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Original Studies |
Andrology Unit, Royal Prince Alfred Hospital, and the Department of Medicine, University of Sydney, Sydney, New South Wales 2006, Australia; and the First Municipal Hospital (Z.Z.) and Changdong Factory Hospital (E.L.Z.), Yue Yang, Hunan Province, Peoples Republic of China
Address all correspondence and requests for reprints to: Prof. D. J. Handelsman, Department of Medicine (D02), University of Sydney, Sydney, New South Wales 2006, Australia. E-mail: djh{at}med.usyd.edu.au
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Abstract |
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-dihydrotestosterone (DHT) concentrations and International
Prostate Syndrome Scores were significantly lower, in CR compared with
either ACM or AR, whereas the scores of the latter two groups were
similar. Almost all of the population difference in total prostate
volumes could be accounted for by differences in central prostate
volumes. The strongest correlates of age-adjusted prostate volume were
prostate-specific antigen and DHT, the latter presumably reflecting the
quantitative importance of prostatic stromal type II 5-reductase
activity to circulating DHT concentrations. Sex hormone-binding
globulin concentrations were significantly higher in CR and
significantly lower in ACM compared with those in AR, but the
significance of these observations is unclear. These findings highlight
the importance of the central zone of the prostate as well as provide
evidence for an environmental factor influencing prostate growth. This
factor operates over a relatively short time period compared with the
evolution of prostate disease. Hence, this study provides evidence that
ethnicity and geographical factors, such as migration, can influence
the growth of the normal human prostate during midlife and may
facilitate future studies of the origins and pathogenesis of human
prostate disease. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The well established epidemiological determinants of prostate disease
are age, exposure to androgens in early manhood, and genetics (9). The
dramatic increase in the age-specific prevalence of prostate disease
(10) does not occur among men lacking adequate androgen exposure. This
requires prolonged exposure to adult circulating testosterone
concentrations (11, 12), a normal androgen receptor (13), and
intraprostatic amplification of testosterone to
5-dihydrotestosterone (DHT) via type II 5-reductase (14). Yet the
long range mechanism and the intervening steps by which early life
androgen exposure predisposes to late life prostate diseases remain
unknown. Few studies have examined human prostate size and its
determinants during the intervening years in midlife, when prostate
pathology is evolving but not yet clinically evident. In the present
study we compared prostate size (total, central, and peripheral
prostate volumes by planimetric ultrasound) in native-born men residing
in China and in Australia and in Chinese migrants from South East Asia
to Australia. In all three groups the relationships among age, prostate
size, and its hormonal determinants [plasma testosterone, DHT,
estradiol, and sex hormone-binding globulin (SHBG)] were measured.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Men recruited in Sydney by advertisement (n = 163) were
divided into Australian non-Chinese men (AR; n = 116; age, 23–69
yr) and Chinese migrants (ACM; n = 47; age, 24–77 yr). Chinese
migrants were born in mainland China (n = 21), Hong Kong (n =
20), and other South-East Asian countries (n = 6) and had lived in
Sydney for a median of 7.3 yr (range, 0.2–25 yr; 29 of 47 resident for
10 yr). The men born and residing in China (CR; n = 210; age,
18–74 yr) were recruited by the First Hospital of Yue Yang City (Hunan
Province, Peoples Republic of China) from workers at an aircraft
factory. The volunteers originated from a remote mountainous rural
area, but had recently (
6 months) been relocated to Yue Yang. The
study was approved by the local institutional ethics committees in
Sydney, Australia, and Yue Yang, China.
All volunteers were recruited and interviewed in their own language by doctors and provided with the same written study information document in English or Chinese translation. The International Prostate Syndrome Score (IPSS) forms were used in the standard authorized English and Chinese versions (15). General medical examination included measurement of blood pressure, body weight, height, and testis size (by orchidometer).
