flow, and prostate size measured by community- or population-based studies in various countries, including Japan, to determine their prevalence. In addition, the prevalence of clinical BPH specifically defined will be estimated. Several symptom index systems, such as the Boyarsky Symptom Index2 and the Madsen-Iversen Symptom Index,23 were used before the American Urological Association (AUA) Symptom Indexz4 or the International Symptom Score (I-PSS)25 were established. However, the former indices were not widely accepted. The AUA Symptom Index or the I- PSS (this consists of an essential part of the AUA Symptom Index) have been evaluated for their sensitivity, validity, reliability and responsiveness of the questionnaire^.^^ They have been widely used for evaluating LUTSs in a clinical setting. In particular, the I-PSS was translated into various languages so that international comparison of LUTSs of men in various countries has been possible, while translation and cross-cultural validation is intended to minimize linguistic differen~e. ~,~~ Lower Urinary Tract Symptoms. Using the I-PSS or the symptom score compatible with I-PSS, the prevalence of significant urinary symptoms has been studied in various countries. Our study, done in a small fishing village using a community-based approach, recruited nearly 43% of eligible men in the area. We found that the percentage of those having moderate and severe urinary symptoms (> 7 points) evaluated by I-PSS increased steadily with the increasing of the age decade (Fig. 2).27 Our study was done following a similar protocol to that used in the study in Olmsted County, Minnesota, USA, except that the latter study randomly selected participants by age-stratification from the eligible men.28 The comparative study results showed that the prevalence of moderate or severe LUTSs increased by age, while the prevalence of such symptoms in American men was lower than that in the Japanese men for each age decade. The precise causes of the difference in prevalence are not yet known, but many factors may be involved. The use of I-PSS translated into a native language in various countries and the employment of similar study designs in a number of community-based studies enabled us to conduct an international comparison of LUTS prevalence. Sagnier et al.29 did this type of comparison in men 50 years old or older from 4 countries, France, Stirling (Scotland, UK), Olmsted County (Minnesota, USA), and Shimamaki (Hokkaido, Japan). Their results show that French and Scottish men are less frequently symptomatic, followed in frequency by American men, when the prevalence of moderate or severe symptoms by I-PSS 235

4 Int J Urol 1997;4: Age (years) Fig. 2. Age-specific prevalence of moderate or severe lower urinary tract symptoms (I-PSS or AUS Symptom Score with > 7 points) in community- or population-based studies done in various countries. Each prevalence is estimated from the data of community- or population-based studies done in France (2011 men); Stirling, UK (1990 men); Canada (508 men); Madrid, Spain (1797 men); the Netherlands (502 men); Oimsted County, Minnesota, USA (2119 men) and Shimamaki, Japan (289 men),27, The prevalence of men in their fifties and seventies in the Netherlands, as shown in the figure, are derived from those of men 55 to 59 years of age and 70 to 74 years of age, respectively. Numbers over columns are actual percentages., UK (Stirling); a, Canada; a, Spain (Madrid); in parentheses are percentages., the Netherlands; a, USA (Olmsted County); m, Japan (Shimama was considered. The Japanese men had the highest symptom score. Although the study protocol, and in particular, the enrollment method of participants, was different from those in the community-based study, Homma et a1.30 determined the age-specific prevalence of moderate or severe symptoms (> 7 points) defined by I-PSS in 4072 men 40 years old or older in Asian countries, Japan, Taiwan, Korea, the Philippines, Thailand, Singapore, Pakistan and India. The results were derived from 4 community-based studies, and 9 studies that recruited men who had visited, or had been admitted to, a hospital department other than the urology department. In their studies, the agespecific prevalence of the symptoms in Asian men was 18% in their forties, 29% in their fifties, 40% in their sixties and 56% in their seventies; these are lower values than those we found for the Japanese in our community-based studies. Differences in enrollment method, response bias, area differences such as urban or rural, or cultural background may affect the results. There was 1 report from Korea of a community-based study of LUTS prevalence enrolling 428 men." It is interesting that the age-specific prevalence of the moderate or severe symptoms (> 7 points) evaluated by I-PSS was very much like that in our study. In Korean men, the prevalence was 42% in their fifties, 52% in their sixties, and 70% in their seventies. As we mentioned earlier, French men had an agespecific prevalence of LUTSs different from that of American men. However, the age-specific incidence of initial prostatectomy is almost the same in men between these 2 countries.18 This implies that LUTS is not the only determinant for seeking medical care for BPH. Indeed, when the bother score was compared between men in Shimamaki and Olmsted County, we found that the Japanese men who had a significantly higher I-PSS at each age decade tended to have the same or a lower bother score at a given severity of I-PSS than did the American men, although a different perception of symptoms and willingness to report them between men in the 2 countries may be involved in this result. Nonetheless, this may partly explain a lower incidence of clinical BPH and surgery for BPH in Japanese men.27 Figure 2 summarizes the age-specific prevalence of moderate or severe LUTSs in men among various countries, as evaluated by I-PSS or AUA Symptom Index (or rescaled to these symptom scoring systems from the original ones) in community- or populationbased st~die~.