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Original Studies |
Department of Medicine, Division of Endocrinology, Pennsylvania State University, Milton S. Hershey Medical Center (S.J.S., B.A., M.S., L.M.D., R.J.S.), Hershey, Pennsylvania 17033; the National Research Institute for Family Planning (G.-y.Z. G.-h.Z.), Beijing 100081, China; the Department of Medicine, University of California-Los Angeles-Harbor General Hospital (C.W.), Torrance, California 90509; and the Clinical Mass Spectrometry Facility, Children’s Hospital, Oakland Research Institute (C.S.), Oakland, California 94609
Address all correspondence and requests for reprints to: Dr. Richard J. Santen, Division of Endocrinology, Department of Internal Medicine, University of Virginia Medical School, Jordan Annex, Room 2232, Box 513, Jefferson Park Avenue, Charlottesville, Virginia 22908.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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-androstanediol glucuronide and androsterone
glucuronide in Chinese than in Caucasian men. Based upon these
findings, investigators postulated that Chinese men could have
diminished 5-reductase activity with a resultant decrease in
prostate tissue dihydrotestosterone levels and clinically apparent
prostate cancer. An alternative hypothesis suggests that decreased
3-androstanediol glucuronide and androsterone glucuronide levels
might reflect reduced production of androgenic ketosteroid precursors
as a result of genetic or environmental factors. The present study
examined 5-reductase activity, androgenic ketosteroid precursors,
and the influence of genetic and environmental/dietary factors in
groups of Chinese and Caucasian men. We found no significant
differences in the ratios of 5ß-:5-reduced urinary steroids (a
marker of 5-reductase activity) between Chinese subjects living in
Beijing, China, and Caucasians living in Pennsylvania. To enhance the
sensitivity of detection, we used an isotopic kinetic method to
directly measure 5-reductase activity and found no difference in
testosterone to dihydrotestosterone conversion ratios between groups.
Then, addressing the alternative hypothesis, we found that the
Caucasian subjects excreted significantly higher levels of individual
and total androgenic ketosteroids than did their Chinese counterparts.
To distinguish genetic from environmental/dietary factors as a cause of
these differences, we compared Chinese men living in Pennsylvania and a
similar group living in Beijing, China. We detected a reduction in
testosterone production rates and total plasma testosterone and sex
hormone-binding levels, but not in testosterone MCRs in Beijing Chinese
as a opposed to those living in Pennsylvania. Comparing Pennsylvania
Chinese with their Caucasian counterparts, we detected no significant
differences in total testosterone, free and weakly bound testosterone,
sex hormone-binding globulin levels, and testosterone production rates.
Taken together, these studies suggest that environmental/dietary, but
not genetic, factors influence androgen production and explain the
differences between Caucasian and Chinese men. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase activity. This would result in a lowering of prostate
tissue dihydrotestosterone (DHT) levels and potentially of the rate of
progression from latent to clinically apparent prostate cancer (4, 5).
Alternatively, environmental or dietary factors that are prevalent in
China but not in western countries could provide an explanation for the
differences in cancer risk (6). These possibilities have led us to a
series of studies comparing Chinese with Caucasian subjects.
We initially demonstrated that Chinese men have less facial and chest
hair than age-matched Caucasian men and suggested the possibility that
reduced conversion of testosterone to DHT in the Chinese might explain
this difference (7, 8). In addressing this issue, we detected lower
levels of the 5-reduced androgen metabolites, 3-androstanediol
glucuronide (3-Diol-G) and 3-androsterone glucuronide (3A-G)
in plasma of normal Chinese males and females compared to their
Caucasian counterparts. It was apparent to us, however, that plasma
levels of these conjugated metabolites provide only an indirect measure
of tissue 5-reductase activity. The amount of circulating
3-Diol-G and 3-A-G is determined not only by tissue
5-reductase activity, but also by the amount of precursor
ketosteroid secreted by the gonads and adrenals (9, 10). Accordingly,
the present study used more direct measurements of 5-reductase
activity and quantitative assessment of ketosteroids to evaluate
differences between Chinese and Caucasian subjects. We chose techniques
previously used to demonstrate 5-reductase deficiency in subjects
with an inherited decrease in the activity of this enzyme. These
methods involved measurement of the 5ß:5 ratios of several urinary
metabolites using gas chromatography and mass spectrometry as well as
isotopic kinetic determinations of the conversion of testosterone to
DHT (9, 11).
