[CANCER RESEARCH 53. 7VO-794. February 15.
1993]
Elevated Serum Testosterone Levels and Risk of Hepatocellular
Ming-Whei Yu and Chien-Jen Chen2
Comprehensive Cancer Center and Division of Environmental Sciences, School of Public Health. Columbia University, New York, New York 10032 ¡M-W. Y.(, anil Institute of
Public Health, College of Medicine, National Taiwan University, Taipei ¡0018. Taiwan ¡C-J.CJ
ABSTRACT
Serum samples of 9691 male adults had been collected and frozen for a
prospective study of hepatocellular carcinoma in Taiwan. After an average
follow-up period of 4.6 years, testosterone levels in the stored serum were
measured by radioimmunoassay using commercial kits for 35 cases of
newly developed hepatocellular carcinoma, 63 hepatitis B surface antigen-
negative and 77 hepatitis B surface antigen-positive matched controls.
Elevated testosterone levels were found to be associated with an increased
risk of hepatocellular carcinoma. The association remained significant
after the adjustment for effects of other hepatocellular carcinoma risk
factors, including hepatitis B surface antigen carrier status, positivity of
serum antibody to hepatitis C virus, cigarette smoking, alcohol drinking,
past liver disease history, and dietary habits. The multivariate-adjusted
relative risk of hepatocellular carcinoma for men with testosterone levels
in the upper fertile was 4.1 (95% confidence interval = 1.3-13.2) com
pared with those having levels in the middle or lower tertiles (P = 0.016).
The results consistent with those observed in animal experiments support
the hypothesis that testosterone plays a role in the etiology of human
hepatocellular carcinoma.
INTRODUCTION
Liver cancer, largely HCC,1 is one of the most common fatal
cancers in the world ( 1). Although there has been rapid progress in the
understanding of the etiology of HCC during the past 2 decades, the
reasons for marked male predominance in HCC incidence observed in
both high- and low-risk areas (I, 2) remain to be elucidated. In
Taiwan. HB„Agcarrier status has been well documented as the most
important risk factor of HCC (3-5). However, HCC is 2-3 times more
frequent in males than in females, despite their similarity in HBsAg
carrier rate (2). Differences in life-style habits such as cigarette smok
ing and alcohol drinking have been implicated in the gender discrep
ancy (4). Sex hormone and striking male-to-female differences in
chronic hepatitis (6) and liver cirrhosis (7) may also be important.
A greater susceptibility of male animals to spontaneous and chem
ical carcinogen-induced HCC has long been observed in experimental
mice and rats (8-14, 15). The increased susceptibility to hepatocar-
cinogenesis in males has also been observed in HBV transgenic mice
(16, 17). These observations are in agreement with epidemiological
data suggesting that men are much more prone to HCC than women.
Although the marked sex difference in HCC incidence observed in
mice and rats may result from the tumor-inhibiting effects of estrogen
in female animals as well as the tumor-promoting effects of testos
terone in male animals, the persuasive evidence in the animal models
indicating that testosterone may enhance the development of HCC
suggests that the testosterone may explain, at least in part, the greater
Received 6/29/92; accepted 12/4/92.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by the Department of Health. Executive Yuan. Republic of China.
: To whom requests for reprints should be addressed, at Institute of Public Health.
National Taiwan University College of Medicine. No. 1 Jen-Ai Road, Section 1. Taipei
I(K)I8, Taiwan.
1The abbreviations used are: HCC. hepatocellular carcinoma; HBsAg. hepatitis B
surface antigen; HBV. hepatitis B virus; HCV. hepatitis C virus; RIA. radioimmunoassay;
CI. confidence interval; RPHA, reverse passive hemagglutination assay; RR. relative risk.
790
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Carcinoma1
incidence of liver tumor observed in men. Male castration signifi
cantly decreases the frequency of chemically induced HCC (10, 12,
15, 18, 19), whereas administration of testosterone to castrated male
rats or to female mice increases the growth of preneoplastic hepatic-
foci ( 11) or the incidence of spontaneous (8) or chemical carcinogen-
induced HCC ( 18). An experiment on rats also showed that hypophy-
sectomy in males inhibits liver tumor induction by aflatoxin (20).
In contrast to the abundant data in animal models, the evidence
showing the effect of testosterone on human hepatocarcinogenesis is
scanty in spite of several documented HCC cases following andro-
genic-anabolic steroid treatment (21) and the presence of androgen
receptors in human HCC tissues (22, 23). We therefore carried out a
nested case-control study using serum samples collected and frozen in
1984-1986 from a cohort of 9691 male adults to investigate the role
of elevated testosterone in the etiology of HCC.
