serum androgens and sex hormone-binding globulins in ... · on serum concentrations of androgens...

Vol. 4, 735-741, October/November 1995 Cancer Epidemiology, Biomarkers & Prevention 735

2 The abbreviations used are: DHT, dihydrotestosterone; SHBG, sex hormone-

binding globulin: CV, coefficients of variation.

Serum Androgens and Sex Hormone-binding Globulins in Relation toLifestyle Factors in Older African-American, White, and

Asian Men in the United States and Canada

Anna H. Wu,t Alice S. Whittemore,Laurence N. Kolonel, Esther M. John,Richard P. Gallagher, Dee W. West, Jean Hankin,Chong Z. Teh, Darlene M. Dreon, andRalph S. Paffenbarger, Jr.

Department of Preventive Medicine, University of Southern California. Los

Angeles. California 90033 [A. H. WI; Department of Health Research and

Policy. Stanford University School of Medicine, Stanford, California [A. S. W.,

E. M. J.. R. S. P.1; Cancer Research Center of Hawaii, University of Hawaii atManoa, Honolulu, Hawaii [L. N. K., J. H.]: Division of Epidemiology and

Cancer Prevention. British Columbia Cancer Agency. Vancouver, British

Columbia, Canada [R. P. G.. C. Z. T.]; Northern California Cancer Center,

Union City. California [D. W. wI: Children’s Hospital Oakland Research

Institute. Oakland, California [D. M. D.]

Abstract

Differences in endogenous androgen levels have beenhypothesized to explain ethnic differences in prostatecancer risk. To examine this hypothesis, we gathered dataon serum concentrations of androgens and sex hormone-binding globulin (SHBG) in healthy older men from fourethnic groups at different levels of prostate cancer risk.

As part of a population-based case-control study ofprostate cancer we conducted in California, Hawaii, andVancouver, Canada, 1 127 African-American, white,Chinese-American, and Japanese-American control men,mostly ages 60 years or older (mean age, 69.9 years)provided information on various lifestyle factors anddonated an early morning fasting blood sample betweenMarch 1990 and March 1992. We used these data toexamine the distributions of serum androgens[testosterone (total, free, and bioavailable),dihydrotestosterone (DHT)], the ratio of DHT to totaltestosterone (DHT:testosterone ratio), and SHBG in thesefour ethnic groups. We also assessed correlations betweenconcentrations of these measures with age, body size,physical activity, and other personal characteristics, andwe evaluated ethnic differences in concentrations ofandrogens and SHBG after adjusting for thesecharacteristics.

In each of the four ethnic groups, concentrations offree and bioavailable testosterone declined with age,whereas SHBG concentrations increased with age. Age-adjusted concentrations of all androgen measures andSHBG decreased with increasing levels of Quetelet’sindex. After adjustment for age and Quetelet’s index,

androgens and SHBG showed no clear and consistentrelationships to physical activity, alcohol consumption, ortobacco use. DHT:testosterone ratio was higher in menreporting a history of benign prostate disease than inmen without such a history, and higher in vasectomizedmen than in nonvasectomized men. SHBG concentrationswere higher in men reporting one or more first-degreerelatives with prostate cancer than in men without such afamily history. After adjustment for age and Quetelet’sindex, the levels of total and bioavailable testosteronewere highest in Asian-Americans, intermediate inAfrican-Americans, and lowest in whites. However, theDHT:testosterone ratio was highest in African-Americans,intermediate in whites, and lowest in Asian-Americans,corresponding to the respective incidence rates in thesegroups and providing indirect evidence for ethnicdifferences in 5a-reductase enzyme activity.

Introduction

There is strong evidence that endogenous hormones, especiallyandrogens, are involved in the development of prostate cancer.Testosterone and its metabolite, DHT,2 are necessary for thenormal growth and maintenance of the prostate gland (1, 2).However, men with prostate cancer have not consistentlyshown higher serum levels of testosterone, DHT, or other

androgens (3).Previous studies on determinants of androgen levels have

been conducted mainly in white males, and little is knownabout these associations in other ethnic groups with substan-

tially higher or lower incidence of prostate cancer. Moreover,

few studies have examined simultaneously the levels of variousandrogens and SHBG in multiethnic populations. To evaluatewhether ethnic differences in prostate cancer rates may be due

to ethnic differences in endogenous androgen levels, we mea-sured serum androgen and SHBG concentrations in healthyolder African-Americans, whites, and Asian-Americans (Chi-nese and Japanese in the United States and Canada) who are,respectively, at high, intermediate, and low risk of prostatecancer. The serum androgens we measured included testoster-one (total, free, and bioavailable) and DHT. DHT:testosteroneratios were calculated as an indirect measure of activity of