The data reported here suggest that a genetic alteration of
5-reductase activity does not explain the reduced 3-Diol-G and
3-A-G levels in Chinese men. Instead, reduced levels of the
androgenic ketosteroid precursors of these plasma metabolites provide
the most likely explanation. Dietary or other environmental factors
appear to alter the serum levels and production rates of testosterone
of Chinese men living in China. These factors require consideration
when postulating a causal link between the reduction of prostate cancer
incidence, reduction of ketosteroid excretion, and lowered testosterone
production rates in Chinese men living in China.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Overnight urine samples were obtained from 20 Caucasian men and
20 women living in the United States and from 20 Chinese men and 20
women living in Hong Kong. All subjects were normal medical students
taking no medications that would alter androgen levels. Thirty-eight
steroids were measured by gas chromatography-mass spectrometry (12).
Assessment of 5-reductase activity, as previously described (9, 10),
involved calculation of the ratios of four 5ß-:5-steroid pairs
measured in overnight urine samples. For assessment of ketosteroid
excretion, values were normalized by dividing by the urinary creatinine
level. Total ketosteroid levels were calculated by adding all
individual ketosteroid values together. These are expressed per mg
creatinine to correct for variances in duration of collection of
samples.
Measurement of androgens and sex hormone-binding globulin (SHBG) in Caucasian and Chinese men
Serum samples were obtained from an additional 10 Caucasian men (aged 22–27 yr) and 10 Chinese men (aged 20–37 yr) living in Pennsylvania and from 10 Chinese men (aged 24–39 yr) living in Beijing, China. Subjects living in Pennsylvania were examined at Pennsylvania State University Hospital and had a normal physical examination and no evidence of underlying illness. Subjects living in Beijing were examined by one investigator (G.-y.Z.) who noted that 9 of 10 had fathered children, and 1 had normal sexual function but was using condoms for contraception. No evidence of endocrine disorders or other illness was detected. Testis size was normal in all men, ranging from 15 mL (right and left testes) to 25 mL (right and left testes). Samples obtained from these subjects were used for measurement of testosterone, bioactive testosterone, and SHBG levels. All volunteers signed informed consents, and all protocols were approved as required by the institutions where the research was conducted. Total testosterone was measured by RIA as previously described (7, 8). Bioactive testosterone (free and weakly bound) was measured using the ammonium sulfate precipitation method (13, 14). SHBG was measured using a solid phase 125I immunoradiometric assay kit from Diagnostic Products Corp. (Los Angeles, CA).
Measurement of the interconversion of androgens in Caucasian and Chinese men
Eighty microcuries of [3H]testosterone were
infused iv over a 3-h period after a 5-mL loading dose bolus of 2.5
µCi was given to the 30 male subjects. Identical infusion pumps and
aliquots from centrally prepared radiolabeled testosterone were used
for studies in the United States and China. Sixty milliliters of blood
were collected after 2, 2.5, and 3 h of infusion. Serum was
obtained and stored at -20 C until processed. Samples from Chinese men
were flown to Pennsylvania frozen and processed identically to those
collected in Pennsylvania. Upon thawing, the volume was measured, and
[14C]testosterone, DHT, and androstenedione were added to
each sample to determine recoveries. This was followed by 3 extractions
with 200 mL methylene chloride. The methylene chloride fractions were
combined, partially evaporated, backwashed twice with 3 mL distilled
water, and taken to dryness. The samples were then purified by thin
layer chromatography and high pressure liquid chromatography using
solvent systems previously developed (15, 16) and outlined in Fig. 1
. Calculations of conversion ratios and
MCRs followed the methods of Mahoudeau et al. as extensively
described previously (17).