Prostate ultrasound
To ensure comparability of measurements, all ultrasound measurements were performed by a single investigator (B.J.) using the same equipment at both centers. Prostate size was measured by planimetric ultrasound with the volunteer resting in the supine position. Ultrasound examination used a 7.5-MHz B-mode biplanar sector scanner in a rectal transducer (2-cm diameter) attached to an OPUS 1 (Ausonic, Sydney, Australia) ultrasound machine. Planimetric reconstruction of prostate volume is based on serial cross-sections of the prostate obtained at 2.5-mm steps from base to apex using a calibrated stepper device. For each cross-section, the area and maximal orthogonal dimensions were measured by manually tracing the outlines with the tracker ball. Central and total prostate volume were measured directly from planimetric sections, and peripheral prostate volume was defined as their difference. The central zone refers to the sonographically lucent region in the central part of cross-sectional images of the prostate. This sonographically defined central zone contains the anatomical region defined by McNeal as the transitional zone (16, 17), but is larger and includes adjacent regions. This central zone has sometimes been described in ultrasound studies as the transitional zone; however, that description creates terminological confusion between the original anatomical description and the larger ultrasound-defined region that we and others (18) prefer to call the central zone. Within-subject reproducibility of planimetric prostate volume was estimated at 8.4% for total and 13.8% for central zones in 13 healthy men without prostate disorders who were reexamined at a median of 3 months (range, 0.5–11 months). Volunteers with a history of rectal bleeding, serious hemorrhoids, or significant ano-rectal disorders on prestudy digital rectal examination were excluded.
Assays
Blood was sampled before digital rectal examination, and serum was stored frozen until assayed in the same laboratories at the Royal Prince Alfred Hospital (Sydney, Australia). Blood samples were measured in established immunoassays for testosterone, SHBG, DHT, and prostate-specific antigen (PSA) within a single batch. Between-assay coefficients of variability were less than 10% for each assay. The free testosterone index was defined as the ratio of testosterone to SHBG (in nanomoles per L), expressed as a percentage.
Data analysis
Data were analyzed by ANOVA or analysis of covariance (using age as covariate), and correlation. Data are expressed as the mean and SEM, and P < 0.05 was considered statistically significant.
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Results |
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There were no significant differences in age among the three
groups of men (Table 1
). Nevertheless, as
most of the important study end points were known to vary with age, all
subsequent analyses were age adjusted by covariance to eliminate any
confounding effects of age maldistribution. Chinese residents and
migrants were equivalent in body weight, body mass index, and testis
volume, whereas Australian non-Chinese were taller and heavier and had
larger testis size than both groups of Chinese men. ACM were slightly
taller than CR.
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Prostate volumes and PSA
Central and total prostate volumes were smaller and PSA
concentrations were lower in CR than in ACM and AR men; the latter two
groups had no significant difference in volumes (Table 1
and Fig. 1). PPV did not differ between
groups. The ratio of central/total prostate volume was significantly
different; it was highest in AR, lowest in CR, and intermediate in
ACM.
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Plasma DHT and the DHT/T ratio were significantly lower in CR than
ACM or AR, with the latter two groups being equivalent (Fig. 2). Plasma testosterone was
significantly higher in CR than in either AR or ACM, but there was no
significant difference between groups resident in Sydney. Plasma SHBG
concentrations were highest in CR, followed by AR and then ACM.
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The hormonal determinants of prostate volume were examined after adjusting for age in partial correlation. After removing the effects of age, central prostate volume remained significantly correlated with body weight (r = 0.294; P < 0.001), BMI (r = 0.160; P < 0.001), testosterone (r = -0.108; P = 0.020), DHT (r = 0.300; P < 0.001), PSA (r = 0.369; P < 0.001), and SHBG (r = -0.200; P < 0.001) and marginally with free testosterone index (r = 0.098; P = 0.098). In contrast, total and peripheral prostate volume remained correlated with DHT, PSA, and body weight, but not total or free testosterone, SHBG, or body mass index after adjustment for age effects.
Prostate symptoms
IPSS total scores were significantly lower among CR compared with either ACM or AR. Overall, IPSS total scores were significantly correlated most strongly with central (r = 0.244; P < 0.001) and less strongly with total (r = 0.119; P = 0.032) prostate volumes, but were not correlated with peripheral prostate volume (r = 0.023; P = 0.679). IPSS score was also correlated weakly with BSA (r = 0.184), BMI (r = 0.135), DHT (r = 0.141; P = 0.014), and total testosterone (r = -0.130; P = 0.019), but not with PSA (r = 0.033; P = 0.549) or SHBG (r = -0.022; P = 0.691).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study highlights the value of studying the central zone of the prostate. The differences in total prostate volume between Chinese residents and migrants could be almost all accounted for by changes in the central zone, as the volume of the peripheral prostate zone was not different among the three groups studied. The findings confirm previous observations that the central zone of the prostate, defined sonographically as the lucent, hypoechoic area and which includes the anatomical transitional zone (16, 17) where the nodular benign prostatic hyperplasia originates (16, 17), is the most hormonally sensitive region of the primate (19, 20) and human (21) prostate. It is also the fastest growing region during middle and later life in men (18). This indicates that future epidemiological and clinical studies of the evolution, prevention, and treatment of prostate disease should include measurement of the central zone of the prostate. For clarity, it should be noted that the ultrasonically defined central zone includes but is more extensive than the anatomically defined transitional zone. Although the term transitional zone has been used in some ultrasound studies to refer to the same ultrasonically defined lucent region, to avoid terminological confusion, we and others (18) refer to this sonographic region as the central zone rather than using the term transitional zone ambiguously.