5a-reductase, the enzyme which controls the intracellular con-version of testosterone to DHT and, thus, cell division in the

prostate (1, 4). We examined correlations between concentra-tions of these androgens and SHBG with age, body size, phys-ical activity, and other personal characteristics, and we evalu-

Received 2/21/95: revised 7/7/95: accepted 7/11/95., To whom requests for reprints should be addressed, at University of Southern

California, Department of Preventive Medicine, 1420 San Pablo Street, PMB

B3t)0. LoS Angeles. CA 901)33.

on May 18, 2020. © 1995 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from

http://cebp.aacrjournals.org/

736 Serum Androgens and SHBG in Relation to Lifestyle Factors

ated ethnic differences in androgens and SHBG concentrationsafter adjusting for these characteristics.

Subjects and Methods. African-Americans, whites, Chinese,and Japanese in the United States and Canada (hereafter re-ferred to as Chinese-Americans and Japanese-Americans) whowere interviewed during the period of March 1990 to March

1992 as controls in a multicentered population-based case-control study of prostate cancer were included in this analysis

(5). Participants were selected randomly from the populationsof Hawaii, Los Angeles, CA, San Francisco, CA, and Vancou-ver, British Columbia, Canada. Controls were matched to cases

in an appropriate ratio of 1:1 by ethnicity (African-American,

white, Chinese-American, and Japanese-American), age (5-

year intervals), and region of residence (one of the four geo-

graphical areas). Participants in Hawaii were selected from alist of randomly selected Oahu, HI, residents interviewed by the

Health Surveillance Program of the Hawaii Department ofHealth. Participants in Los Angeles and San Francisco wereselected by random digit dialing; those ages 65 years and older

also were selected from computerized lists of the Health Care

Financing Administration. Participants in Vancouver were se-

lected randomly from rosters of the British Columbia MedicalServices Plan (covering virtually the entire population of theprovince; Ref. 5).

Eligible interviewed controls (i.e., excluding those with

blood clotting disorders or on anticoagulant medication) wereasked to donate 40 ml of venous blood for determination of

levels of androgens, SHBG, cholesterol, and prostate specific

antigen. Results presented here pertain to analyses of the an-drogen and SHBG data. Participants were asked to fast for 12h before the blood specimen collection. To the extent possible,

specimens were collected early in the morning, usually before10:00 AM. After the specimens were collected, they werereturned to the laboratory on ice and processed within 2 h of theblood draw. After processing, the specimens were stored at-70#{176}Cuntil shipment in dry ice to a commercial laboratory

(Endocrine Sciences, Calabasas Hills, CA) for analysis. FromApril 1991 to October 1992, blood specimens from each of the

study centers were sent to Endocrine Sciences at approximately

3-month intervals for hormone analysis. In each shipment of

specimens, about 10% blind duplicate samples were sent. An-drogen and SHBG levels of duplicate samples were typicallywithin 5% of the values of each other. Specimens from men of

different ages and ethnicities were analyzed simultaneously toavoid potential confounding of these variables with time ofanalysis.

We measured SHBG and the following androgens: totaltestosterone, and bioavailable testosterone (i.e. , unbound to

SHBG), percentage of free testosterone (i.e. , unbound to eitherSHBG or albumin), and DHT. Total testosterone was measuredby alumina column chromatography (6), and RIA was used to

quantify the testosterone in each sample. Binding capacity of

SHBG was determined by saturation kinetics (7). Quadruplicatealiquots of serum were incubated with known amounts oftritiated testosterone. After incubation, SHBG-bound and non-

SHBG-bound testosterone were separated by ammonium sul-

fate precipitation, and binding capacity was calculated from theamount of tritiated label displaced from the SHBG. DHT wasfirst extracted from the sample, and then the extract was oxi-dized, and the amount of DHT was measured by RIA. Percent-

age of free (nonprotein-bound) testosterone was determined byequilibrium dialysis (8). The actual free testosterone concen-tration was derived from the product of serum testosteronedetermined and the percentage of free testosterone. Bioavail-

able testosterone was determined by incubating the serum with

purified tritiated testosterone and separating the SHBG-boundand non-SHBG-bound testosterone by ammonium sulfate pre-cipitation. The percentage of labeled testosterone that is non-