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All samples were collected in the morning to minimize differences due to circadian variation in steroids. Due to the small number of individuals in each group and the known lack of normal distribution of hormonal data in these populations (18), data were expressed as median values with 25th and 75th percentiles in parentheses (in the tables) or were presented as box plots of the 25th and 75th percentiles with the median indicated by the line within the box and the range depicted by the bars outside the box (in the figures). Testing of statistical differences among groups used Kruksal-Wallis one-way ANOVA (when three groups were compared) and Mann-Whitney tests (when two groups were compared). All analyses were performed using the Systat computer package (Systat, Evanston, IL). The Bonferonni correction was used to compensate for multiple urine comparisons, and only P < 001 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase activity than their Caucasian
counterparts. The ratios of 5ß-:5-reduced urinary steroids were
determined as a method to detect these differences. No significant
differences in 5ß:5 ratios (or even suggestive trends) were found
to suggest a diminution of 5-reductase activity in the Hong Kong
Chinese compared to the Pennsylvania Caucasian medical students. (Table 1). Levels in the Chinese subjects were
6- to 30-fold lower than those in patients with known 5-reductase
deficiency (9, 10) and were essentially the same as those in
Caucasians. We next used the more sensitive isotopic kinetic
methodology to enhance the likelihood of detecting small differences in
5-reductase activity (10, 11). To evaluate the possibility that
dietary/environmental factors might confound interpretation, we
compared Chinese living in Pennsylvania with Chinese living in Beijing
and with Caucasians living in Pennsylvania. The percent conversion of
testosterone to DHT as a direct measure of 5-reductase activity did
not differ among the three groups studied (Fig. 2). As an additional marker of androgen
metabolism, the conversion of testosterone to androstenedione also did
not differ among these three groups of subjects (Fig. 2). Considering
both the urinary and plasma isotopic data, we concluded that the
Chinese subjects, whether living in China or in the United States, did
not have lower 5-reductase activity than their Caucasian
counterparts.
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-reduced
metabolites in Chinese subjects than in their Caucasian counterparts
might reflect a reduction of androgenic ketosteroid precursors as first
proposed by Rittmaster and colleagues (19). To test this possibility,
we measured a series of urinary ketosteroids, which serve as markers
for adrenal androgen production. We detected lower levels of several of
these components in the urines of Chinese compared to Caucasian
subjects (Table 2). Androsterone and
etiocholanolone were significantly lower in the Chinese subjects (data
from males and females combined, P < 0.001 and
P < 0.001, respectively), and
11ß-hydroxyetiocholanolone was marginally lower (P =
0.025). To integrate data from multiple steroid measurements, we also
calculated the total level of excreted ketosteroids in each subject.
With this methodology, we found total ketosteroid excretion to be
significantly lower in Chinese than in Caucasian subjects
(P = 0.006; Fig. 3). When
examined separately by gender, the differences appeared to be greater
in females than in males, but variances were substantial. As a control
for potential confounding factors, such as the amount of creatinine
excreted, we also measured glucocorticoid metabolites. These levels, in
contrast, were not lower in Chinese than in Caucasian subjects (Table 2). Interestingly, three minor compounds, 6ß-hydroxycortisol,
20-dihydrocortisol, and 20ß-dihydrocortisol, were higher in the
Chinese group (data from males and females combined, P
= 0.044, 0.02, and 0.007, respectively), but not sufficiently to reach
the Bonferonni limits of significance (i.e. P <
0.001).
