This is the first cross-sectional study of racial and ethnic variation in circulating sex steroid hormone and SHBG concentrations in a representative sample of adult U.S.men. There was no significant difference in circulating concentrations of testosterone or free testosterone concentrations between non-Hispanic black and white men overall, but Mexican-American men had higher levels than non-Hispanic white men. However, non-Hispanic black men had the highest estradiol level overall and across all ages, which was not explained by racial differences in the prevalence of factors that influence hormone levels.
We cannot confirm observations of a difference in circulating testosterone concentration between African-American and Caucasian men as reported previously in some studies (6, 9, 17, 18), including in young men (6, 9, 17). Differences between our results and the results of previous studies comparing circulating total testosterone concentrations between racial groups might be due to differences in age variation or in sample size or due to lack of representation of the general population. In our analysis, serum testosterone concentration was similar in young non-Hispanic white and non-Hispanic black men, which has also been reported in three U.S. cross-sectional studies (19–21). In a U.S. longitudinal study, testosterone concentration was higher in young black than white men after adjustment for age and BMI (22). However, after further adjustment for waist circumference, there was no difference between non-Hispanic white and non-Hispanic black men. In our study, non-Hispanic black and non-Hispanic white men did not differ notably on their extent of adiposity. Thus, the results did not change after we adjusted for waist circumference in addition to BMI (data not shown) or after we adjusted for percent body fat instead in the regression models. A recent review concluded that high circulating testosterone concentrations are associated with a lower risk of type 2 diabetes in men (23). Although several cross-sectional studies reported that men with low testosterone levels have an increased risk of coronary artery disease, this association is not clearly seen in prospective studies (24). Testosterone is important for prostate development and function and is a target for treatment of metastatic prostate cancer, yet results from epidemiological studies that examined the association between total and bioavailable testosterone and prostate cancer have been inconclusive (25–27). Our study provides little evidence for the hypothesis that racial variation in testosterone and free testosterone accounts, in part, for the higher risk of prostate cancer in African-American men, at least as measured by circulating levels.
AAG concentration is commonly used in epidemiological studies as an indirect measure of 5α-reductase activity and, thus, the conversion of testosterone to dihydrotestosterone. Serum AAG concentration was significantly higher in non-Hispanic whites than in men of the other two racial/ethnic groups. This was observed overall and in the different age groups. Higher AAG in white compared with black men has been seen in other studies in middle-aged (8, 28) and in elderly (29) but not in young adult men (30). A lower AAG concentration in non-Hispanic black than white men is not compatible with the hypothesis that a greater 5α-reductase activity could be associated with the increased risk of prostate cancer in African-American men based on a meta-analysis that reported an increased risk of prostate cancer with higher circulating AAG concentration (31). Lower AAG might result in men who have a lower conversion of dihydrotestosterone to 3α-androstanediol or, alternatively, a higher reconversion of 3α-androstanediol to dihydrotestosterone (32). However, not much is yet known about racial variation in the activity of the enzymes that catalyze these conversions. Second, lower AAG could result in men with a greater efficiency of conversion of testosterone to estradiol via higher aromatase activity. Polymorphisms in the CYP19 gene, which encodes aromatase, have been reported. However, plasma concentration of total testosterone, AAG, and SHBG did not differ by genotype in a Caucasian population (33). Racial variation in CYP19 alleles has been observed in women (34), but to our knowledge, no study has been published with respect to differences in hormone concentrations in men for most of these CYP19 polymorphisms.
We observed higher serum estradiol concentrations and higher estradiol/SHBG ratios in non-Hispanic black than in non-Hispanic white or Mexican-American men, a difference that was pronounced in young and mid-adulthood. Previous studies aside from one small study of young men (35) did not report differences in circulating estradiol concentrations between African-Americans and Caucasians in young (6, 17, 20), middle-aged (28), or older men (18). It has been hypothesized that higher estradiol concentrations in African-American men might contribute to higher bone mass and, thus, lower fracture risk (7) because estradiol inhibits bone resorption (36). The role of estrogens in the development and progression of prostate cancer, which is more common among African-American than Caucasian or Hispanic men (4), is not clear. In the Physicians’ Health Study, an inverse association between circulating estradiol concentration and prostate cancer was observed after taking testosterone and SHBG concentrations into account statistically (37), whereas other studies did not report statistically significant positive or inverse associations (25).