SHBG bound represents the percentage of the total testosteronethat is either free or weakly bound to albumin. The bioavailabletestosterone was estimated as the product of this percentage andthe total testosterone. The interassay CV, determined in pooledserum samples for testosterone, SHBG, and bioavailable tes-tosterone was 7.5, 1 1.7, and 1 1.4%, respectively. The interassay

CVs for free testosterone were 12.2 and 11.4% for medium andhigh pools, respectively. The interassay CVs for DHT were18.4, 12.0, and 9.6% for low, medium, and high pools, respec-

tively.Participants’ ages at the time of specimen collection were

used in all analyses. Information on weight, height, and phys-ical activity, history of benign prostate disease and vasectomy,family history of prostate cancer, and dietary history werecollected at interview (results on diet and serum hormones will

be reported in a subsequent manuscript). Self-reported weight,height, and physical activity reported for reference year (de-

fined as 1 year before interview) were used in the presentanalysis. Current smoking habits and alcohol consumption pat-tern during the year before blood draw was obtained at the timeof specimen collection, which typically occurred within several

months of the initial interview. The methods used to estimatephysical activity levels have been described elsewhere (5). Inbrief, total energy expenditure was calculated based on thenumber of hours spent in sleeping, sitting, light activity, andvigorous activity, weighted by the respective metabolic equiv-alent score for each of these activities and the subject’s body

weight.We used ANOVA and analysis of covariance to assess

relationships between androgen and SHBG levels and life-style factors. The measurements were expressed as loga-rithms to achieve approximate normal distributions. Analy-sis of covariance assumed a linear relationship between the

covariate(s) and log-hormone values (9). We also examined

the mean levels of androgens and SHBG by ethnic group.Results for all subjects combined were adjusted for age (insingle years), ethnic group (African-American, white, Chi-

nese-, and Japanese-Americans), and when appropriate,

Quetelet’ index (weight in kg divided by the square of height

in meters) (as a continuous variable).

Results

Among 2844 eligible control subjects, 1645 (58%) were inter-viewed. Response rates for the interview component of thestudy varied by ethnicity; they were highest in Japanese-Amer-icans (71%), followed by Chinese-Americans (70%), whites(63%), and African-Americans (45%) (5). The response ratewas higher (about 80%) when names of potential subjects were

selected from lists of residents (in Hawaii) or lists of medicalservice plan members (in Vancouver), whereas the responserate was lower (about 50%) when subjects were selected byrandom digit dialing or from Health Care Financing Adminis-tration lists (in the Los Angeles County and San Francisco Bayarea). Among the interviewed controls, 168 subjects had bloodclotting disorders or were taking anticoagulant medications;thus, they were not eligible for the blood draw. Blood sampleswere provided by 1 127 (76%) men among those eligible for theblood draw: 315 African-Americans, 41 1 whites, and 401Asian-Americans (126 Chinese-Americans and 275 Japanese-

Americans). The participation rate for blood donation was



Cancer Epidemiology, Blomarkers & Prevention 737

Table I R egres sion coefficients an d SE-relating androg ens and SHBG leve Is to selected variab les, by ethnicity

.

Ethnic group AgeQuetelet’s

. bindex

Physical. .

activity

Smoking. �

(cigarette/week)

Alcohol.

(drink/week)

Testosterone (ngldl) X 10)) A

W

C

J

All

0.21 (0.30)

-0.32 (1)26)

-0.37 (0.44)

-0.()4 (0.40)

-0.11 (0.16)

-3.72 (0.50)”

-3.02 (0.51)”

-4.08 (0.88)”

-4.74 (0.84)”

-3.63 (031)d

0.42 (0.29)

0.60 (0.36)

0.50 (0.68)

0.19 (0.63)

0.37 (0.20)

0.02 (0.1)3)

0.04 (0.03)

0.07 (0.12)

0.09 (0.06)

0.04 (0.02)�

-0.12 (0.26)

-0.08 (0.15)

0.44 (t).45)

-0.19 (0.23)

-0.1 1 (0.11)