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) in the Beijing compared with the
Pennsylvania Chinese (P = 0.034). In contrast,
testosterone MCRs did not differ between these two groups (Fig. 4). We
also detected significantly lower levels of total testosterone and SHBG
levels (P = 0.031 and 0.038, respectively) in Beijing
than in Pennsylvania Chinese (Fig. 5).
The lower SHBG levels probably explain the inability to demonstrate
lower bioavailable testosterone levels in the Chinese men living in
Beijing than in those in Pennsylvania. Taken together, these data
suggest that the lower levels of total testosterone in the serum of
Beijing residents are due to a decrease in testosterone production
rather than an increase in testosterone MCRs in these subjects.
Additionally, these differences are probably due to
dietary/environmental factors.
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). These data suggest that no major genetic
differences exist with respect to these parameters. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-Diol-G and 3-A-G
levels suggested that genetic alterations of 5-reductase might be
present in Chinese men (7, 8). We hypothesized that a resultant
lowering of prostatic tissue DHT levels might explain the lack of
progression from latent to clinically apparent prostate cancer in the
Chinese. However, we recognized that dietary or other environmental
factors altering androgen metabolism might also be important.
The present study sought to examine both genetic as well as
environmental/dietary influences on androgen metabolism. Initially, we
used two proven methods to examine 5-reductase activity in patients:
determination of 5ß:5 ratios of excreted urinary steroids and
isotopic kinetic measurements of testosterone to DHT conversion
(9, 10, 11). Neither method demonstrated diminished 5-reductase activity
(or even a trend in that direction) in Chinese men living in China
compared with those in the United States. Taken together, these studies
suggest that there are no major genetic differences in 5-reductase
activity levels between Chinese and Caucasian subjects.
Dietary/environmental factors did appear important. Study of one group
of Chinese men living in the United States and another living in
Beijing, China, allowed us to directly test these factors. Significant
differences in serum testosterone levels and production rates between
these two groups clearly substantiated the importance of these
nongenetic influences.
Our prior data demonstrated a clear reduction in 5-reduced androgen
metabolites such as 3-Diol-G and 3-A-G levels in the plasma of
Chinese compared to Caucasian subjects (7, 8). The present study
provides an explanation for these differences. Our isotopic as well as
ketosteroid data suggest that a lowering of androgenic precursors,
which serve as substrates for these metabolites, is responsible rather
than a diminution of 5-reductase enzyme activity.
It should be pointed out that our original studies comparing Chinese
and Caucasian subjects were predicated on the concept that plasma
3-Diol-G and 3-A-G levels primarily reflect the rate of tissue
5-reduction of androgens (7, 8). This idea originated from studies
of Mahoudeau et al. (17) and was extended by Toscano and
Horton (24) and others (25, 26). Later studies, however, indicated that
steroids secreted by the adrenal, such as androstenedione and
androsterone, can also contribute substantially to the levels of
3-Diol-G and 3-A-G (19, 27). Based upon this reasoning, we
considered it necessary to examine these two components directly by
determining 5-reductase activity by isotopic and urinary methods and
the levels of precursor substrates by measuring ketosteroids in urine.
The results point to decreased ketosteroid precursor levels as the
primary factor to explain lower plasma 3-Diol-G and 3-A-G
levels.
Other investigators have also demonstrated lower 17-ketosteroid levels in Oriental than in Caucasian subjects (28). Although genetic differences among groups provide one potential explanation for this finding, dietary or other environmental factors could equally explain the differences observed. Unfortunately, we did not compare ketosteroid levels in Chinese living in the United States with those living in China to address the environmental/dietary issue directly. However, our isotopic kinetic studies do shed some light on this issue. Testosterone production rates, SHBG levels, and serum total testosterone levels were substantially lower in Chinese living in Beijing than in those living in the United States. It should be noted that the physiological interactions between non-SHBG-bound testosterone and its effect on testosterone MCR and total testosterone are complex and cannot be inferred from our results. Taken together, our findings point directly to environmental/dietary influences on androgen metabolism. These factors could also have contributed to the differences in ketosteroid levels observed between Caucasians living in the United States and Chinese living in Hong Kong. Further studies of ketosteroid excretion must be now conducted in Chinese living in the United States and compared with those of Chinese living in China.