~~,~~,~~-~~ As discussed earlier, Japanese men had the highest prevalence, but the reason for this is not yet understood. Most important is that, irrespective of differences in prevalence at each age decade, men in each country have a consistent increase in symptom prevalence with age. Of men in these countries, 23% (average of prevalence in 7 countries) in their fifties, 30% in their sixties, and 37% in their seventies have significant LUTSs. However, the impact of the symptoms on their quality of life does not seem to be similar, which may affect a difference in the incidence of surgery for BPH. It is necessary to understand how the symptoms affect the quality of life of patients with a diagnosis of BPH who are undergoing treatment for LUTSs. The Agency for Health Care Policy and Research for Diagnosis and Treatment of BPH in the United States 236

5 Epidemiology and Natural History of BPH recommends that optimal treatment decisions for individual patients need to take into account how a given level of symptoms affect each quality-of-life score (or bothersomeness) for the patient^,^*,^* as well as evaluating the LUTS score.39 Indeed, Girman et al.40 reported that urinary symptoms have a negative impact on the quality of life of men, and that this impact was more pronounced among those having more severe symptoms. However, a given level of symptom severity does not always provide the same impact on a patient s quality of life.27>78 Thus, whenever urologists evaluate patients with urinary symptoms, a quality-of-life assessment of the patients symptoms is essential. Impaired Urinary Flow. Urologists generally have had an impression that urinary flow becomes impaired with increasing age, although this has not been proven. This impression likely arose from patients in a clinical setting, which may be biased. Our data from mass screenings for prostate diseases, while subject to some bias, show that the maximum flow rate (MFR) of 1361 men who participated decreases with increasing age, as well as with increase in prostate size (determined by DRE).*l Even in men with the same size prostate, MFR decreases with age. In men having no enlargement of the prostate on DRE, MFR decreases from 17.0 k 8.3 mws (mean f SD) for men in their fifties to 13.7 k 6.7 ml/s for those in their seventies, although voided volume also decreases with age. A similar result can be also found in the groups of men who have slight, moderate, or marked enlargement of the prostate. Even after eliminating the influence of voided volume, the MFR nomogram4 score clearly decreases, depending on the age decade, in every prostate-size group.* Kitagawa et al.,43 who conducted a study with the same design as our mass screening, reported that there was a negative relationship between age and MFR in men having an estimated weight of the prostate of < 30 g (controlling for an influence of large prostate size). In a study of urinary flow rates in elderly men in a community, Diokno et al.44 showed that even men 60 years old or older not reporting obstructive LUTSs had an average MFR of < 15 ml/s. To confirm the decline of MFR with age in a study with less bias in enrollment of participants, we refer to data in our community-based study and the other population-based studies that shared the same study protocol; these studies have indicated that MFR declined with advancing age In the Japanese study of 279 men in a single community, average MFR declined from 23.4 f 9.9 mus (mean f SD) for men in their forties, to 20.2 f 8.0 mws for men in their fifties, to 16.7 f 7.9 ml/s for men in their sixties, and to 12.3 f 5.7 ml/s for men in their seventies.46 While T. Tsukamoto and N. Masurnori only 4% to 6% of men in their forties and fifties had an MFR < 10 mws, the corresponding proportion jumped up to nearly 20% for men in their sixties and 40% for men in their seventies. The American men had a similar trend of MFR decline, but there was a lower proportion of men in their seventies with an MFR < 10 ml/s. Men in these countries had a marked difference of estimated prostate volume in each age decade, which will be shown later, suggesting that prostate volume alone does not necessarily determine urinary flow rate,45 as was previously reported. Urinary flow rate is not directly indicative of lower urinary tract obstru~tion.