Bioavailahle testosterone (ng/dl) X it) A

W

C

J

All

-0.16 (0.03)”

-0.18 (0.03)”

-0.21 (004)d

-0.18 (0,04)d

-0.18 (0.02)”

-0.21 (0.05)”

-0.18 (0.05)”

0.04 (0.09)

� (0.08)

-0.17 (0.03)”

1)03 (0.03)

0.01 (0.t)4)

0.07 (0.07)

0.01 (0.06)

0.01 (0.02)

-0.002 (0.004)

0.002 (t).()03)

-0.002 (0.1)1)

0.003 (0.006)

0.001 (0(8)2)

t).t)3 (0.03)

0.t)I (0.02)

-0.002 (0.05)

-t).t)5 (0.02)

-t).0l (0.01)

Free testosterone (pg/mI) X 10 A

wC

J

All

-0.07 (0.03y

-0.13 (003)d

-1)09 (0.05)�

-0.08 (0.04)”

-1)10 (0.02)”

-0.30 (006)d

-0.17 (0.05)”

-0.36 (0.09y’

-0.21 (0.08)�

-0.24 (0.03)”

0.03 (0.03)

0(14 (0.04)

0.09 (0.07)

-0(14 (0.()6)�

0.02 (1)02)

0.000 (0.003)

0.1)00 (0(104)

0.012 (0.013)

0.008 (0(8)6)

t).002 (0.18)2)

0.02 (0.03)

0.18)3 (0.02)

0.t)4 (0.05)

-1)1)3 (0.02)�

-0.005 (0.t)l)

SHBG (�zgJdl) X 100 A

wC

J

All

0.22 (0.03)”

0.ls (0.03)”

0.18 (005)d

1)19 (0.04)”

0.20 (0.02)”

-0.26 (0.06)”

-0.26 (0.06)”

-0.52 (0.1 1)d

-0.59 (007)d

-0.33 (003)d

0.02 (0.03)

0.03 (0.04)

0.03 (t).08)

0.01 (t).05)

0.02 (0.02)

0.003 (0.0(W)

0.006 (0(1(14)

0.012 (0.015)

0.003 (0.005)

0.005 (0.0()2)�

-t).t)4 (1)03)

-t).tX)5 (0.t)2)

0(19 (t).06)

0.03 (0.02)

0.1)02 (0.02)

DHT (ngjdl) X lOt) A

W

C

J

All

0.57 (0.33)

-0.27(0.28)

0.23 (0.51)

0.91 (0.43)�

0.27 (0.18)

-3.93 (056)d

-3.15 (0,57)J

-3.38 (1.08)�

-5.58 (0.90)”

0.54 (0.32)

0.27(0.39)

0.47 (t).83)

0.15 (0.67)

0.38 (0.22)

0.03 (t).04)

0.02 (0.t)4)

-0.04 (0.14)

0.06 (0.06)

0.03 (0.02)

-0.17 (0.29)

-0.29 (0.17)

0.17 (1)54)

-0.22 (1)25)

-0.23 (0.12)

DHT/testosterone X 1(X) A

W

C

J

All

0.07 (0.04)’

-0.02 (0.03)

1)1)6 (0.06)

0.14 (0.04)”

0.t)5 (0.02)”

-0.31 (006)”

-0.23 (0,06)”

-0.16 (0.13)

-0.45 (0.10)”

-0.28 (0.04)”

0.t)5 (0.04)

-0.02 (0.04)’

0.()4 (0.10)’

-0.01 (0.07)

0.02 (0.t)2)

1)004 (0.01)4)

-0.001 (0.tX)4)

-0.013 (0.017)

0.000 (0.18)7)

0.001 (0.18)3)

-1)1)2 (t).03)

-0(14 (0.02)’

-t).Ol (t).06)�

-t).02 (0.t)3)

-0.03 (0.01)

“ A. African-American; W, white: C, Chinese-American; J, Japanese-American; All, combined group with adjustment for ethnicity. Because of missing information on one

or more lifestyle factors in the analysis. the number ofcontrol men in each analysis varied. The sample size ranged from 1115 to 1127 men for analyses, including all ethnic

groups combined. In the ethnic-specific analyses. the range in sample was 311-315 African-Americans, 405-411 whites, 125-126 Chinese-Americans, and 274-275

Japanese-Americans.