Androgen metabolism and plasma levels in patients who ultimately develop prostate cancer or currently carry this diagnosis have been the subject of several very recent studies (5, 20, 29, 30, 31, 32, 33, 34, 35, 36, 37). In one, androgen levels were compared in groups of Japanese and Dutch men (20) with the finding of lower androgen levels in Japanese men. Another failed to find lower testosterone levels in Japanese subjects living in Japan compared to Caucasians living in the United States (5). These observations, taken in context with our results, emphasize the complexity of distinguishing genetic from environmental/dietary effects. In addition, it is necessary to prove cause and effect relationships. Although lowered androgen production could provide a hormonal explanation for the different incidence rates of clinically evident prostate cancer between Japanese and Europeans, these findings may equally represent associated, but not causally related, phenomena. Further studies are clearly necessary to distinguish among the various possibilities.
Epidemiological studies provide strong evidence that environmental/dietary factors are important in accelerating the transition between latent and clinically apparent prostate cancer. Japanese men experience an increase in the incidence of clinically apparent prostate cancer when they move to Hawaii (23). African men have a much lower incidence of prostate cancer than do African-Americans. An increase in the rate of clinically apparent prostate cancer is associated with increases in fat intake. There are also other data suggesting that increased fat intake can increase the levels of androgen production (29). Further studies will be necessary to assess the influence of diet and body composition or body surface area on androgen metabolism. The present study, although providing no definitive mechanisms, suggests the importance of dietary or other environmental influences on androgen metabolism.
Several limitations are inherent in the studies reported. We recognize
that the limited numbers of study subjects available and the
nonparametric distribution of data reduce the power of statistically
based conclusions. Nonetheless, the absence even of trends supporting a
diminution of 5-reductase activity in the Chinese men strengthens
the conclusions of this study. Our data do not preclude the possibility
that certain tissues may have isolated alterations of either type I or
type II 5-reductase activity (38, 39). Thus, it remains possible
that Chinese subjects could have diminished 5-reductase activity
isolated to hair follicles or prostate. Additional studies are required
to address these issues. Finally, the exact dietary or environmental
factors influencing androgen metabolism have not been identified in our
studies.
In conclusion, dietary or environmental factors, and not a diminution
of 5-reductase, appear to be responsible for differences in androgen
metabolism between Caucasians living in the United States and Chinese
living in China. These results highlight the necessity of carefully
controlling for multiple factors before concluding that the observed
differences result from genetic factors.
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Footnotes |
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Received December 16, 1997.
Revised February 24, 1998.
Accepted March 11, 1998.
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References |
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-Reductase activity and risk of prostate cancer among Japanese and
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chest hair density in men. J Clin Endocrinol Metab. 67:986–991.[Abstract]
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deficiency. J Clin Endocrinol Metab. 54:931–941.[Medline]
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ambiguous genitalia in the Dominican Republic. J Urol. 136:867–873.[Medline]
-androstanediols. J Clin Invest. 50:1338–1344.
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prostate cancer: a case-control analysis. Cancer Epidemiol Biomarkers
Prevent. 6:189–192.[Abstract]
-Reductase activity and prostate cancer:a case-control study using
stored sera. Cancer Epidemiol Biomarkers Prevent. 6:21–24. reductase. J Clin Invest. 89:293–300.
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4A). Cau(U), Caucasians living in the
U.S. Ch(U), Chinese living in the U.S. Ch(C), Chinese living in China.
+ indicates values lying greater than 1.5 times the difference between
the 25th and 75th percentile values above or below the box. All
statistical comparisons were nonsignificant. In the text, Beijing
Chinese is frequently used in place of Ch(C), and Pennsylvania Chinese
is used for Ch(U).