The difference between Chinese men residing in the two countries reflects the changing epidemiology of prostate disease in China during the last century. Whereas in the 1930s prostate disease was regarded as rare among Chinese men (22), 5 decades later the prevalence of prostate diseases has increased markedly, especially in urbanized regions of China (23). Even allowing for the impact of changing diagnostic criteria (24), improved access to health services, and increasing longevity of the population, there may be important trends in disease susceptibility. In this setting, migration provides a valuable window on the influence of environmental factors on disease susceptibility (25). Studies of prostate cancer rates in migrant populations from regions with low rates of prostate cancer (Asia and Eastern Europe) to regions of high rates of prostate cancer (U.S, United Kingdom, and Australia) have shown consistently that migrants continue to experience lower rates of prostate cancer (26) even into the second generation (25). We now estimate that significant changes in the sonographically defined central prostate zone volume may be measurable within a decade after migration. This provides a way in which clinical studies of the origins and progression of human prostate disorders can be telescoped into a realistic timeframe so as to overcome the unusually long latency in the natural history of prostate disorders.
Genetic factors are important in determining susceptibility to prostate disease. This is evident from twin studies. In these, higher concordance rates for monozygotic compared with dizygotic twins indicate that unspecified genetic factors are important in determining prostate diseases (27, 28), prostate size (29), and its hormonal determinants (30, 31). Such genetic factors presumably are significant components of the familial clustering (32) and ethnic and/or geographical variations in the occurrence of prostate diseases. In addition, numerous environmental factors have been identified in epidemiological studies as potential contributors to the development of prostate diseases (4, 26, 33, 34). Inconsistencies in these retrospective case-control studies may be due to recall bias and the long latency of prostate diseases. This involves reliance on case definition of men with the diagnosis of prostate cancer compared with unaffected controls, where recall bias is difficult to eradicate. The present study provides strong evidence for the operation of an environmental factor(s), susceptible to modification by migration, on prostate growth during the preclinical phase of latelife prostate diseases.
This study reinforces the relationship of DHT and SHBG as correlates of
prostate disease, whereas plasma total testosterone, estradiol, and the
calculated free testosterone index were unrelated to the population
differences observed. The 28% reduction in circulating DHT in Chinese
residents compared with Chinese migrants and Australian men was
striking. This difference was closely correlated with differences in
prostate zonal volumes, but it most likely represents an effect of
prostate size on circulating DHT concentrations. The alternative
possibility, that circulating DHT is an important determinant of
prostate growth, is biologically unlikely. Rather, it appears more
likely that prostatic 5-reduction of testosterone to DHT is a
major contributor to circulating DHT concentrations, so that the
lowered circulating DHT concentrations are due to a smaller prostate
size with reduced net type II 5-reductase activity. This is
supported by pharmacodynamic modeling indicating that 80% of
circulating DHT derives from type II 5-reductase (35). This is also
consistent with the only available study of the hormonal effects of
radical prostatectomy on circulating sex hormone levels, which showed
that removal of the prostate reduces circulating DHT by 21% in
absolute terms and by 37% taking into account ambient testosterone
concentrations (36). Also, higher circulating DHT concentrations have
no particular growth-promoting effect on the human prostate. For
example, transscrotal delivery of testosterone produces
disproportionately higher circulating DHT concentrations due to the
exposure of T during transdermal absorption to the high scrotal
5-reductase activity. Yet, prostate volume in such men is comparable
to but no larger than that in age-matched eugonadal controls who have
absolutely and relatively lower DHT concentrations (37, 38). Similarly,
therapeutic administration of transdermal DHT in aging men is
associated with decreased or unchanged prostate size rather than
increased prostate volume (39). These interpretations about the
significance of circulating DHT are not at variance with the
understanding that intraprostatic DHT has an important influence on
prostate size, as clearly shown by the effects of 5-reductase
inhibitor to reduce both intraprostatic generation of DHT, prostate
size (notably the central zone) and PSA concentrations (40). Our
findings of a lowered circulating DHT concentrations differ from those
of a previous study of Hong Kong Chinese compared with American
non-Chinese men (41) in which the Chinese men had lower, but not
statistically significantly different, DHT concentrations. This
discrepancy may reflect either the higher power of our study and/or the
more Westernized environment of Hong Kong. Previous reports have also
claimed that whole body 5-reductase activity was lower in Chinese
men residing in Hong Kong (41) as well as in Japanese residents (42)
compared with that in American resident non-Asian men, although more
recently these findings have not been confirmed (43). In an analogous
fashion to the role of the prostate in expressing 5-reductase
activity, the differences in whole body 5-reductase activity between
Asian and American men may be attributable to the differences in body
hair distribution, as terminal hair follicles exhibit prominent
5-reductase activity. Hence, the differences between Asian and
American men in the distribution of body hair, which corresponds to
whole body 5-reductase activity (44), may contribute to net whole
body 5-reductase activity.