SUBJECTS AND METHODS
The study population consisted of 9691 men aged 30-85 years who attended
a community-based study carried out in six townships of Taiwan for the early
detection of cancer between September 1984 and February 1986. At the initial
recruitment examination, a total of 15 ml blood were collected from each study
subject. They were also personally interviewed according to a structured ques
tionnaire on sociodemographic characteristics, long-term habits of cigarette
smoking, alcohol drinking, and dietary pattern, as well as personal and family
history of chronic diseases by well-trained public health nurses in local health
centers. Habit of cigarette smoking was defined as having smoked cigarettes
more than 4 days a week for at least 6 months. Alcohol drinking was defined
as having drunk alcohol more than 3 days a week for at least 6 months.
Vegetable consumption frequency was defined as the number of meals includ
ing fresh vegetables per week. Vegetarian habit was defined as having one or
more meals without eating food from animal sources every day for more than
1 year. The personal and family history of chronic liver diseases diagnosed by
physicians was also obtained.
The participants of this study cohort were followed by telephone interviews
and home visits annually until March 1990. The person-year under observation
for each subject was defined as the period of follow-up from recruitment to the
dale when he was affected with liver cancer or died from other causes or the
date this nested case-control study started, i.e.. March 1990. The follow-up
period ranged from 0.5 to 5.5 years, with an average of 4.6 years. Death
certificates were also reviewed to examine the causes of death for those who
died. During the follow-up period, 36 newly diagnosed liver cancer cases were
identified. The annual incidence of liver cancer was 91 Al \OO.(KX)person-
years. Although the coding of liver cancer in death certificates combined
cancers of the liver and the intrahepatic bile duct (1CD 155) according to the
8th Revision of the International Classification of Diseases, Injuries and
Causes of Death, more than 95% of the deaths classified into this category in
Taiwan were HCC. The most accepted diagnostic criteria for HCC in Taiwan
are assigned on the basis of either pathological examinations or elevated
a-fetoprotein level (>40() ng/ml) combined with at least one positive image on
angiography. sonography. liver scan, and/or computerized tomography scans.
Among the 36 liver cancer cases, 8 were double-checked with hospital records
(4 were confirmed histologically and 4 were diagnosed by an elevated a-fe
toprotein level and liver images compatible to HCC). and 15 were double-
checked with data files of the National Cancer Registry in Taiwan (about
one-half of them were diagnosed pathologically and another half by elevated
a-fetoprotein and liver images). The remaining 13 cases were identified
through the national death certification system only. Since HCC is a common
 SERUM TESTOSTERONE
cancer and most HCC patients are referred to teaching hospitals for diagnosis
and treatment in Taiwan, the possibility of misdiagnosis of HCC was rather
low.
Because liver cirrhosis has been reported to be frequently associated with
hypogonadism (241 and most HCC patients in Taiwan may have a long-term
underlying liver cirrhosis before they are affected by HCC. it is essential to
evaluate the effect of liver cirrhosis on serum testosterone in the preclinical
phase of HCC patients. The deep-fro/.en serum samples from IS study subjects
who died from liver cirrhosis during the 5-year follow-up period were used to
assess whether liver cirrhosis may cause a significant change in serum testos
terone levels and distort the association between serum testosterone levels and
HCC risk. Since all of these cirrhotic patients died within 5 years after the
recruitment but only 3 reported a history of physician-diagnosed liver cirrhosis
in the baseline interview, it was believed that these patients already had a
subclinical liver cirrhosis at the time of blood collection, the same as most
HCC patients identified in this study.
All subjects in the study cohort were tested for their HBsAg carrier status by
RPHA at the initial recruitment examination. Because some HB„Agcarriers
may have chronic liver diseases, it is essential to obtain a valid estimation of
serum testosterone level for HB„Ag-positive and HB„Ag-negative subjects,
respectively. Two HBsAg-positive and two HB„Ag-negativecontrols matched
with each liver cancer case were selected in order to recruit enough and equal
numbers of subjects not affected with HCC. Controls were randomly selected
from study subjects who were alive and free from liver cancer on the dates at
the diagnosis of liver cancer cases to whom they were matched. Cases and
controls were matched with respect to age (within 5 years), date of question
naire interview and blood collection (within 3 months), and residential town
ship. As the frozen serum sample of one liver cancer case was not enough for
the test of testosterone, the statistical analysis was based on the data of 35
matched case-control sets.
