AMERICAN JOURNAL OF HUMAN BIOLOGY 26:565–569 (2014)

Short Report

Estradiol Concentrations in Young Healthy US versus Chinese Men LIN XU,1 SHIU LUN AU YEUNG,1 SUSHMA KAVIKONDALA,1 AND CATHERINE MARY SCHOOLING1,2* 1 School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China 2 City University of New York School of Public Health and Hunter College, New York, NY, USA

Objectives: The role of estrogens among men has rarely been explicitly considered. We examined differences in total, free, and bioavailable estradiol (Bio E) between young men from the United States (US) and the most economically developed part of China, that is, Hong Kong (HK). Methods: Cross-sectional analysis was conducted based on 365 young men from the Third National Health and Nutrition Examination Survey in the US and 299 young Chinese men. All participants were aged from 18 to 29 years. Main outcome measures were total estradiol (E2) and calculated Bio E and free estradiol (FE). Results: In both young US and Chinese men, E2 concentrations peaked at ages 25–29 years, at 43.3 pg/ml [95% confidence interval (CI) 41.9–44.8] in US men and 29.0 pg/ml (95% CI 26.2–32.0) in Chinese men. After adjustment for age and ethnicity, in all participants, US men had higher average concentrations of E2 [39.0 (95% CI 38.6–39.4) versus 28.3 (95% CI 28.3–28.4) pg/ml], FE [72.9 (95% CI 72.7–73.7) versus 56.8 (95% CI 56.6–56.9) ng/dl], and Bio E [17.9 (95% CI 17.7–18.1) versus 14.9 (95% CI 14.8–14.9) pg/ml] than HK men. Further adjustment for height or body mass index did not change the results. Conclusions: Estradiol, and free and Bio E concentrations are much lower in young healthy Chinese men than US men. However, these findings based on comparison between the two assays in the two different locations need further C 2014 Wiley Periodicals, Inc. V confirmation. Am. J. Hum. Biol. 26:565–569, 2014. INTRODUCTION Sex steroid hormones, including estrogens, may be involved in the development of common diseases among men, such as prostate cancer (Salonia et al., 2012), diabetes (Morimoto et al., 2011), and cardiovascular disease (Byar and Corle, 1988; Coronary Drug Project Research Group, 1973; Xu et al., 2013). The incidence of these conditions varies by ethnicity, with Caucasians often having higher prevalence of prostate cancer (Calistro Alvarado, 2010) and ischemic cardiovascular disease (Yusuf et al., 2001), but lower diabetes than Chinese, despite a more obese population (Yoon et al., 2006). Some, but not all, of the variation in disease incidence may be explained by ethnic differences in lifestyle, such as smoking, physical activity, use of alcohol and diet. In addition, variation in hormone levels has been hypothesized to contribute to the ethnic disparities in the incidence of these important diseases (Alvarado, 2010; Yoon et al., 2006; Yusuf et al., 2001), although the role of estrogens among men has rarely been explicitly considered. Chinese men have lower testosterone than Caucasian men (Calistro Alvarado, 2010; Lookingbill et al., 1991). Given aromatization of testosterone to estrogen is the main source of estrogen for men, Chinese men might also be expected to have lower estrogen than Caucasians. Sex hormones may vary with age and ill-health, different studies using different samples of varying age ranges may not be appropriate for direct comparison. Comparisons in young adulthood may be most relevant. To the best of our knowledge, no studies have examined population differences in levels of estradiol between young men, especially in China compared to the United States (US). We hypothesized that plasma concentration of estradiol would be lower among men in China than the US. We compared total (E2), calculated free (FE), and bioavailable estradiol (Bio E) in young healthy men from the Third National Health and Nutrition examination Survey (NHANES III) in the US and from a region of China with a similar living standard to the US, that is, Hong Kong (HK). C 2014 Wiley Periodicals, Inc. V

METHODS Hong Kong Young Adult Survey (HKYAS) Two hundreds and ninety nine Chinese men students aged 18–29 years were recruited from the University of Hong Kong from February to December 2011. The participants were restricted to (1) those whose parents and at least three grandparents were born in HK or Guangdong province and (2) those who were not taking medication which affects serum sex steroid concentrations. Selfadministered questionnaires were used to collect other relevant information, such as socioeconomic position and health status. The Institutional Review Board of the University of Hong Kong and the Hospital Authority Hong Kong West Cluster approved the study. All participants gave written, informed consent before participation. Morning blood samples were collected for sex steroid assessment. Estradiol (E2) was assessed by competitive chemiluminescent immunoassay (Ortho-Clinical Diagnostics). This assay is traceable to Ortho-Clinical Diagnostics in-house reference calibrators, which have been valueassigned to correlate to samples measured by isotope dilution-gas-chromatography/mass spectrometry (MS). Sex hormone binding globulin (SHBG) was measured by twosite chemiluminescent immunometric assay (IMMULITE; Siemens Diagnostics). Measured E2, albumin, and SHBG were used to calculate free estradiol (FE) and Bio E using the mass action equations described by Sodergard et al. (1982). Contract grant sponsor: Research Grant Council General Research Fund; Contract grant number: 769710; Contract grant sponsor: Research Grant Council of Hong Kong, Hong Kong SAR, People’s Republic of China. *Correspondence to: C.M. Schooling; G/F Patrick Manson Building (North Wing), 7 Sassoon Road, Hong Kong, China. E-mail: [email protected] Received 11 December 2013; Revision received 26 February 2014; Accepted 15 March 2014 DOI: 10.1002/ajhb.22548 Published online 3 April 2014 in Wiley Online Library (wileyonlinelibrary.com).

