REVIEW
RACIAL DIFFERENCES IN PATHOGENETIC MECHANISMS, PREVALENCE, AND PROGRESSION OF BENIGN PROSTATIC HYPERPLASIA GERALD HOKE, WILLIAM BAKER†, CARLTON BARNSWELL, JAMES BENNETT, RODNEY DAVIS, TERRY MASON, AND WALTER RAYFORD
B
enign prostatic hyperplasia (BPH) is the most common condition affecting men of all ethnicities who are older than 50 years of age.1 The prevalence of BPH increases with age, affecting more than 50% of men aged 60 years and 90% of those aged 80 years.2,3 The underlying prostatic hyperplasia results in an increase in prostate volume (PV), which can be associated with obstructive and irritative lower urinary tract symptoms (LUTS). Evidence from a large number of epidemiologic studies and placebo arms of clinical trials has demonstrated that BPH is a progressive disease in many men, characterized by increasing prostatic enlargement, worsening symptoms, and a heightened risk of acute urinary retention (AUR) and requiring BPH-related surgical intervention.4 The greater prevalence of prostate cancer in certain ethnic groups such as African-American men has received worthy attention; however, increasing evidence has shown that the prevalence and natural history of BPH may differ in this ethnic group. The aim of this review was to examine the studies †
Deceased G. Hoke has been a paid consultant to GlaxoSmithKline in the past. W. Baker was a paid consultant to GlaxoSmithKline and was a member of the speaker’s bureau for Boehringer Ingelheim. C. Barnswell is a paid consultant to GlaxoSmithKline. T. Mason is a paid consultant to Pfizer, GlaxoSmithKline, Eli Lilly/ICOS, and Sanofi-Aventis. W. Rayford is a paid consultant to Sanofi-Aventis. From the Department of Surgery, Harlem Hospital Center, Columbia University, New York, New York; Department of Urology, University of California, Davis, School of Medicine, Sacramento, California; Department of Radiation Oncology, Long Island Jewish Medical Center, New York, New York; Midtown Urology Surgical Center, Atlanta, Georgia; Department of Urology, Tulane University Health Sciences Center, New Orleans, Louisiana; Department of Urology, Mercy Hospital, Chicago, Illinois; and Southeast Urology Network and University of Tennessee, Memphis, Tennessee Reprint requests: Walter Rayford, M.D., Ph.D., Southeast Urology Network, 995 South Yates, Suite 1, Memphis, TN 38119. E-mail:
[email protected] Submitted: July 12, 2005, accepted (with revisions): August 14, 2006 © 2006 ELSEVIER INC. 924
ALL RIGHTS RESERVED
evaluating whether the underlying pathogenetic mechanisms, prevalence, and progression of BPH differ between African-American and white American men. ROLE OF ANDROGENS IN BPH DEVELOPMENT Androgens exert a major influence on normal prostate development, and it is also widely accepted that they have a role in the pathogenesis of BPH.5 It is believed that long-term systemic exposure to high levels of testosterone may have a number of adverse effects.6 The effects of testosterone are mediated by way of the androgen receptor (AR) pathway (Fig. 1).7 Testosterone is mainly produced by the Leydig cells of the testis and is the predominant circulating androgen. However, dihydrotestosterone (DHT), converted from testosterone by the ⌬(4),3 ketosteroid, 5-alpha-reductase type 1 and type 2 isoenzymes, is the most potent stimulator of prostate growth.8 This may result from the greater affinity for, and binding stability with, the AR. DHT is a potent androgen and cannot be aromatized to estrogens; thus, it acts as a “pure androgen.” Tissue DHT has been shown to stimulate epithelial cell growth and reduce apoptosis.9 In BPH, an imbalance occurs in the DHT-maintained homeostasis of prostate epithelial cell turnover, resulting in greater cell proliferation than cell death and, therefore, prostate enlargement.10 Despite a decrease in plasma testosterone, DHT levels in the prostate remain constant with aging.11 TESTOSTERONE LEVELS The central role of the androgen axis in BPH suggests that differences in the androgen pathways between ethnic groups could influence the prevalence and course of the disease. Across the age range, African-American men have been shown to have greater levels of total, bioavailable, and free testosterUROLOGY 68: 924 –930, 2006 • 0090-4295/06/$32.00 doi:10.1016/j.urology.2006.08.1067
FIGURE 1. Androgen/AR pathway. 5AR ⫽ 5-alpha-reductase; ARE ⫽ androgen response element.