~~ Uroflow rate measurement has many flaws. Straining artifact, influences by voided volume, age, and many other factors clearly affect its result. In addition, impaired flow indicates not only bladder outlet obstruction, but also detrusor impairment. While we do not want to further explore issues of urodynamics such as pressure-flow studies, it should be remembered that urinary flow rate is not a sole indicator of a disease condition. The study of age-specific prevalence of impaired flow shows that even among men having never asked urologists for medical care, a significant percentage have impaired urinary flow (10 ml/s or less). This finding should be taken into consideration when urologists diagnose LUTSs and treat patients, and again, it indicates that the measurement should be just one integral part in the initial evaluation programs. Increased Prostate Size. Since the study by S~cyer,~ the natural course of prostate growth has been recognized as having 2 different types, the first of which is that the prostate rapidly increases in size starting after puberty and continuing to 20 to 30 years of age, followed by a plateau phase (no enlargement), until 50 to 60 years of age, with a subsequent decrease in size. The second type is initially the same as the first one, but with a rapid increase in size starting again around 50 to 60 years of age, which results in enlargement of the prostate. Berry et al. collected and summarized data from autopsy series, which suggested that the average weight of the prostrate gradually increases from 20 g in men in their thirties to 31 g in men in their seventies (Table 1). When the average weight of the prostate is classified by pathologic finding, prostates having no pathologic BPH showed only very subtle change (increase or decrease) in weight after reaching 30 years of age, but prostates having pathologic BPH showed an increase in weight with advancing These results support the idea that prostate growth tends to separate into 2 natural courses between 50 to 60 years old. The idea has been confirmed in a study for men who participated in mass screening for prostate diseases. Watanabeso conducted a longitudinal study using transrectal ultra- 237

6 Int J Urol 1997;4: Table 1. Changes in average prostate weight by age and by evidence of benign prostatic hyperplasia (BPH) in autopsy studies. Table 2. Prostate volume (mean: ml f SD) by age, estimated by using transrectal ultrasonography in community- or population-based studies. All autopsies in Masumori et a'.46 Garraway et ai.?-' Bosch et a1.5i Berry et al." No evidence of BPH Evidence of BPH Age Japan Minnesota Scotland Netherlands Mean g f SD (No. Mean g f SD (No. of Mean g f SD (No. of (y) (279 men) (467 men) (699 men) (502 men) Age iy) of autopsies autopsies) autopsies) f 2.7 (130) t 5.4 (31)" f f f f 6.9 (10Iiq f i f ? k 3.2 (130) 20.5? 5.7 (27)'' 28 8 f 5.6 (4)" 23.4 f 5.0 (1 1j4" 28.0 * 8.7 (3)"' k ? i f 11.6 SO * 4.5 ( k4.3 (31)'' 27.3 k 8.2 (22)" f k 6.2 (28)" 27.8 * 7.0 (5)" f f f (141) f k 7.4 (19)" 22.4 f 6.2 (29P 34.9 f 18.8 (41 1'' 28.7 f 12.4 (7Y f 13.0 ( k 5.5 (3)" 40 5 f 30.3 (37)" 25.3 f 6.5 (22)*' 38.1 i 13.4 (14)@' sonography (TRUS) of prostate growth in 16 men with 6 to 8 years of follow-up. In the course with ultimate enlargement of the prostate, rapid progression of glandular growth before 50 to 60 years of age would achieve prostate enlargement, followed by a phase without a subsequent increase in size. If the prostate had not increased in size by these ages, the size of the prostate would likely not increase any more. This issue will be discussed again using data from community-based studies. From autopsy studies, we understand that the prostate increases in size at around 50 to 60 years of age. The question is: what percentage of men in the general population achieve a marked increase of prostate size, and when does this growth start? This question is hard to answer, since no studies without bias in participant enrollment were conducted until recently, and a longitudinal study of greater than 10 years duration is necessary for resolving the issue. The crosssectional study is an incomplete alternative, because of the inappropriateness of drawing longitudinal inference based on cross-sectional results. In addition, measurement of prostate size is influenced by many factors. To overcome a few, but not all, of these problems, we will compare prostate size revealed by 4 community- or population-based studies with similar study protocols. Of these, 3 were done by the same study protocol with the same method of TRUS and the same formula for estimated volume calculation. The other study had a similar protocol for participant enrollment and TRUS method, but a different calculation method for size estimation with TRUS. Masumori et al.46 have reported that the increase of prostate volume in Japanese men is very gradual from 17 ml in their forties to 22 ml in their seventies (Table 2). From this cross-sectional study, the predicted increase of prostate volume per decade is about 1.5 ml. This gradual increase of prostate size in Japanese men partly contributes to the finding that the percentage of men having a prostate volume exceeding 20 ml, which is regarded as a minimum size of an abnormal enlargement, is 20% in their forties, 35% in their fifties, 38.8% in their sixties, and 37.3% in their seventies. These prostate volumes and the percentages are very similar to those of Korean men, while estimation of the prostate volume seemed marginally different.31 Korean men had a prostate size of 16.5 f 5.6 ml (mean k SD), in their fifties, 17.1 k 6.2 mlin their sixties, and 20.4 zk 12.2 ml in their seventies. Percentages of men with a prostate volume with 20 ml or larger were also similar among Korean men; 24.5% of men in their fifties, 27.5% of those in their sixties, and 35.7% of those in their seventies. In contrast, American men have a more rapid increase in prostate size of 5.5 ml per decade, based on cross-sectional data. Moreover, more than 60% of American men in all age decades have a prostate size > 20 ml, and more than 80% of these men were in their