Serum samples were separated on the same day as blood collection.
Two aliquots were frozen in deep freezers and transported in dry ice to the
central laboratory at National Taiwan University College of Medicine. The
serum samples were kept at -30°C for further examination until this nested
case-control study was carried out. Serum samples of 35 liver cancer cases and
140 matched controls were tested in April 1991. The HB„Agstatus of liver
cancer cases and matched controls who were HB„Ag-negative in the initial
RPHA were retested by RIA using commercial kits (Abbott Laboratories,
North Chicago, IL). Seven controls who were HB^Ag-negative on RPHA were
found to be HBsAg-positive on RIA. In other words, there were 77 HBsAg-
positive and 63 HBsAg-negative controls based on RIA results. Anti-HCV was
examined in duplicate by enzyme immunoassay (Abbott Laboratories) accord
ing to the manufacturer's instructions. Positive samples at the first test were
retested. Only repeatedly positive samples were considered anti-HCV-positive.
Serum testosterone levels were measured by RIA using commercial kits
(Biomerieux. Marcy l'Etoile, France). Specimens for each liver cancer case
and the matched controls were tested blindly in the same batch for all labo
ratory examinations.
A age-adjusted serum testosterone value was used when we compared the
mean levels of the hormone of liver cirrhosis cases to those of controls. Since
the distribution of the age-adjusted testosterone values showed no substantial
deviation from the normal distribution, judging from histogram and coeffi
cients of skewness and kurtosis. a r test was applied to compare the mean levels
of serum testosterone between groups. To assess the effect of elevated serum
testosterone on the risk of HCC. the serum testosterone level was dichotomized
using the lowest value of the upper tertile of testosterone levels in controls, i.e.,
5.69 ng/ml. as the cutoff point. The relative risk of liver cancer for the higher
testosterone level was estimated by the odds ratio using the lower testosterone
level as the referent group. Conditional logistic regression analyses were used
to calculate matched crude and multivariate-adjusted odds ratios and their 95%
CI for various risk factors of HCC. Statistical significance of the risk estimates
was examined by Z test. All P values for tests of statistical significance were
based on two-tailed tests.
This study was conducted with the approval of the Department of Health
and in compliance with regulations for the protection of human research
subjects.
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Research.
AND Hi;i>AT(X'i;Ll,UI.AR CARCINOMA
RESULTS
There were 20 HBsAg-positive and 15 HBsAg-negative liver cancer
cases. The age of liver cancer cases at the initial recruitment exami
nation ranged from 40 to 74 years. The mean age ±SD at recruitment
was 60.1 ±8.8, 58.6 ±8.9. 58.3 ±9.8, and 59.2 ±9.2 years,
respectively, for HB„Ag-negativecontrols. HBsAg-positive controls,
HBsAg-negative liver cancer cases, and HBsAg-positive liver cancer
cases. The age distribution of liver cancer cases was similar to that of
their matched controls.
The age of patients who died from liver cirrhosis ranged from 38 to
66 years, with a mean ±SD of 52.5 ±9.6 years. They were younger
than controls. Since the serum testosterone level in men has been
reported to decline gradually with age after 40 years (25), age-ad
justed testosterone values were derived for comparison. The age and
testosterone level of controls were used to build a regression line. A
residual was first calculated by subtracting the predicted value ob
tained through the regression equation from the observed testosterone
level. The residual of each study subject was then added to the mean
testosterone level of controls to derive an age-adjusted value of serum
testosterone. Since the regression coefficient (b = 0.00056, P = 0.98)
of this regression line indicated that the testosterone level did not
significantly change with age, the adjustment would not alter the
observed association between liver cirrhosis and serum testosterone
levels. The age-adjusted serum testosterone levels of liver cirrhosis
cases and controls by HBsAg carrier status were compared in Table 1.
There were 12 HBsAg-positive and 3 HBsAg-negative cases of liver
cirrhosis. The HB^Ag-negative liver cirrhosis cases had the lowest
testosterone level among the four groups. But the difference in mean
serum testosterone level was not significant between any two groups.
The proportion of a testosterone level above 5.69 ng/ml was signifi
cantly higher in HBsAg-positive controls than in HBsAg-negative
controls (P = 0.045). The proportion was slightly higher in HBsAg-
positive controls than HBNAg-positive liver cirrhosis cases.