,, Adjusted for age at blood draw.( Adjusted for age at blood draw and Quetelet’s index. Self-reported weight, height, and physical activity during reference year (i.e.. 1 year before interview). Smoking

and alcohol use pertained to habits during year before blood draw.

“P < t).t)Ol.‘. P < t).t)5.

higher among Japanese-Americans (86%) and whites (89%)

and lower among African-Americans (68%) and Chinese-Americans (54%).

The mean age for control men who donated blood sampleswas 69.6 versus 70.9 years for those who did not donate bloodsamples (range in ages was 35.0-89.0 years). Among men whodonated blood samples, 8.2% were ages 60 years or younger,

45.6% were between ages 60 and 70 years, and 46.1% wereages 71 years or older. Compared to men who did not provideblood specimens, those who did were significantly more likelyto have had at least a high school education (73% of those withblood samples versus 60% of those without samples), to havebeen more physically active (52 versus 46%), and to have hada history of vasectomy (12 versus 5%). However, Quetelet’sindex, family history of prostate cancer, and history of benignprostate conditions did not differ significantly between menwho donated blood specimens and those who did not. Educa-tion was not associated with androgen or SHBG levels and,thus, was not considered in the regression analysis presentedbelow.

Age. Results from the linear regression analysis are shown in

Table 1. Levels of bioavailable and free testosterone de-

creased significantly with age in all four ethnic groups.

Although levels of total testosterone also decreased with agein all groups except African-Americans, the associations

were not statistically significant. On the other hand, levels of

SHBG were positively associated with age in each of the

four ethnic groups (P < 0.001 in each group). DHT:testos-terone ratios increased with age (except among whites); the

association was statistically significant for all ethnic groups

combined (P < 0.001).

Quetelet’s Index. Table 1 shows statistically significant in-verse relationships between Quetelet’s index and virtually all

androgen measures (total, free and bioavailable testosterone,

DHT, and DHT:testosterone ratio), as well as SHBG, for eachof the four ethnic groups. Similar observations were obtainedwhen we investigated relationships between androgen and

SHBG levels and weight (data not shown).

Physical Activity, Smoking, and Alcohol Consumption.After adjustment for age and Quetelet’s index, there were no

clear or consistent relationships between physical activity,

alcohol consumption, and levels of androgens and SHBG.

Current cigarette smokers generally showed higher levels of



738 Serum Androgens andSHB6 in Relation to Lifestyle Factors

Table 2 Median serum concentration of androgens and SHBG” by history of benign prostate conditions,5 vasectomy,’ and family history of prostate cancer,” by

ethnicity

. -ntc

group’

Benign prostate. .

condition

Yes No

Vasectomy

Yes No

Family

prostat

history of

e cancer

Yes No

No. of subjects 304 789 136 977 66 1010

Testosterone (ng/dl) X 1(8) A 465.4 476.7 467.9 470.9 555.0 468.9

wC

J

All

437.6 450.2

484.4 474.2

465.1 481.5

457.1 467.8

433.8

398.9

365.2

422.7

450.4

483.8

4853/

468.5�

455.2

512.3

523.3

505.8

448.2

476.7

475.2

463.8

SHBG (�.sgJdl) X 11)0 A

wC

J

All

112.4 110.7

99.2 111.0’

109.2 99.5

ll3.t) 114.4

107.3 110.5

103.1)

100.0

94.5

105.3

101.5

112.7

108.6

101.9

114.7

110.6’

125.9

116.5

106.2

140.1

123.9

111.5

106.1

101.8

ll2.V

108W

DHT (ngjdl) X 11K) A 46.2 45.8 50.7 45.4 54.2 45.6

wC

J

All

43.6 42.0

47.7 40.7

44.5 43.6

45.0 43.3

43.3

44.9

39.2

44.5

42.5

41.7

44.0

43.6

43.6

49.3

47.0

48.0

42.7

41.7

43.5

43.6

DHT/testosterone X 1(10 A

wC

J

All

99.6 96.1

99.6 93,31

98.2 85.2�

95.7 90.6

98.5 92.5/

109.1

99.9

108.3

107.3

105.2

96.5�

94.4

86.1�

90.6�

93.l�

98.1

95.9

96.0

89.8

94.9

97.4

95.3

86.9

91.5

94.0

,‘ Androgens and SIJUG levels adjusted for age and Quetelet’s index. Median concentrations presented for a hypothetical man aged 70 years with a Quetelet’s index of

25.,‘ Includes self-reported history of benign prosiaiic hyperplasia (BPH), transurethral resection (TUR), and prostatitis (PS). TUR alone (n - 18), TUR and BHPIPS (a =

88), BPH alone (a = 1 1 1), BPH and PS (a 38). PS alone (a 49). The number of African-American, white, Chinese- and Japanese-American control men with a positive

history was any benign prostate conditions was 77, 151, 21, and 55, respectively., The number of African-American, white, Chinese- and Japanese-American control men with a positive history of vasectomy was 20, 92, 9, and 15, respectively.