fifties, sixties, and seventies. Adjustment for age, height and weight did not affect this distinct difference in prostate volume between Japanese and American men. Garraway et al.,32 who conducted a study similar to ours, showed that men in Scotland had similar prostate volume and increment with age as those of American men. Although the calculation formula is somewhat different, Bosch et al.51 reported from their results in a community based-study that men in the Netherlands had almost the same prostate volume, and its increment with age, as did American men. Thus, although the age-specific prevalence of enlarged prostate becomes higher with advancing age in many countries, prostate volume in each age decade has a distinct difference among nationalities, as does the rate of increment. Asian men have a similar prostate growth rate, which is slower than that of white men. This may imply that, while factors to induce pathologic BPH might be common among different nationalities, promoters necessary for an increase in prostate size might be regulated by genetic or epi- 238

7 Epidemiology and Natural History of BPH genetic factors. The age-specific prevalence of enlarged prostate seems higher than expected. Although prostate volume alone does not necessarily determine voiding function, urologists should be mindful of the general distribution of prostate volume in elderly men. Changes in internal architecture of the prostate with age As described earlier, our community-based study is cross-sectional, but not longitudinal. Thus, changes in indices with age do not always reflect real correlation with aging. For that purpose, we would need a longitudinal study that has a long-term follow-up of the participants. However, even in a cross-sectional study, if it is a community- or population-based study, the results may provide some clues to the sequential changes in the prostate. Thus, we tried to see changes in image patterns of the prostate with TRUS. Watanabeso has already used TRUS to show sequential changes of the prostate over years in 16 men who participated in mass screening for prostate diseases. In spite of a small number of subjects in his study, his findings are interesting, and our study results support them. When we studied age-related differences or changes in internal architecture of the prostate on TRUS in 279 men who participated in the community-based study, we found that their prostate findings can be classified into 3 distinct gro~ps.~ In the first group, the whole tissue is seen as homogeneous (TRUS cannot distinguish the transition zone in the prostate from other zones or surrounding tissues that have the same echogenicity). In the second group, there is a visible transition zone, but no clear demarcation between this zone and the peripheral and central zones. In the third group, the transition zone is clearly separated from the other zones by a hypoechoic lesion (typical BPH findings). More than 80% of men in their forties had internal architecture classified as group 1 on TRUS. This architecture was found with almost the same frequency in men in their fifties or older (35% to 40% ), but the group 3 pattern was seen most frequently in men in their seventies (> 50%), followed in frequency by men in their sixties (33%), fifties (23%), and forties (9%). Interestingly, the increase in the median volume of the prostate by age decade was substantial only in those with the group-3 pattern, although this increase was associated with wide variations in volume. Thus, changes in incidence of internal architecture and the increase of median volume on TRUS with advancing age suggest that substantial growth developed mainly in the prostate with the group-3 pattern, but that the growth rate still varies widely in each prostate in the group. 1. Tsukamoto and N. Masumori When we consider the natural history of BPH development, results by TRUS may indicate that TRUS-detectable prostatic hyperplasia may develop in men in their early fifties. In other words, the prostate in some proportion of men progresses from normal to diffusely enlarged hyperplasia at around 50 years of age, and a small proportion of these men further develop TRUS-detectable nodularly enlarged hyperplasia. Epigenetic or genetic factors may modify this process. It is possible that men in other countries would have different TRUS-detectable changes because of a possible difference in increase of prostate volume. Benign prostatic hyperplasia case specifically defined As described earlier, several definitions of clinical BPH have been used in epidemiologic studies. Estimation of its prevalence varies by the definition used. Thus, we specifically defined a BPH case and tried to estimate this prevalence by measuring LUTSs, urinary flow and prostate volume, although this definition would not be a standardized one. Garraway et al. have already reported on the prevalence of BPH cases defined in one such way.32 According to their definition of BPH, their community-based study showed that the prevalence was 14% in men in their forties, increasing to 43% in those in their sixties (Table 3). When these age-specific prevalences were compared with those in the study of Japan and Minnesota done by a similar protocol, American men had a similar prevalence and Japanese men had a lower prevalence. However, suggested that the prevalence of BPH in each age decade for Japanese men, estimated by using this definition, is similar to that found in a study of mass screening for prostate diseases in the Japanese, evaluated mainly by TRUS. Thus, the Japanese may have a lower prevalence of BPH, when BPH was defined by the method of Garraway et al.32 Finally, we estimated the age-specific BPH prevalence by a different definition. Garraway et al. included an MFR < 15 mljs as one of their definitions of BPH in the above study. However, this level of MFR may contribute to overestimation of BPH pre- Table 3. Age-specific prevalence of benign prostatic hyperplash* (BPH) in community- or population-based studies. Age (Y) Japan (Shimarnaki) Tsukamoto et al.27 Masumori et al.46 (286 men) % % % % *As defined in Garraway et a1.i2 MI n inesota (Olmsted County) Guess et a1.l Scotland (Stirling) Garraway et a(. * (471 men) (699 men) 6% 14% 17% 23 % 32% 43% 36% 40 /o 239