one. Ross et al.6 showed that testosterone levels were up to 15% greater in healthy African-American men compared with healthy white American men.6 Ellis and Nyborg12 investigated the serum testosterone levels in 525 African-American and 3654 non-Hispanic white men. African-American men aged 31 to 34 years had a 6.6% greater mean serum testosterone level than did white American men, yet in those aged 40 to 50 years, this difference was only 0.5%. Kubricht et al.13 reported greater serum testosterone levels in African-American men (424.30 ng/dL) compared with white American men (380.19 ng/dL) undergoing prostate biopsy, although this difference was not statistically significant. One possible explanation for the greater serum testosterone levels observed in African-American men in some of these studies is the in utero effect of maternal testosterone. Testosterone levels have been shown to be 50% greater in African-American women than in white American women, suggesting that male fetuses of African-American women are exposed to greater testosterone levels. This increased hormonal exposure for the male fetus in utero could reset the “gonadostatin feedback loop” that regulates testosterone secretion and has been hypothesized to result in greater circulating levels of testosterone in adult men.7
tase activity than are serum levels of testosterone and DHT.14 Ross et al.15 evaluated the serum DHT metabolite levels in African-American, white American, and native Japanese men. Their results showed that levels of both androstanediol glucuronide and androsterone glucuronide were significantly greater in African-American and white American men than in native Japanese men.15 This suggests that Japanese men have lower 5-alpha-reductase activity than the other ethnic groups. In addition, the DHT/T ratio, a marker of 5-alpha-reductase activity, was greater in African-American men than in the white American and Japanese men in this study. This could be significant, because studies have shown that the DHT/T ratio is greater in men with BPH.16 Cumulatively, these data suggest that the conversion of testosterone to the more active androgen DHT may be enhanced in African-American men: an observation that may be attributable to the altered pattern of 5-alpha-reductase activity. 5-ALPHA-REDUCTASE GENOTYPES Genetic polymorphisms in the gene encoding 5-alpha-reductase type II (SRD5A2) enzyme have been described.14 SRD5A2 is uniquely expressed in the prostate and is located on the short arm of chromosome 2, band 2p23. Makridakis et al.17 identified three allele families (containing 87, 103 to 107, and 121 to 131 base pairs) when comparing the allele frequencies in African-American, Asian, and white American men. Of particular significance was the 121 to 131 base pair allele, which was present in 18% of African-American men but not in white American or Asian men. This racially unique variation was shown to have a statistically significant correlation with increased SRD5A2 activity and DHT synthesis. The V89L missense substitution, in which valine at codon 89 is substituted by leucine, is a common aberration in the SRD5A2 gene found in both African-American and white American men but significantly less frequently in Asian men.17 The greatest level of V89L substitution was observed in African-American men. The presence of a homozygous genotype for this substitution is also associated with an increased level of androsterone glucuronide, suggesting that the substitution has functional consequences.