“ Includes self-reported history of prostate cancer among fathers, brothers, and sons. The number of African-American, white, Chinese- and Japanese-American control

men with a positive family history was 17, 31, 4, and 14, respectively.

.. A. African-American; W, white: C, Chinese-American; J, Japanese-American; All, combined group with adjustment for ethnicity.

, P value < 1)05, for difference between subjects with positive and negative history.

total, bioavailable, and free testosterone, DHT, SHBG, andhigher DHT:testosterone ratios than did nonsmokers. Thiseffect of smoking on total testosterone and SHBG levels wasstatistically significant for all ethnic groups combined (P <

0.05; Table 1).

Personal and Family History of Prostate Conditions. Table2 shows relationships between androgens and SHBG and his-

tory of benign prostate condition, vasectomy, and family his-tory of prostate cancer (in fathers, brothers, and sons). Sum-

mary medians of androgen and SHBG levels for men with andwithout the specific histories are presented. There were no

consistent differences in levels of testosterone (total, free, andbioavailable), and SHBG between men with a history of abenign prostatic condition (based on self-reports of benign

prostatic hyperplasia, transurethral resection and benign pros-

tatitis) and those without such a condition (data on free andbioavailable testosterone not shown). However, DHT and

DHT:testosterone ratios were higher in men with a positivehistory of benign prostate disease compared to men with noreported history (P < 0.05; for DHT:testosterone ratios). Lev-

els of total testosterone and SHBG were lower, whereas DHT:testosterone ratios were higher in men with a prior vasectomycompared to men without this surgical procedure; these asso-ciations were statistically significant for all ethnic groups com-

bined (P < 0.05; Table 2). Levels of total testosterone, DHT,and SHBG were somewhat higher in men with a history of

prostate cancer among first-degree relatives than in men with-

out a known family history; however, only the elevation in

SHBG level was statistically significant for all men combined(P < 0.05; Table 2).

Ethnic Comparisons. Table 3 shows the mean levels of an-drogens (total, bioavailable, and free testosterone and DHT),SHBG, and DHT:testosterone ratios in African-Americans,whites, Japanese-, and Chinese-Americans and the correspond-ing age-adjusted prostate incidence rates in 1983-1987 (10).

After adjustment for age, Quetelet’s index, and physical activ-ity, African-American men showed higher levels of total, bio-available, and free testosterone than did white men, althoughthe differences were not statistically significant. However, totaltestosterone levels were also significantly higher in Japanese-Americans (P < 0.01) and Chinese-Americans (P < 0.05)

compared to whites (Table 3). Compared to whites, both Afri-can-Americans and Japanese-Americans showed higher levelsof SHBG and DHT; the differences in DHT levels were statis-

tically significant (P < 0.05). Although there were no largedifferences in the absolute value of the DHT:testosterone ratiobetween ethnic groups, the DHT:testosterone ratio was highestin African-Americans, intermediate in whites, and lowest inJapanese- and Chinese-Americans, corresponding to the pros-tate cancer incidence patterns in these groups. The DHT:tes-tosterone ratio in Chinese-Americans was significantly lowerthan those ratios for whites and African-Americans (P < 0.01),but the ratios in African-Americans and whites were not sig-

nificantly different.