8 Int 1 Urol 1997;4: valence in Japanese men, since a significant proportion of those in the community without a history of seeking medical care for BPH had an MFR of 10 ml or less.46 Thus, we compared the prevalence of BPH in Japanese men with that of American men by using the definition of BPH as having an I-PSS with > 7 points, an MFR < 10 ml/s, and estimated prostate volume > 20 ml (Fig. 3). For reference, these data are compared with those of the Prostate Research Foundation in Japan, which estimated BPH prevalence in Japan from 9 years of cumulative data from nationwide mass screenings for prostate diseases.54 In this report, BPH was defined as that diagnosed by participating urologists as requiring treatment. Interestingly, the prevalence of BPH in Japanese men, irrespective of study protocols, is similar across age decades, except for the fifth decade. In contrast, the prevalence of BPH in American men is higher than that of the Japanese men participating in the community-based study. However, it should be understood that BPH tends to be diagnosed in American men because they have a larger prostate, but that it is done so in Japanese men because they have a higher I-PSS. This difference in the basis for diagnosis will affect the differences in prevalence. These results emphasize that, at least 10% of Japanese men older than 60 have BPH, most cases of which should be treated. This figure may be higher in American men. r? a I Age (y) Fig. 3. Age-specific prevalence of benign prostatic hyperplasia (BPH) as defined by lower urinary tract symptoms, urinary flow rate, and estimated prostate volume in community- or population-based studies and that of the disease in mass screening for prostate diseases conducted in Japan. The prevalence in Shirnarnaki, Japan, and Olmsted County, Minnesota, was determined by the results from community- or population-based studie~.~~~~~~~ Age-specific prevalence of BPH in mass screening is derived from cumulative data of BPH cases in 51,680 men who received mass screening for prostate diseases conducted from 1986 to 1994 (from the report by the Prostate Research Foundation of Japans4). They had a different definition of BPH cases from that in studies of Shirnamaki and Olmsted County (see text for definition). n, Shimamaki (Japan, 279 men); a, mass screening (Japan, 51,680 men);, Olmsted County (Minnesota, 468 men). Numbers in parentheses are percentages. We used specific criteria for the definition of clinical BPH to estimate its prevalence. It is emphasized again that our definition of BPH may not be standardized. Using the criterion of MFR < 10 mus would underestimate prevalence, and using that of prostate volume > 20mL would overestimate it. Bosch et a1.51,55 suggested that using a criterion for BPH of a prostate volume of 20mL or more would overestimate the prevalence, since more than 90% of men in their study had a prostate larger than 20 ml. They have also pointed out that a lack of information on risk for treatment in each man can produce the result that such prevalence estimated from indices in a daily clinical setting seems to be ~pen-ended.~~ In addition, the issue for prostate size may not be directly translated into BPH prevalence for men in Asian countries, since 2 community-based studies have consistently indicated that Asian men have a smaller prostate. mat we must learn from the attempt to estimate prevalence is not to immediately identify an individual who should be treated, but rather, to gradually unveil hidden aspects in the epidemiology of BPH. We are still on the way to this final destination. We need to conduct a longitudinal study of the natural history LUTS and clinical BPH. In considering the prevalence of clinical BPH, one should remember that BPH has a heterogeneous cause and growth development, which may be involved in heterogeneous profiles in men with BPH around the world. In particular, the prostate shows more accelerated growth in American and Scottish men than in Japanese, and probably Korean men. Since no single definition of BPH has been established, prevalence of the disease has been estimated differently. While prevalence of LUTSs (by using I- PSS) was higher than previously expected in the current studies with well-designed protocols, and varied substantially among countries, this does not imply that all such men have a disease compatible with clinical BPH. If we defined BPH by I-PSS (> 7 points), MFR < 10 mus, and estimated prostate volume > 20 ml, our community-based study in a small fishing,village would show the prevalence of definite clinical BPH as 10% for Japanese men 60 years old or older. However, future studies will be needed to determine whether or not these criteria for a BPH definition are valid. NATURAL HISTORY OF LOWER URINARY TRACT SYMPTOMS AND BENIGN PROSTATIC HYPERPLASIA We do not know exactly what clinical course BPH will take naturally, as it is difficult to study the natural history of development of benign hyperplasia, particularly without a well-accepted definition. Studies on 240