The mean ±SD of serum testosterone levels was 5.20 ±2.52
ng/ml for liver cancer patients. Among the HBsAg-positive matched
case-control sets, 55.0% of liver cancer cases and 47.5% of matched
controls had a testosterone level greater than 5.69 ng/ml, giving a
matched RR of 1.5. Among the HBsAg-negative matched sets, 46.7%
of liver cancer cases and 23.3% of matched controls had an elevated
testosterone level, giving a matched RR of 2.3. In order to increase the
statistical power of detecting a significant effect of elevated testoster
one, all controls (2 HBsAg-positive and 2 HBsAg-negative) matched
with each liver cancer case were included in the analyses. Because the
HB.,Ag carrier rate of the liver cancer cases (57%) was similar to that
of controls (55%), the association between serum testosterone level
and HCC observed in this study is acceptable. The proportion of
elevated testosterone level was compared between liver cancer cases
and matched controls, as shown in Table 2. Eighteen (51.4%) of 35
liver cancer cases and 48 (34.3%) of 140 matched controls had a
serum testosterone level greater than 5.69 ng/ml. There was a signif
icant association between elevated serum testosterone level and liver
cancer, with a RR of 2.3 (95% CI = 1.01-5.14) and a P value of
0.046.
Table 1 Age-adjusted serum lesinstemne levels (ng/ml) of liver cirrhosis cases
and controls h\ HR^Ag carrier status
Controls Liver cirrhosis cases
HBsAg n Mean±SD >3.W (%) « Mean ±SD >5.69 (%)
Negative 63 4.54 ±1.87 25.4 3 2.92 ±1.77 0
Positive 77 5.22 ±3.11 41.6'' 12 5.24 ±2.47 33.3
" The lowest value of upper tertile in the testosterone distribution of controls.
h P = 0.045 compared to HBsAg-negative controls.
791
 SERUM TESTOSTERONE AND HEPATOCELLULAR CARCINOMA

Table 2 Association benreen elevateti serum testosterone levels liver cancer when HBsAg carrier status, anti-HCV positivity, alcohol
anil the risk of HCC
drinking, cigarette smoking, frequency of vegetable consumption,
Serum
vegetarian habit, and past liver disease history were adjusted (Table
testosteronelevel risk
(ng/ml)S5.69 (95% interval)1.02.3(1.01-5.14)
confidence 4). The multivariate-adjusted RR for men whose serum testosterone
levels were in the upper tertile was 4.1 (95% CI = 1.3-13.2), as
>5.69CasesNo.1718<%)(48.6)
(51.4)ControlsNo.92 04.3)Relative
48(%)(65.7) compared with those having serum testosterone levels in the middle or
lower tertiles (P = 0.016). The anti-HCV positivity, past liver disease
history, and low vegetable consumption frequency remained signifi
Table 3 Relative risk of factors associated with HCC
cantly associated with liver cancer. The multivariate-adjusted RR was
CasesVariableAnti-HCVNegativePositiveCigarette 37.0 (95% CI = 4.6-295.2) for anti-HCV positivity, 12.0 (95% CI =
risk
(Ç(97.1)(2.9)(42.1)(57.9)(86.4)(13.6)(90.7)(9.3)Relative for past liver disease history, and 7.2 (95% CI = 1.5-33.8)
'5% 2.4-60.3)
interval)1.011.8(2.4-57.7)1.01.6(0.7-3.5)1.02.6(1.0-7.0)1.02.2
confidence
for low vegetable consumption frequency. Alcohol drinking was also
significantly related to HCC, with an adjusted RR of 4.3 (95% CI =
1.1-16.9). Vegetarian habit was associated with liver cancer at a
smokingNoYesAlcohol borderline significance level, with an adjusted RR of 3.7 (95% CI =
0.9-14.6). No significant association was observed between cigarette
smoking and HCC in this study.