SHBG transports sex steroid hormones in the circulation and, along with albumin, is a determinant of bioavailable testosterone and estradiol. It mediates steroid hormone signal transduction at the plasma membrane, which allows steroid hormones to act without entering the cell by interacting with SHBG membrane receptors (38). SHBG concentration was lower in Mexican-American than non-Hispanic white and non-Hispanic black men in the age-adjusted model; however, the differences were attenuated after taking into account all covariates, particularly percent body fat. The attenuation of the racial/ethnic differences in the multivariable model is explained by SHBG concentration being inversely associated with body fat (16) and the higher percentage of body fat in Mexican-Americans compared with either of the other two racial/ethnic groups. SHBG concentrations were similar in non-Hispanic blacks and non-Hispanic whites. Similar to our results, two cross-sectional studies did not observe significant differences in circulating SHBG concentration between young adult black and white men (17, 19), whereas a third study reported a higher SHBG concentration in young African-American than Caucasian men (6).
To date, Hispanic males infrequently have been examined concerning their sex steroid hormone profile. In a cross-sectional study that included 200 Hispanic men aged 31–44 yr old, Hispanics had a testosterone concentration that was similar to the concentration in non-Hispanic white but lower than in black men (9). Similarly, no differences in total testosterone concentration were observed in the Boston Area Community Health Survey, which included 648 Hispanics, aged 30–79 yr (21). In the Hawaii-Los Angeles Multiethnic Cohort (8), which included 523 U.S. Latinos, aged 47–74 yr, U.S. Latinos had a slight but not significantly lower circulating testosterone concentration than U.S. whites after adjusting for age. AAG concentration was higher than the concentration in African-American men and lower than in U.S. whites, but neither difference was statistically significant (8). In NHANES III, we studied Mexican-American men, which is the largest Hispanic group in the United States. Whether our results for Mexican-American men may be compared with the results in other Hispanic populations may depend on the composition of those Hispanic populations by country of origin.
Several aspects of our study merit further discussion. First, sex steroid hormone and SHBG concentrations in humans are influenced by a number of factors. Our goal was to determine whether there was racial variation in hormones beyond the variation due to differences in prevalence of modifiable factors that influence hormone concentrations. Therefore, we adjusted the regression models for factors that correlate with hormones and that differ by race, i.e. percent body fat, cigarette smoking, alcohol consumption, and physical activity. However, it should be noted that these modifiable predictors of hormone concentrations are also risk factors for chronic diseases and that hormones may mediate their influence on disease risk. Thus, assessment of crude (or age-adjusted) differences in hormone concentrations is key to understanding the contributions of hormones to the racial/ethnic variation in the burden of disease. Second, serum testosterone concentration exhibits diurnal variation. In one study, mean testosterone concentrations were 25–30% lower at 2000 h than at 0800 h, which was similar in African-American and Caucasian men (6). Therefore, we selected only men who participated in the morning session of the first phase of NHANES III (0830–1130 h). Additionally adjusting for time when blood was drawn did not appreciably change the results. Third, due to the number of comparisons we evaluated, we cannot exclude chance as an alternative explanation for any given finding. Fourth, NHANES III is a cross-sectional study representative of the civilian non-institutionalized U.S. population, thus aiding in the broad generalizability of these results. Main characteristics, such as age, percent body fat, smoking, alcohol consumption, or physical activity, of the subset of men used in this analysis were comparable to all men 20 yr and older who participated in the morning session of the first phase of NHANES III (data not shown). Also, the over-sampling of minorities and elderly and the large sample size allowed for reasonably stable estimates even after adjusting for possibly confounding variables. Fifth, the analyses were based on a single hormone measurement and may not perfectly reflect serum hormone levels averaged over time (39), although some studies have shown that using only one sample was highly accurate in predicting sex steroid hormone levels for a time frame up to 3 yr (26, 40). Sixth, NHANES III is a cross-sectional study, and thus, we could not assess differences in the hormones trajectories over age by race/ethnicity.