9 Epidemiology and Natural History of BPH this issue have been extraordinarily sparse relative to the high population prevalence of urinary symptoms. However, during the past decade several studies have investigated the natural history and clinical course of BPH, and especially, of LUTS. In this section, we will review the natural history of enlarged prostate or LUTS, mainly in community- or population-based studies, and the natural course of BPH diagnosed in the clinical setting. Prostate Enlargement One of the longitudinal studies that yielded useful information on prostate enlargement with or without LUTSs was the Baltimore Longitudinal Study of Aging.20 In this study, when eventual surgery for BPH was defined as the endpoint, Arrighi et al. have indicated that the probability that men will receive surgery after 10 and 20 years depends on LUTSs and prostate enlargement, as well as their age at the initial evaluation. In men having prostate enlargement and any obstructive symptoms, the age-specific, 10-year probability was 3% in their forties, 7% in their fifties, 16% in their sixties, and 34% in their seventies or beyond. The 20-year probability increased to 13%, 24%, 39%, and 41%, in respective decades. In contrast, men having neither prostate enlargement or LUTSs are less likely to receive surgery after 10 and 20 years; 2%, 2%, 9%, and 13% for 10-year probability, and 4%, 9%, and 22% for 20-year probability in respective decades (the 20-year probability in the seventh decade or beyond was not given). In this study, change in the size and force of urinary stream, a sensation of incomplete emptying, and enlargement of the prostate by DRE were risk factors for pro~tatectomy.~~ Indeed, when men had none of these 3 factors, only 3% received prostatectomies. In contrast, 37% of men having all these factors received prostatectomies. These data helped elucidate when and how men receive surgery for BPH. However, indications for surgery in individual men may not be similar. Thus, prostate size and LUTSs may be risk factors predictive for indication of surgery, but they are not necessarily determinants for it. lower Urinary Tract Symptoms In the community- or population-based setting, changes of LUTSs over time have been studied by Jacobsen et al.57 They have indicated that a slow but measurable progression of LUTSs was found after a greater than 3-year follow-up. However, some men had a decrease in LUTS score, while others had an increase, partly reflecting the natural course of LUTS. Moreover, even among men with LUTSs, each symptom did not necessarily progress similarly during the follow-up, with the higher correlation of nocturia and weak stream with time. Interestingly, these symptoms 1. Tsukamoto and N. Masumori were strongly associated with increase of age in the previous baseline study.2s The study by Garraway et al.58 has demonstrated that each symptom increased on average by 1 year follow-up, while the frequency of LUTSs varied with within-individual variation. Diokno et al.59 reported on changes of obstructive symptoms over time and demonstrated that remission and progression of the symptoms seemed related to the initial severity of the symptoms. In men having mild or moderate symptoms, 37.5% of those with mild, and 13.2% of those with moderate symptoms became asymptomatic 1 year later; while 12.5% of those with mild, and 31.6% of those with moderate symptoms progressed to have severe symptoms. More than 70% of men with severe symptoms were unchanged 1 year later. These results suggest that LUTSs may generally become worse over time, but that the symptoms in each individual substantially wax and wane. However, when men initially have severe symptoms, they will less likely have a chance of their symptoms improving spontaneously in the absence of treatment. Clinical or Symptomatic Benign Prostatic H yperplasia Clinical experience has shown that some men with clinical or symptomatic BPH become less symptomatic and do not require any surgical interventions, even though their disease conditions wax and wane. Most of such clinical BPH seemed to involve mild LUTSs and slightly impaired urinary flow. Studies on untreated symptomatic BPH, as shown later, support this understanding, although the understanding will need to be strengthened by more scientific, clinical evidence. Summarizing the results on natural history of untreated symptomatic BPH in 4 studies for subjective symptoms, and in 2 for objective finding^,^'-^' is sac^^^ has indicated that during a 2.6- to 5-year follow-up 24% to 45% of the patients experienced increased symptoms, 29% to 48% had decreased symptoms, and 0% to 47% had no changes in subjective symptoms; and similarly, for objective findings, 77% or 49% of patients showed a deterioration, 28% or 15% an improvement, and 23% or 8% no changes, respectively. While clinical profiles of patients and criteria for response of subjective symptoms and objective findings were not identical in each study, these results suggested that subsequent courses of clinical BPH are variable when they are not immediately treated. This variable nature in LUTSs and objective findings over time in clinical BPH correspond to results in longitudinal, community-based studies. A recent study of the natural history of clinical BPH by the Shared Decision-Making Program, in which 1 -year outcomes under a watchful-waiting policy for clinical BPH were partly revealed, showed 24 1