Table 4 Mean” concentrations and SE of androgens and SHBG among

Cancer Epidemiology, Biomarkers & Prevention 739

Table 3 Mean concentrations” with SE of androgens and SHBG and corresponding prostate cancer rates by ethnicity

. .African-Americans

.Whites Japanese

.Chinese

No.of.

subjects

“sndrogens and SHBG levels

Total testosterone (ng/dl) 495.3 (10.5) 470.9 (9.0) 520.5 (1 1.3)” 512.2 (16.7)’ 1113

Bioavailable testosterone (nd/dl) 158.6 (3.6) 153.5 (3.1) 161.3 (3.9) 171.0 (5.7)” 1 tt)9

Free testosterone (pg/mI) 101.3 (2.4) 97.4 (2.1) 103.9 (2.6) 109.1 (3.8)” 1102

SHBG Qig/dI) 1.23 (0.03) 1.16 (0.03) 1.25 (0.03)’ 1.12 (0.05) 11(12

DUT (ng/dI) 49.0 (1.2)’ 45.8 (1.0) 49.1 (1.3)’ 45.4 (1.9) 1111

DHT/testosterone 0.101 (0.002) 0.099 (0.001) 0.095 (0.002) 0.089 (0.003)” 1111

Incidence rates of prostate cancer/100,000” 121 83 40 33

“ Adjusted for age at blood draw, Quetelet’s index, and physical activity. In the analysis including 1 102 men, there were 306 African-Americans, 402 white, 273

Japanese-American. and 121 Chinese-American control men.

I, Compared to whites, P < 0.01.‘. Compared to whites, P < 0.05.

“ Age-adjusted prostate incidence rates (per 1(X),(X)0) for 1983-1987, adjusted to the world population standard. Based on data from the population-based tumor registriesof the United States study centers. Rates for African-Americans included rates from San Francisco Bay area and Los Angeles County, whereas rates in whites, Japanese-

and Chinese-Americans also included rates from Hawaii (10).

Asian-Americans by birthplace

Birthplace

Born in the United States or Canada

n=327

Foreign born

n68

Total testosterone

(ng/dl)

531.0(9.9) 539.9 (21.9)

Bioavailable

testosterone (nd/dl)

164.0 (2.9) 168.2 (6.5)

Free testosterone

(pg/mI)

105.4 (2.1) 1 1 1.9 (4.6)

SHBG (j.eg/dl) 1.28 (0.03) 1.25 (0.06)

DHT (ng/dl) 49.6 (1 . I) 49.5 (2.5)

DHT/testosterone 0.095 (0(101) 0.092 (0.003)

“ Adjusted for age at bI ood draw, Quetelet’s index, and physica I activity.

About one-half of the Chinese-American subjects (61 of

126) and a few of the Japanese-Americans (7 of 273) weremigrants to the United States or Canada. The migrants had livedin the United States or Canada an average of 24.1 years. After

adjustment for age, Quetelet’s index, and physical activity,

levels of testosterone (total, free, and bioavailable) were higher

for Asians born in Asia versus for those Asians born in North

America, whereas levels of SHBG and DHT were similar inboth groups (Table 4). On the other hand, the DHT:testosteroneratio was lower in Asians born in Asia compared to those born

in North America. However, none of the differences between

Asians born in North America and those born in Asia werestatistically significant.

To ensure that the relationships between concentrations of

androgens and SHBG and factors such as age, Quetelet’s index,physical activity, smoking, and alcohol (Table 1) were not

affected by the inclusion of men with history of benign prostate

conditions (i.e., 304 men, Table 2), we repeated the analyses in

Table 1 after exclusion of these subjects. The results remained

unchanged. Similarly, we repeated the analyses in Table 3 after

exclusion of this group of men, and the results on ethnic

differences were unchanged.

Discussion

Androgens are thought to play a role in the development of

prostate cancer although the precise mechanisms by which theyact have remained elusive. Our objectives were to identifylifestyle factors that may influence these hormone levels and to

determine if any of the interethnic differences in levels ofandrogens and SHBG might help explain the high, intermedi-ate, and low incidence rates of prostate cancer in African-

Americans, whites, and Asian-Americans.

Levels of free and bioavailable testosterone decreasedwith age, whereas SHBG concentrations increased with age.

These trends are consistent with results from a meta-analysis of

more than 40 studies (1 1) as well as a cross-sectional study of

-1700 men selected from the general population in Massachu-

setts (12). Our finding of a less consistent decline in totaltestosterone compared to significant decreases in free and bio-

available testosterone levels with age is comparable to resultsreported by other investigators (12, 13). In this study, both

levels of DHT and DHT:testosterone ratios tended to increasewith age. Results from previous studies are inconsistent; in-

creases (14, 15), decreases (16), and invariant (12, 17, 18)serum levels of DHT with increasing age have been reported.Decreasing levels of DHT metabolites have been reported in

some (12, 14, 15, 19) but not in other studies (20, 21). Therelationship between levels of testosterone and DHT and the

conversion of DHT to its metabolites as a function of age are

complex and have yet to be elucidated.