A striking result in this study is the higher SHBG concentrations in Chinese residents, which then fell in Chinese migrants to below the levels in non-Chinese men living in the same city. Genetic factors explain relatively little variability in circulating SHBG concentrations compared with other reproductive hormones (30, 31, 45) consistent with strong environmental influence. The major known determinants of circulating SHBG concentrations in the general population are age and obesity (46), with dietary variations having only inconsistent effects on circulating SHBG concentrations (47, 48, 49). The striking difference in circulating SHBG concentrations between the two Chinese populations of similar age and adiposity suggests that other environmental factors susceptible to change by migration are important in determining circulating SHBG concentrations and prostate size. The persistence of dietary habits after migration (although the source of dietary ingredients may differ) suggests that dietary factors are unlikely to be the sole explanation of these relatively rapid changes. Other nondietary effects need to be investigated. The significance of SHBG in relation to prostate disease is speculative (50). Some evidence suggests that circulating SHBG may impede or modulate androgen action to protect against the progression of prostate disease, but direct evidence to test this hypothesis is lacking.
The lack of relationship between circulating testosterone and estradiol
and any measure of prostate zonal volumes presumably reflects the
biological requirement for intraprostatic metabolism of endogenous
testosterone to its active metabolites to influence prostatic structure
and function. Hence, the physiological action of testosterone on the
prostate is amplified through the formation of the more potent androgen
DHT by type II 5-reductase (51) as well as being diversified to
include effects on the estrogen receptor via conversion to estradiol by
aromatase (52). This contrasts with the effects of pharmacological
doses of estrogens, which have more dramatic effects on the human
prostate (21, 53, 54). The present observation that the calculated free
testosterone index is not correlated with any of the prostate volumes
does not necessarily rule out the biological relevance to the prostate
of free testosterone when measured by valid, direct methods. Most
likely, the noncorrelation of prostate volumes with free testosterone
index reflects the inadequacy of this calculated index, which lacks
theoretical or empirical validity in reflecting free testosterone in
men (55). Another caveat on the interpretation of this study is that
although the epidemiologies of prostate cancer and benign prostatic
hyperplasia are strikingly similar, the anatomical distributions of
these diseases are different. Prostate cancer originates mainly in the
peripheral zone in the posterior regions of the gland, whereas the
nodules of benign prostatic hyperplasia originate in the (anatomical)
transitional zone, a component of the central zone that we have
studied. Hence, until the nature and mechanism of the environmental
influences identified in this study are better defined, it cannot be
assumed that these effects are as relevant for prostate cancer as they
appear to be for benign prostatic hyperplasia.
In summary, our study demonstrates that prostate size in middle life is subject to environmental factors involved in the migration from a region of low to one of high rate of fatal prostate cancer. Although these environmental factors remain to be identified, the present findings, which telescope the progression of potentially modifiable environmental factors on the evolution of prostate growth, make it possible to study the factors influencing the origins of prostate disease over much shorter periods.
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Acknowledgments |
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Footnotes |
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Received April 8, 1999.
Revised May 19, 1999.
Accepted May 21, 1999.
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References |
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