10 Int J Urol 1997;4: preliminary results supporting the general consensus Table 4. Clinical course of subjective symptoms and objecon the variable courses of clinical BpH.65 In this tive findings by placebo treatment in trials determining the study, candidates for elective surgery were followed efficacy of pharmacologic agents for treating benign prostatic hyperplasia. up for 1 year. Six percent of 166 BPH patients with mild LUTSs on the initial evaluation received surgery, 57% had the same level of the symptoms and 33% Response to placebo treatment (YO) Duration of Subjective symptoms Objective findings and 4% progressed to moderate or severe levels, re- Source study (w) Better Same Worse Better Same Worse spectively. Of 310 patients with moderate LUTSs, the 1ssaCsb4* incidence of surgery over the first year was 16%, and 44% of them remained in the moderate symptom Meigs and Barryf5t Kawabe level. However, 22% improved, and 16% deterioet rated, regarding their symptom level. In contrast, pa- Kumamoto tients initially having severe LUTSs had the highest et al.b8p incidence (34%) of surgery over the 1-year follow-up, so that the incidence of symptom improvement to Aso et al.hs" mild (11%) or moderate (26%), as well as mainte- *260 patients allocated to placebo treatment in 12 studies nance of the same symptom level comparatively re- (each percentage is expressed as an average of the studies); +317 patients allocated to placebo treatment in 7 studies duced. Following these results, Barry et a1.66 reported (each percentage is expressed as an average of the studies); those of a study with a 4-year follow-up, which sug- *57 patients who received 0.01 mg finasteride (regarded as gested that initial symptom severity influenced the the extremely low dose equivalent to placebo); $1 04 patients outcome of men with clinical BPH who were candi- in placebo treatment; 1179 patients in placebo treatment. dates for elective surgery. Although in these studies, the definition of clinical BPH and indication for surgery may still be different in each case, these preliminary data support the fact that LUTS severity at the time of diagnosis may be an influential factor on patient outcome, affecting decision-making for surgery. study duration may increase the proportion of men with deterioration. Several recent reports on clinical trials for BPH done in Japan provided a placebo arm or its eq~ivalent.~'-~~ As was found in American or Clinical courses still differ substantially even among patients with initial indications for surgery. More information on the initial size of the prostate or urinary flow status of patients, and the relationship of these factors in those patients who subsequently required surgical treatment will be beneficial to urologists. Because there are only a few longitudinal studies available, we looked at other data sources that may outline the natural history of clinical BPH, such as those of the placebo groups in clinical trials for the efficacy of pharmacologic agents, and those of patients allocated to watchful-waiting treatment in studies of clinical BPH. It should be pointed out that placebo arms are not generally representative of men in the community, particularly given the entry criteria, the blinded nature of trials, and the inherent differences in men willing to participate in clinical trials of a pharmacologic agent. As for the first type of data, I~aacs,~~ and Meigs and Barry65 independently summarized response of clinical BPH to placebo treatment in studies for trial of pharmacologic agents, although a part of the studies overlapped in the 2 summaries (Table 4). Interestingly, proportions of response to placebo treatment are similar in the summaries. Placebo treatment achieved an improvement of subjective symptoms in 40% to 50% of patients with clinical BPH, and a deterioration of symptoms in 10% of the patients, for less than 1 year of study duration, although a longer European studies, these studies indicated that a substantial proportion of clinical BPH showed an improvement of subjective symptoms and of objective findings by placebo during a treatment period of 4 to 12 weeks. Finally, Roehrborn70 studied changes of LUTSs, flow rate, and residual urine in patients who had been allocated to a placebo arm in clinical trials for BPH. A probability for symptom improvement was found in 42% of these patients, symptoms in 54% of the patients were unchanged, and symptoms worsened in 5%. For MFR changes, 36% of the patients achieved an increase in MFR, 41 % remained the same, and 23% had a decrease in MFR. Residual urine volume after placebo treatment decreased in 38%, was unchanged in 26%, and increased in 36%. The percentage with symptom improvement closely corresponds to that achieved by watchful-waiting for clinical BPH, although watchful-waiting treatment yielded a lower probability of symptoms remaining unchanged (26% versus 54%), but a higher probability of symptom worsening (32% versus 5%). A higher probability for the MFR to increase or to show no change was found in placebo treatment, resulting in a higher probability for the MFR to decrease in watchful-waiting treatment. However, the probabilities for residual urine volume (increase, no change, or decrease) were similar for both placebo and watchfulwaiting treatment. Since these data sources were derived from studies 242