In this study of diverse ethnic groups, covering a consid-

erable range in Quetelet’s index, significant inverse relation-ships were found between Quetelet’s index and levels of tes-

tosterone (total, bioavailable, and free), SHBG, DHT, andDHT:testosterone ratio. These results agree with previous re-

ports of decreasing levels of testosterone (22-25) and SHBG(13, 22, 24) with increasing Quetelet’s index and suggest sim-ilar relationships with serum levels of DHT and DHT:testos-

terone ratio. The decrease in SHBG levels with increasing

Quetelet’s index has been proposed to explain the correspond-ing decrease in total testosterone and DHT levels, although the

mechanism for lower SHBG levels is not known (13).

Strenuous physical activity may result in lower levels of

testosterone (26-28). Smoking may inhibit production of es-

trogens in women (29) but data on its effect in men are not



740 Serum Androgens and SHBG in Relation to Lifestyle Factors

3. Nomura, A. M. Y., and Kolonel. L. N. Prostate cancer: a current perspective.

Epidemiol. Rev.. 13: 20t)-227. 1991.

consistent (30, 31). In a study of Caucasian upper middle classmen in a California retirement community, smokers showed

significantly higher serum estrogen levels than did nonsmokers(30). However, in the Multiple Risk Factor Intervention Trial,serum estrogen levels in men were not associated with total

amount of cigarettes smoked (31). Levels of testosterone were

higher among men who smoked compared with men who didnot in both studies (30, 31). Heavy alcohol use may increaseestrone production and, thus, increase conversion of androgensto estrogens (32, 33). The present findings suggest higher totaltestosterone levels in smokers compared to nonsmokers, but

there were few consistent associations between physical activ-ity, alcohol use, and androgen levels.

In this study, men with a self-reported history of a benign

prostate condition showed a significantly higher DHT:testos-(crone ratio, a marker of 5a-reductase activity (34), comparedto men without such history. This observation is compatiblewith the hypothesis that the development of benign prostate

hyperplasia may be related to a failure of testosterone to de-crease with age and, thus, to continue to stimulate the prostate(35). Levels of total testosterone and SHBG were lower andDHT:testosterone ratios were higher among men with vasec-tomy compared to those without such prior operation. Most

previous studies do not show significant changes in hormonalprofile after a vasectomy (36). Levels of SHBG were higher

among men with a positive family history of prostate cancercompared to those with no family history. Genetic influenceson the production and metabolism of SHBG and various an-drogens have been reported in studies of twins (37, 38).

The present study of older men, most of whom were 60years or older, found lower testosterone levels in whites com-

pared to African-Americans, similar to studies conducted inyoung college men (39, 40) and Vietnam veterans ages 31-50

years (41). However, there is little evidence from this and otherstudies that testosterone levels in Asians residing in Asia (40,42) or in North America (41) are lower than those in whites. Onthe other hand, the strongest support for ethnic differences inandrogen levels in this study was based on the DHT:testoster-one ratio, which was highest in African-Americans, intermedi-ate in whites, and lowest in Asian-Americans, reflecting theprostate cancer incidence rates in these groups. Among Asian-Americans, the ratio was higher in Asians born in North-America compared to those born in Asia. The DHT:testosteroneratio is an indirect measure of tissue metabolism of testosteroneto DHT, with a higher ratio indicating greater Scs-reductaseactivity in the prostate (43, 44). More direct measures of Sex-reductase activity (i.e., serum levels of 3-a,17�-androstanediol

glucuronide and androsterone glucuronide) are needed to con-firm the ethnic variations in enzymatic activity suggested in thisstudy and to identify environmental influences on Scx-reductaseactivity.

Acknowledgments

We thank Peggy Wan, Yasamin DiCiccio. Anna Felherg. Annie Fung, Toni

Robinson. and Lynne Wilkens for technical help.

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1995;4:735-741. Cancer Epidemiol Biomarkers Prev A H Wu, A S Whittemore, L N Kolonel, et al. Asian men in the United States and Canada.

andrelation to lifestyle factors in older African-American, white, Serum androgens and sex hormone-binding globulins in

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