DHT LEVELS AND ITS METABOLITES
RACIAL VARIATIONS OF ANDROGEN RECEPTOR EXPRESSION AND GENOTYPES
The isoenzymes of 5-alpha-reductase catalyze testosterone to the more potent metabolite DHT. DHT can be inactivated by either a 3-alpha or a 3-beta-hydroxysteroid dehydrogenase to the metabolites androstanediol glucuronide and androsterone glucuronide. These metabolites are more reflective of tissue DHT levels and 5-alpha-reduc-
The AR acts as a ligand-activated nuclear transcription factor (Fig. 1). The gene encoding this receptor is located on the X chromosome, band q11-12. The binding of androgen causes activation of responsive elements within the promoter regions of androgen-responsive genes, leading to transcription and subsequent protein synthesis. As
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the effects of androgens are mediated by the AR, ethnically related epigenetic or genetic alterations in the level of AR gene expression could have a role in the differences in BPH. Olapade-Olaopa et al.18 observed significantly greater AR expression in BPH and malignant prostatic epithelium of African-American men compared with similar tissue histotypes in European men (P ⫽ 0.0001). This suggests that greater AR expression in the epithelium of benign prostatic glands may contribute to BPH in men of African descent. INSULIN-LIKE GROWTH FACTORS AND THEIR BINDING PROTEINS Insulin-like growth factor 1 (IGF-1) is a growthpromoting polypeptide, structurally similar to insulin and synthesized in a number of tissues, including the prostate and liver.19 IGF-1 acts locally through activation of IGF-1 receptors in the prostate to stimulate prostate-specific antigen (PSA) production and proliferation of normal, hyperplastic, and malignant epithelium.19 Circulating IGF-1 is complexed to a family of structurally related binding proteins, with IGF binding protein-3 (IGFBP-3) the primary carrier.20 In in vitro studies, IGF-1 has shown mitogenic and antiapoptotic effects on prostate cells.21 The putative role of IGF-1 and IGFBP-3 in prostate cancer has led to the investigation of its role in BPH. Recent evidence has suggested that IGF-1 levels are similar between men with metastatic prostate cancer and BPH but that IGFBP-3 levels are lower in those with prostate cancer than in those with BPH.22 Furthermore, significant inverse correlations have been demonstrated between serum IGFBP-3 and serum free PSA in both prostate cancer and BPH.22 However, evidence from a cohort of 471 men from the Olmsted County Study has shown that a low IGFBP-3 level is associated with an enlarged prostate (odds ratio 1.72, 95% confidence interval 1.05 to 2.82), suggesting that a diminished level of IGFBP-3 is associated with BPH.23 Tricoli et al.24 evaluated the overall plasma levels of IGF-1 and IGFBP-3 in a group of African-American and white American men aged 35 to 69 years at increased risk of prostate cancer. Although no significant difference was found in the mean plasma IGF-1 level between African-American (162.3 ng/mL) and white American (172.1 ng/mL) men, the mean plasma IGFBP-3 levels were significantly lower in the African-American men (2789 versus 3216 ng/mL, P ⫽ 0.0045). Because prostate epithelium is sensitive to IGF-1, the lowered plasma levels of IGFBP-3 are thought to result in greater systemic IGF-1, which has been shown to result in increased stimulation of prostate epithe926
lium, increased DHT and PSA levels, and decreased apoptosis.24 Taken together, these data suggest that a decreased level of IGFBP-3 is associated with a greater risk of BPH. Because African-American men appear to have decreased IGFBP-3 levels compared with white American men, this may provide a marker for increased prevalence of BPH in this ethnic group. Furthermore, sex hormone-binding globulin levels, which are required to enable steroid hormones to bind to tissue receptors, have been shown to be greater in African-American men compared with white American or Japanese men (53% and 40%, respectively, P ⬍0.01).16 Data have indicated that racial differences in central adiposity in men are established in early adulthood and influence circulating sex hormone-binding globulins and thereby testosterone levels. Sex hormonebinding globulin increases cyclic adenosine monophosphate production in the prostate, and cyclic adenosine monophosphate-dependent protein kinase A is a coactivator of the androgen receptor. Data from these studies provide a possible mechanism by which circulating androgens contribute to an increased risk of BPH among African-American compared with white American men.25 PROSTATE VOLUME AND COMPOSITION Evidence