drinkingNoYesVegetarian

DISCUSSION
habitNoYesNo.2871124269296(%)(80.0)(20.0)(31.4)(68.6)(74.3)(25.7)(82.9)(17.1)ControlsNo.136459811211912713(%)
The striking male:female ratios in the incidence of HCC in ethni
(0.7-6.7) cally and geographically diverse populations (1, 2) as well as the
greater susceptibility of male animals to spontaneous and chemical-
Vegetable consumption (meals/week)"
induced HCC (8-14, 18) suggest that sex-related factors may be
>6 27 (79.4) 131 (93.6) 1.0
<6 7 (20.6) 9 (6.4) 4.1(1.3-13.4) involved in its development. The male predominance in HCC is
independent of the hereditary diversity of different races and animal
Past liver disease history species, as well as the varying environmental exposures in different
No 29 (82.9) 134 (95.7) 1.0
Yes 6 (17.1) 6 (4.3) 5.0(1.4-18.2) geographical areas and animal experiments. It seems resonable to
" One case without data on vegetable consumption frequency. assume that sex hormone is primarily responsible for the gender
discrepancy. This study shows that elevated serum levels of testoster
Because subclinical HCC might be present at the time of blood one were associated with an increased risk of developing HCC. The
collection and the observed elevation of serum testosterone might be association remained significant after adjusting for the effect of
HBsAg carrier status, anti-HCV positivity, alcohol drinking, cigarette
due to the presence of cancer, the association between serum testos
terone level and HCC was further examined for two distinct follow-up smoking, past liver disease history, and dietary habits. These results
periods by stratifying the cases into two groups: early-onset cases who reveal that the association between testosterone level and HCC was
were diagnosed within 1 year after blood collection (7 cases) and independent of other HCC risk factors. They are also compatible with
late-onset cases who were diagnosed more than 1 year after blood the hypothesis that testosterone has a role in the etiology of human
collection (28 cases). The effect of elevated testosterone on develop HCC.
ing HCC was stronger after the exclusion of the early-onset cases The testosterone levels in this study were determined from serum
diagnosed within 1 year after blood collection. The matched RR samples collected 6 months to 5 years (average, 2.4 years) before the
of developing HCC for a serum testosterone level greater than diagnosis of HCC. To investigate whether subclinical HCC influences
5.69 ng/ml was 2.7 (95% CI = 1.04-6.80). the testosterone-HCC relationship, the association between elevated
Table 3 shows the frequency distribution of other HCC risk factors testosterone and HCC was further examined according to the interval
in liver cancer cases and controls. Liver cancer cases had a signifi between blood collection and the diagnosis of HCC. Inasmuch as the
cantly higher proportion of anti-HCV-positive status (20.0%) than effect of elevated testosterone on the development of HCC was stron-
matched controls (2.9%), with a RR of 11.8 (95% CI = 2.4-57.7).
More liver cancer cases (68.6%) than matched controls (57.9%) were Table 4 Conditional logistic regression analysis of multiple risk factors
associated with HCC"
cigarette smokers, but the difference was not statistically significant.
The percentage of habitual alcohol drinking was higher among liver
relative risk
cancer cases (25.7%) than matched controls ( 13.6%), with a RR of 2.6 VariableTestosterone (95% interval)4.1
confidence
(95% CI = 1.0-7.0) at the borderline significance level (0.05 < P < (1.3-13.2)''
(ng/ml) versus <5.69
0.10). There were more vegetarians who consumed mostly preserved Anti-HCV Positive versus negative 37.0(4.6-295.2)'
4.3(1.1-16.9)*1.2(0.4-3.1)
vegetables and foodstuffs made from beans among liver cancer cases Alcohol drinking Yes versus no
Cigarette smoking Yes versus no
(17.1%) than among matched controls (9.3%), with a RR of 2.2 (95% Vegetarian habit no<6
Yes versus (0.9-14.6)i/7.2(1.5-33.8)*
3.7
CI = 0.7-6.7). Liver cancer cases had a lower percentage of fresh Vegetable consumption
vegetable consumption, defined as fewer than 6 meals/week (20.6%), (meals/week) versus >6
Past liver disease
than matched controls (6.4%), with a significant RR of 4.1 (95% CI historyComparison>5.69 Yes versus noMultivariate-adjusted
12.0(2.4-60.3)*'
= 1.3-13.4). More liver cancer cases had a history of liver diseases " HBsAg carrier status was also included in the regression model to adjust for its
diagnosed by physicians (17.1%) than matched controls (4.3%), with confounding effect.
hP< 0.05.
a RR of 5.0 (95% CI = 1.4-18.2). ''/>< 0.001.
Multiple conditional logistic regression analysis also showed a ^ 0.05 </>< 0.1.
f P<0.0\.
significant association between elevated serum testosterone level and
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 SERUMTESTOSTERONI;
ANDHKPATOCI-U.ULAR
CARCINOMA
ger after the exclusion of the early-onset cases diagnosed within 1 year
after blood collection, it is unlikely that the elevated testosterone
levels in HCC cases were a result of this cancer. However, preclinical
disease may also have an effect on serum testosterone. Previous
studies have shown that most male patients with chronic liver disease
had clinical and biochemical evidence of hypogonadism, and their
serum testosterone levels fell further as the disease progressed (24).