In conclusion, in this large, nationally representative sample, there was no difference in circulating testosterone concentrations between non-Hispanic black and white men overall. However, black men had the highest estradiol level overall across all ages, which was not explained by racial differences in the prevalence of factors that influence hormone levels. Mexican-American men had hormonal profiles similar to non-Hispanic white men, with the exception of higher testosterone. Given these findings, it may be equally if not more important to investigate levels of estradiol than testosterone in relation to diseases that show racial disparity, such as prostate cancer
原地址
https://academic.oup.com/jcem/article/92/7/2519/2598282
We cannot confirm observations of a difference in circulating testosterone concentration between African-American and Caucasian men as reported previously in some studies (6, 9, 17, 18), including in young men (6, 9, 17). Differences between our results and the results of previous studies comparing circulating total testosterone concentrations between racial groups might be due to differences in age variation or in sample size or due to lack of representation of the general population. In our analysis, serum testosterone concentration was similar in young non-Hispanic white and non-Hispanic black men, which has also been reported in three U.S. cross-sectional studies (19–21). In a U.S. longitudinal study, testosterone concentration was higher in young black than white men after adjustment for age and BMI (22). However, after further adjustment for waist circumference, there was no difference between non-Hispanic white and non-Hispanic black men. In our study, non-Hispanic black and non-Hispanic white men did not differ notably on their extent of adiposity. Thus, the results did not change after we adjusted for waist circumference in addition to BMI (data not shown) or after we adjusted for percent body fat instead in the regression models. A recent review concluded that high circulating testosterone concentrations are associated with a lower risk of type 2 diabetes in men (23). Although several cross-sectional studies reported that men with low testosterone levels have an increased risk of coronary artery disease, this association is not clearly seen in prospective studies (24). Testosterone is important for prostate development and function and is a target for treatment of metastatic prostate cancer, yet results from epidemiological studies that examined the association between total and bioavailable testosterone and prostate cancer have been inconclusive (25–27). Our study provides little evidence for the hypothesis that racial variation in testosterone and free testosterone accounts, in part, for the higher risk of prostate cancer in African-American men, at least as measured by circulating levels.
AAG concentration is commonly used in epidemiological studies as an indirect measure of 5α-reductase activity and, thus, the conversion of testosterone to dihydrotestosterone. Serum AAG concentration was significantly higher in non-Hispanic whites than in men of the other two racial/ethnic groups. This was observed overall and in the different age groups. Higher AAG in white compared with black men has been seen in other studies in middle-aged (8, 28) and in elderly (29) but not in young adult men (30). A lower AAG concentration in non-Hispanic black than white men is not compatible with the hypothesis that a greater 5α-reductase activity could be associated with the increased risk of prostate cancer in African-American men based on a meta-analysis that reported an increased risk of prostate cancer with higher circulating AAG concentration (31). Lower AAG might result in men who have a lower conversion of dihydrotestosterone to 3α-androstanediol or, alternatively, a higher reconversion of 3α-androstanediol to dihydrotestosterone (32). However, not much is yet known about racial variation in the activity of the enzymes that catalyze these conversions. Second, lower AAG could result in men with a greater efficiency of conversion of testosterone to estradiol via higher aromatase activity. Polymorphisms in the CYP19 gene, which encodes aromatase, have been reported. However, plasma concentration of total testosterone, AAG, and SHBG did not differ by genotype in a Caucasian population (33). Racial variation in CYP19 alleles has been observed in women (34), but to our knowledge, no study has been published with respect to differences in hormone concentrations in men for most of these CYP19 polymorphisms.
We observed higher serum estradiol concentrations and higher estradiol/SHBG ratios in non-Hispanic black than in non-Hispanic white or Mexican-American men, a difference that was pronounced in young and mid-adulthood. Previous studies aside from one small study of young men (35) did not report differences in circulating estradiol concentrations between African-Americans and Caucasians in young (6, 17, 20), middle-aged (28), or older men (18). It has been hypothesized that higher estradiol concentrations in African-American men might contribute to higher bone mass and, thus, lower fracture risk (7) because estradiol inhibits bone resorption (36). The role of estrogens in the development and progression of prostate cancer, which is more common among African-American than Caucasian or Hispanic men (4), is not clear. In the Physicians’ Health Study, an inverse association between circulating estradiol concentration and prostate cancer was observed after taking testosterone and SHBG concentrations into account statistically (37), whereas other studies did not report statistically significant positive or inverse associations (25).