has shown that the PV may be increased in African-American men compared with a similar group of white American men. Fowler et al.26 reported that African-American men had a significantly greater mean PV than did agematched and prostate biopsy-negative white American men (41 cm3 versus 36 cm3, P ⫽ 0.004). Kaplan et al.27 showed that African-American men had larger mean transition zone volumes than did white American men (6.9 cm3 versus 5.4 cm3, respectively, P ⬍0.04). The transition zone index was also significantly greater in African-American men. This finding was also observed by Roehrborn et al.28 in an analysis of the baseline data of a Phase III dutasteride study. African-American men (n ⫽ 161) had a significantly larger transition zone volume compared with white American men (n ⫽ 3961), but a similar total PV.28 Aoki et al.29 found no significant differences in the stromal/epithelial and stromal/glandular ratios, or in the proportion of epithelial lumen for whole prostates, between African-American and white American men. However, African-American men did appear to have a lower proportion of epithelial lumen in their transition zones compared with that in white American men, indicating more stromal than glandular hyperplasia. Therefore, it appears that benign prostatic enlargement may be more UROLOGY 68 (5), 2006
These ethnic differences in serum PSA level have led to revisions of the normal age-related ranges for African-American men, aimed at ensuring that the sensitivity of PSA testing for prostate cancer remains intact.38 However, as with studies examining ethnic variations in PV, not all studies of serum PSA levels have demonstrated that African-American men have a different profile than that of white American men.39,40 EPIDEMIOLOGY OF BPH
FIGURE 2. Serum PSA level stratified by age and ethnicity. AA ⫽ African American. Data from Henderson et al.37
common in “at-risk” African-American versus white American men and that this may be driven by larger transition zone PVs. PSA PROFILES PSA is a glycoprotein produced predominantly by the epithelial component of the prostate. Serum PSA levels are dependent on the total PV, transition zone volume, and transition zone epithelial volume,30 correlating significantly with prostatic epithelial volumes in patients with BPH.30,31 Several studies have reported greater serum PSA levels in African-American men than in white American men without prostate cancer.32–36 Henderson et al.37 observed that the PSA density (serum PSA/PV ratio) was significantly greater in African-American men (0.19 ⫾ 0.03 versus 0.11 ⫾ 0.01, P ⬍0.0001). When the data were examined by age, the mean PSA level was greater in AfricanAmerican versus white American men in all age groups (50 to 59, 60 to 69, 70 to 79, and 80 years or older), except for in the 40 to 49-year age group (Fig. 2). These findings are supported by those of another study.26 Fowler et al.26 examined the serum PSA levels and PV in 810 African-American and white American men older than 65 years with a PSA level of 4.0 ng/mL or greater and/or abnormal digital rectal examination findings plus prostate cancer-negative biopsy findings. Overall, the serum PSA levels were significantly greater statistically in the African-American men than in the white American men (4.7 versus 3.9 ng/mL, P ⬍0.0001). Furthermore, multiple linear regression analyses showed that being African American was significantly associated statistically with increased serum PSA level when controlled for age and PV (P ⫽ 0.002) and increased PSA density when controlled for age (P ⫽ 0.007). UROLOGY 68 (5), 2006
Early studies conducted in the 1930s suggested that African-American men had a greater occurrence of LUTS compared with white American men.41,42 A recent study of LUTS in African-American men compared the data from the Flint Men’s Health Study, which was specifically designed to examine the prevalence of LUTS in a community sample of 364 African-American men, and the data from Olmsted County Study of Urinary Symptoms and Health Status, which recruited largely white American men.43 The Flint Men’s Health Study used community-sampled men to minimize referral bias and a self-administered symptom questionnaire, rather than BPH surgery, as an indicator for BPH. The study, with 2480 men, demonstrated that moderate-to-severe LUTS were more common in African-American than in white American men (41% versus 34%, P ⬍0.001), although AfricanAmerican men were less “bothered” by their symptoms than were white American men. It appears from these studies, therefore, that African-American men have a similar prevalence of LUTS