One study also reported that patients of alcoholic cirrhosis combined
with HCC had significantly lower levels of circulating testosterone
than patients affected with alcoholic cirrhosis alone (26). HCC usually
occurs in cirrhotic livers (27). Chronic hepatitis, liver cirrhosis, and
HCC may be successive sequelae of chronic HBV infection (28). In
this study, we cannot exclude the possibility that underlying cirrhosis
has an effect on testosterone levels in the preclinical phase of some
HCC cases and thus leads to an underestimation of the relative risk of
HCC associated with elevated testosterone levels. In other words, the
relative risk estimate in this study was obtained under conservative
circumstances. After HB„Agcarrier status and past liver disease his
tory were adjusted for by the conditional logistic regression analysis,
an increase in RR associated with elevated testosterone levels was
observed.
It has been well established that testosterone plays a prominent role
in mouse hepatocarcinogenesis (8, 10-12, 14, 19), but the importance
of this male hormone in the development of HCC was reported less
frequently in rats (15, 18). In animal models, male castration de
creased the incidence of chemically induced HCC (10, 12, 15, 18. 19),
while chronic administration of testosterone to female or castrated
male animals increased the growth of preneoplastic hepatic foci (11)
or the risk of spontaneous (8) or chemically induced HCC (18). These
results suggest that testosterone may promote the development of
HCC, even at physiological levels. This is consistent with our data
suggesting that men with elevated testosterone levels are at an in
creased risk for HCC. The mechanism of testosterone involvement in
the genesis of HCC remains to be elucidated. However, in the light of
animal studies, this may be related to the ability of testosterone to
promote the growth of preneoplastic hepatic lesions (11, 19). The
marked sex difference in susceptibility to chemically induced hepa
tocarcinogenesis may also be related to the sexual dimorphism in the
metabolism of environmental carcinogens (12, 20, 29-31). The path
way leading to the active metabolite of aflatoxin was reported to be
more active in male animals than in females (29). Recent animal
studies also indicated that male hormone may mediate the activity of
sulfotransferase (30) and the expression of cytochrome p450 genes
(31). However, the role of testosterone in carcinogen metabolism in
humans remains to be explored. A HBV transgenic mouse model also
suggested that sex hormones may play a role in HBV gene expression
(32). HBV-associated chronic hepatitis (6) and liver cirrhosis (7) are
found more frequently and may have a more aggressive behavior in
men than in women (28). It would be worthwhile to determine
whether the effect of testosterone on the development of HCC occurs
through the regulation of HBV gene expression, which causes a higher
incidence of chronic hepatitis and liver cirrhosis in males than in
females.
A significantly higher proportion of serum testosterone levels above
5.69 ng/ml was also observed among HBsAg-positive controls than
HBsAg-negative controls in this study. There was no established
mechanism to explain this phenomenon. The higher testosterone lev
els in HB„Agcarriers than in noncarriers may result from some
unexplored factors which were associated with serum testosterone
levels and distributed differently between the two groups. It might also
be possible that chronic HBV infection itself increases the circulating
793
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Research.
testosterone level. Whether increased testosterone production is also
one of the mechanisms for HBV-relatcd hepatocarcinogenesis remains
to be studied.
Although our study suggests that the positive association between
serum testosterone level and risk of HCC observed in many animal
experiments may apply to human beings, there may be some uncon
trolled factors such as genetic factors, environmental factors not stud
ied here, or circulating hormones other than testosterone which may
also partly result in an association between elevated testosterone and
HCC risk in this study. Because testosterone is converted into estrogen
and other metabolites in peripheral tissues, the circulating level of
testosterone may not completely reflect the level of testosterone func
tioning directly at the target site. It is worthwhile to examine the
interindividual variation in the rate of testosterone conversion into
estrogen and other metabolites and to assess the importance of this
individual discrepancy in the induction of HCC. This is the first report
on the role of serum testosterone level in the development of HCC:
further studies on other populations are needed to validate this finding.
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Elevated Serum Testosterone Levels and Risk of Hepatocellular
Carcinoma
Ming-Whei Yu and Chien-Jen Chen

Cancer Res 1993;53:790-794.

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