11 Epidemiology and Natural History of BPH that had significant differences in profiles of patients, use of pharmacologic agents, and treatment interval, direct comparisons are not valid. However, as described above, the results are quite similar, so that some conclusions can be drawn. These results indicate that patients in whom clinical BPH is initially diagnosed, and who urologists believe are in need of treatment, may not necessarily be candidates for immediate treatment. More appropriate selection of candidates would avoid overtreatment. The second type of data available to understand better the natural history of BPH can be derived from watchful-waiting treatment for clinical BPH. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate5 reported that TURP is more effective for treating patients with clinical BPH associated with moderate or severe LUTSs than watchfid-waiting. Patients with mild symptoms (AUA Symptom Index or I-PSS of < 8 points) will benefit from watchful-waiting. In some patients with moderate LUTSs, watchful-waiting may be an effective alternative to TURP, if they are not bothered by the symptoms. These results confirm that some proportion of patients with clinical BPH who are initially indicated for surgery may achieve a favorable clinical course with watchful-waiting. Thus, we need more knowledge to appropriately select patients for treatment. Indeed, surgery was canceled after reassessment of voiding condition in 48% of patients who had been placed on a waiting list for TURP for 1 to 9 years.71 This may be attributed to the specific situation in the United Kingdom, but also may support the validity of watchful-waiting in treatment of some patients with clinical BPH. In summary, the natural history of LUTSs and clinical BPH have not yet been fully understood. Our knowledge about this issue is still limited. However, studies during the last decade have suggested that the symptoms of men usually become worse gradually over time, but they wax and wane in each individual, in particular when the symptoms are mild or moderate. Some men having LUTSs or clinical BPH have an uneventful course without treatment, even though they are initially diagnosed as having BPH that requires surgery. Some factors, such as the severity of the initial LUTS, may affect the clinical course. Moreover, how bothersome the symptoms are may be a strong factor in determining the clinical course, such as the need for surgery. Thus, watchful-waiting can be indicated for men having mild symptoms, or moderate symptoms which are less bothersome. Unfortunately, we have not had studies on the natural history of LUTSs and clinical BPH for Japanese men. Since Japanese men have a smaller prostate than American men, and the size may partly affect the determining indication for surgery, such studies for the Japanese 1. Tsukamoto and N. Masumori seem mandatory. Homma et al.72 have recently advocated criteria for diagnosis and severity of BPH. We hope this criteria will enable us to compare each patient with BPH, so that clinically meaningful data can be accumulated. CONCLUSION Scientific evidence in the area of the epidemiology and the natural history of BPH is still inadequate for building an understanding of BPH. However, new information has been accumulating during the last decade. What we have learned from community- or population-based studies done during these years is, first, that a significant number (larger than previously anticipated) of men throughout the world have LUTSs. Interestingly, development of prostate enlargement may not be similar among different nationalities or races, suggesting that promoting factors determined genetically or epigenetically may be involved. In addition, different diets and cultural factors may be promoting factors as well, and smoking, alcohol and medication use may play a stronger role in occurrence of LUTSs than previously appreciated. Men having LUTSs are not necessarily candidates for treatment, since the symptoms may not be bothersome or associated with a decrease in the quality of life, and are not specific for bladder outlet obstruction. This seems to be related to the fact that not all men who initially are candidates for prostate surgery will have subsequent surgery or treatment. This implies that watchful-waiting may be an appropriate treatment option for some patients with clinical BPH. Although we have not identified all determinants for the indication of prostate surgery, men having mild LUTSs are likely to benefit from the watchful-waiting policy. Further studies will identify other determinants. Since studies such as those investigating the natural history of clinical BPH in Japan are insufficient, whether or not the results found in white American men can be applied to the Japanese men, who have smaller prostate size, is not known at this time, although prostate size is not the only factor influencing treatment decisions. The medical community needs more data, both scientific and clinical, to explain the natural history of BPH in Japanese men, as well as those in other countries. ACKNOWLEDGMENTS The authors thank Doctors Harry A. Guess and Cynthia A. Girman of Merck Research Laboratories, and Doctors Michael M. Lieber and Steven J. Jacobsen, Mayo Clinic, for their continued support and cooperation in conducting our 243

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