secondary to BPH compared with white American men but may have a greater prevalence of moderate or severe (versus mild) symptoms than do white American men. However, more recent studies have shown varying results.44 – 47 In a study of 527 patients with BPH (19% African American, 78% white American, and 3% other races) older than 50 years of age receiving medical care within the University of North Carolina Health Care System urology clinics, AfricanAmerican men were shown to have a mean International Prostate Symptom Score that was 1.4 points greater than that for white American men, although the sample size provided insufficient power to detect statistical significance for this parameter.47 NATURAL HISTORY OF BPH The progressive nature of BPH has been established in a large number of studies that have used markers of progression such as increasing PV, worsening symptoms, and peak urinary flow, or episodes of AUR and BPH-related surgery.3,48 –52 However, most of these studies examined popula927
tions of men with mixed ethnicity and did not specifically confirm the progressive nature of BPH in African-American men. A number of studies have addressed the natural history of BPH specifically in African-American men. The Flint Men’s Health Study demonstrated that the mean PV increased, peak urinary flow decreased, and urinary symptoms and bother worsened significantly with increasing age in AfricanAmerican men.53 These data are supported by those of a subset of men from the third National Health and Nutrition Examination Survey (NHANES III), which showed a significantly greater proportion of non-Hispanic African-American men with three or four LUTS or surgery in the 70-year-old or older age group versus the 60 to 69-year-old age group.44 Furthermore, data from a recent retrospective cohort study, conducted using observational, longitudinal data from 4517 men (976 African American and 3541 white American) with BPH in a U.S. healthcare system, support the observation that African-American men are at a significantly greater risk of BPH progression than are white American men. The PSA level was significantly greater in African-American men compared with that of white American men. Furthermore, within 1 year of diagnosis, significantly more African-American men had a record of BPH-related surgery (35% versus 21%, P ⫽ 0.037 for African-American versus white American men, respectively) and AUR (6% versus 2%, P ⫽ 0.01, for African-American versus white American men, respectively). The differences in the risk of progression between African-American and white American men were statistically significant after controlling for age and PSA level.54 However, it should be noted that prostate cancer was not excluded in the patients included in these analyses. TREATMENT PATTERNS FOR BPH The patterns of treatment for BPH may also differ between African-American and white American men. A case-control study, comparing men of mixed ethnicity who underwent prostatectomy with no evidence of prostate cancer with a control population, observed that African-American men had a relative risk of 1.6 for undergoing surgery for BPH versus white American men, although this did not reach statistical significance.55 An additional study examining the risk of surgery for BPH, however, failed to show African-American ethnicity to be a predictive factor, with a relative risk of 1.0 for African-American men compared with white American men.56 It should be remembered, however, that the number of prostatectomies for BPH has been declining since the 1980s. It is clear from examining the discharge rates for prostatectomies for African-American and white American men 928
that, in the 1980s, African-American men were less likely than white American men to undergo prostatectomy. However, this difference had disappeared by the early 1990s.57 However, the mean length of stay, although decreasing in both groups during this period, continued to be shorter for African-American than for white American men. CONCLUSIONS The pathophysiologic mechanisms responsible for the development and progression of BPH may differ in African-American men compared with the white American population. Circulating testosterone levels are greater in African-American men than white American men, and the DHT/testosterone ratio is elevated in older African-American men. These observations, coupled with studies demonstrating an increase in 5-alpha-reductase activity, suggest that DHT trophic effects on the prostate are greater in African-American men. This is supported by the findings that AR, IGF-1, and sex hormone-binding globulin levels are elevated and