SHBG transports sex steroid hormones in the circulation and, along with albumin, is a determinant of bioavailable testosterone and estradiol. It mediates steroid hormone signal transduction at the plasma membrane, which allows steroid hormones to act without entering the cell by interacting with SHBG membrane receptors (38). SHBG concentration was lower in Mexican-American than non-Hispanic white and non-Hispanic black men in the age-adjusted model; however, the differences were attenuated after taking into account all covariates, particularly percent body fat. The attenuation of the racial/ethnic differences in the multivariable model is explained by SHBG concentration being inversely associated with body fat (16) and the higher percentage of body fat in Mexican-Americans compared with either of the other two racial/ethnic groups. SHBG concentrations were similar in non-Hispanic blacks and non-Hispanic whites. Similar to our results, two cross-sectional studies did not observe significant differences in circulating SHBG concentration between young adult black and white men (17, 19), whereas a third study reported a higher SHBG concentration in young African-American than Caucasian men (6).
To date, Hispanic males infrequently have been examined concerning their sex steroid hormone profile. In a cross-sectional study that included 200 Hispanic men aged 31–44 yr old, Hispanics had a testosterone concentration that was similar to the concentration in non-Hispanic white but lower than in black men (9). Similarly, no differences in total testosterone concentration were observed in the Boston Area Community Health Survey, which included 648 Hispanics, aged 30–79 yr (21). In the Hawaii-Los Angeles Multiethnic Cohort (8), which included 523 U.S. Latinos, aged 47–74 yr, U.S. Latinos had a slight but not significantly lower circulating testosterone concentration than U.S. whites after adjusting for age. AAG concentration was higher than the concentration in African-American men and lower than in U.S. whites, but neither difference was statistically significant (8). In NHANES III, we studied Mexican-American men, which is the largest Hispanic group in the United States. Whether our results for Mexican-American men may be compared with the results in other Hispanic populations may depend on the composition of those Hispanic populations by country of origin.
Several aspects of our study merit further discussion. First, sex steroid hormone and SHBG concentrations in humans are influenced by a number of factors. Our goal was to determine whether there was racial variation in hormones beyond the variation due to differences in prevalence of modifiable factors that influence hormone concentrations. Therefore, we adjusted the regression models for factors that correlate with hormones and that differ by race, i.e. percent body fat, cigarette smoking, alcohol consumption, and physical activity. However, it should be noted that these modifiable predictors of hormone concentrations are also risk factors for chronic diseases and that hormones may mediate their influence on disease risk. Thus, assessment of crude (or age-adjusted) differences in hormone concentrations is key to understanding the contributions of hormones to the racial/ethnic variation in the burden of disease. Second, serum testosterone concentration exhibits diurnal variation. In one study, mean testosterone concentrations were 25–30% lower at 2000 h than at 0800 h, which was similar in African-American and Caucasian men (6). Therefore, we selected only men who participated in the morning session of the first phase of NHANES III (0830–1130 h). Additionally adjusting for time when blood was drawn did not appreciably change the results. Third, due to the number of comparisons we evaluated, we cannot exclude chance as an alternative explanation for any given finding. Fourth, NHANES III is a cross-sectional study representative of the civilian non-institutionalized U.S. population, thus aiding in the broad generalizability of these results. Main characteristics, such as age, percent body fat, smoking, alcohol consumption, or physical activity, of the subset of men used in this analysis were comparable to all men 20 yr and older who participated in the morning session of the first phase of NHANES III (data not shown). Also, the over-sampling of minorities and elderly and the large sample size allowed for reasonably stable estimates even after adjusting for possibly confounding variables. Fifth, the analyses were based on a single hormone measurement and may not perfectly reflect serum hormone levels averaged over time (39), although some studies have shown that using only one sample was highly accurate in predicting sex steroid hormone levels for a time frame up to 3 yr (26, 40). Sixth, NHANES III is a cross-sectional study, and thus, we could not assess differences in the hormones trajectories over age by race/ethnicity.
In conclusion, in this large, nationally representative sample, there was no difference in circulating testosterone concentrations between non-Hispanic black and white men overall. However, black men had the highest estradiol level overall across all ages, which was not explained by racial differences in the prevalence of factors that influence hormone levels. Mexican-American men had hormonal profiles similar to non-Hispanic white men, with the exception of higher testosterone. Given these findings, it may be equally if not more important to investigate levels of estradiol than testosterone in relation to diseases that show racial disparity, such as prostate cancer
原地址
https://academic.oup.com/jcem/article/92/7/2519/2598282