that of IGFBP-3 is diminished. Furthermore, DHT metabolite levels are greater in African-American men, indicating increased 5-alpa-reductase activity. This may also be a result of a missense substitution in the SRD5A2 gene commonly found in African-American men. Although some studies have identified a greater mean PV in African-American versus white American men, the findings from different studies are not wholly concordant. The balance of evidence suggests that the transition zone volumes are likely, on average, to be greater in African-American men in the BPH age range. Again, controversy exists over the PSA levels in African-American versus white American men, although a weight of evidence exists for a greater mean level in older men. Because the PSA level is known to reflect the PV, the cumulative findings from the PSA and PV studies point toward a greater prostate epithelial volume in African-American men. In common with white American men, LUTS secondary to BPH are prevalent in African-American men from late middle age, and evidence has suggested that their severity may be greater in African-American men. The progressive nature of BPH is also evident in African-American men. Furthermore, recent retrospective data have shown an increased risk of BPH progression (defined as an episode of AUR or a requirement for surgery) in African-American men versus white American men. Overall, the pattern of BPH differs in AfricanAmerican compared with white American men, and these differences may translate into differences in the risk of BPH progression. Adjusted reference UROLOGY 68 (5), 2006
ranges for serum PSA as a marker for PV, in addition to its role in prostate cancer detection, may be appropriate for African-American men. This has implications for the screening of men with LUTS and for treatment aimed at managing the underlying disease. However, direct comparative studies that prospectively recruit African-American and white American men in which prostate cancer has been excluded are needed to further elucidate the epidemiology, pathogenesis, and natural history of BPH in this ethnic group. This will allow specific recommendations to be made on the detection and management of BPH in African-American men. REFERENCES 1. Guess HA, Arrighi HM, Metter EJ, et al: Cumulative prevalence of prostatism matches the autopsy prevalence of benign prostatic hyperplasia. Prostate 17: 241–246, 1990. 2. Berry SJ, Coffey DS, Walsh PC, et al: The development of human benign prostatic hyperplasia with age. J Urol 132: 474 – 479, 1984. 3. Chute CG, Panser LA, Girman CJ, et al: The prevalence of prostatism: a population-based survey of urinary symptoms. J Urol 150: 85– 89, 1993. 4. Emberton M, Andriole GL, de la Rosette J, et al: Benign prostatic hyperplasia: a progressive disease of aging men. Urology 61: 267–273, 2003. 5. Griffiths K, Eaton CL, Harper ME, et al: Steroid hormones and the pathogenesis of benign prostatic hyperplasia. Eur Urol 20(suppl 1): 68 –77, 1991. 6. Ross R, Bernstein L, Judd H, et al: Serum testosterone levels in healthy young black and white men. J Natl Cancer Inst 76: 45– 48, 1986. 7. Pettaway CA: Racial differences in the androgen/androgen receptor pathway in prostate cancer. J Natl Med Assoc 91: 653– 660, 1999. 8. Steers WD: 5Alpha-reductase activity in the prostate. Urology 58: 17–24, 2001. 9. Carson C, and Rittmaster R: The role of dihydrotestosterone in benign prostatic hyperplasia. Urology 61: 2–7, 2003. 10. Griffiths K, and Eaton CL: The pathogenesis of BPH: role of hormones. Prog Clin Biol Res 386: 33– 41, 1994. 11. Bartsch G, Rittmaster RS, and Klocker H: Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia. Eur Urol 37: 367–380, 2000. 12. Ellis L, and Nyborg H: Racial/ethnic variations in male testosterone levels: a probable contributor to group differences in health. Steroids 57: 72–75, 1992. 13. Kubricht WS III, Williams BJ, Whatley T, et al: Serum testosterone levels in African-American and white men undergoing prostate biopsy. Urology 54: 1035–1038, 1999. 14. Reichardt JK: Prostatic steroid 5 alpha-reductase, an androgen metabolic gene. Mayo Clin Proc 75(suppl): S36 – S39, 2000. 15. Ross RK, Bernstein L, Lobo RA, et al: 5-alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 339: 887– 889, 1992. 16. Wu AH, Whittemore AS, Kolonel LN, et al: Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada. Cancer Epidemiol Biomarkers Prev 4: 735–741, 1995. 17. Makridakis N, Ross RK, Pike MC, et al: A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. Cancer Res 57: 1020 –1022, 1997. UROLOGY 68 (5), 2006
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