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NHANES III

DISCUSSION

NHANES III is a survey conducted in the US by the National Center for Health Statistics between 1988 and 1994. Details of NHANES III have been reported elsewhere (National Center for Health Statistics, 1994). The protocols for the conduct of NHANES III were approved by the institutional review board of the National Center for Health Statistics, Centers for Disease Control and Prevention. Informed consent was obtained from all participants. The assay of stored serum specimens for the Hormone Demonstration Program was approved by the Institutional Review Boards at the Johns Hopkins Bloomberg School of Public Health and the National Center for Health Statistics, Centers for Disease Control and Prevention. Blood drawn after an overnight fast for 1529 men, who were randomly selected from the overall men for the morning examination session, was used to reduce extraneous variation due to diurnal production of hormones. Sex steroid hormones and SHBG have been reported to be stable when exposed to multiple freeze–thaw cycles (Comstock et al., 2008). Competitive electrochemiluminescence immunoassays on the 2010 Elecsys autoanalyzer (Roche Diagnostics, Indianapolis, IN) were used to quantify serum estradiol and SHBG concentrations at the Children’s Hospital Boston, MA. The samples were randomly ordered for testing, and the laboratory technicians were blinded to the men’s identities and ages (Rohrmann et al., 2011). Quality control specimens with known hormone concentrations spanning higher and lower concentrations were used to determine reliability. FE and Bio E were estimated from measured estradiol, SHBG, and albumin (Sodergard et al., 1982). To minimize any confounding by age and to establish whether estradiol levels differ by ethnicity under the age of 30 years, we only included men aged from 18 to 29 years. Thus 365 men with measured sex steroids in NHANES III were included in the current study.

To our knowledge, this is the first study on two comparative samples of young healthy men aged 18–29 years showing that US men have much higher estradiol, FE, and Bio E than Chinese men living in a similarly economically developed location. We found only one previous comparative study, which included 26 Caucasian men and 8 Asian men aged from 18 to 33 years and found no difference in estradiol (Veldhuis et al., 2005), probably because of the very small sample size. In a much larger sample, we found about 10 pg/ml lower estradiol in HK men than US men. These population differences, if substantiated, may be relevant to clinical investigation of differences in hormone-related disease patterns between these, and possibly similar, populations. Given the likely role of estrogens in prostate cancer (Coronary Drug Project Research Group, 1973), perhaps via estrogen signaling (Bonkhoff and Berges, 2009; Ellem and Risbridger, 2010) or estrogen receptors (Bonkhoff and Berges, 2009; Salonia et al., 2011), and cardiovascular disease (Byar and Corle, 1988; Coronary Drug Project Research Group, 1970, 1973; Rossouw et al., 2007), our findings are consistent with the much higher incidence of prostate cancer (Calistro Alvarado, 2010) and cardiovascular disease (Yusuf et al., 2001) in US compared to Chinese men. Moreover, our findings also shed light on other unexplained differences between Chinese and other populations, such as the greater tendency to central obesity in Chinese and other Asian populations (Yoon et al., 2006), which a recent, very elegant trial has shown would be expected from lower levels of estrogen (Finkelstein et al., 2013). Whether, this same mechanism, that is, low estrogen or its precursor in men, low testosterone, is also related to the greater vulnerability of Chinese to diabetes compared to US populations, either directly or via central obesity, remains to be determined. As such, examining population differences in estradiol should be of interest to public health and clinical health care workers. Our study clearly showed that US men had higher estradiol than Chinese men. Taking a life history perspective, we have previously suggested that the much more limited living conditions over generations experienced in China than in the West (Maddison, 2003) would result in lower levels of sex hormones (Schooling and Leung, 2010). These observations are consistent with our theoretical predictions, but we cannot rule out other competing explanations, such as genetics, lifestyle, or body composition. Relevant genetic differences between Chinese and Caucasians have not yet been identified. Further adjustment for BMI or waist-to-hip ratio, because aromatization of testosterone to estrogens may occur in adipose tissue, did not affect the magnitude of the difference. Future studies in young populations with comparable lifestyle and living conditions in the US including Chinese migrants and other ethnic populations are needed to distinguish between explanations. There are several limitations of the current study. First, the US men in our current study were selected from NHANES III, a nationally representative study of children and adults in the US from 1988 to 1994, whereas the Chinese men were selected from student volunteers from the University of Hong Kong in 2011. The selection of student volunteers, in theory, is not representative of all young adults, however in the US young men, estrodiol was not associated with education after adjustment for

Statistical analysis Linear regression was used to calculate age adjusted means of E2, FE and Bio E and 95% confidence intervals (CIs) were used to compare age adjusted differences between the two samples. Data analysis was performed using STATA to weight the US sample back to the US population and to take account of the complex survey design. RESULTS Among the 365 US men, 151 (41%) were MexicanAmerican, 101 (28%) were non-Hispanic white, and 113 (31%) were non-Hispanic black. In both young US and Chinese men, E2 concentrations peaked at 25–29 years of age, at 43.3 (95% CI 41.9–44.8) pg/ml in US men and 29.0 (95% CI 26.2–32.0) pg/ml in Chinese men. Figure 1 shows that in all age groups and ethnicities of the US men, including Mexican Americans, non-Hispanic White, and non-Hispanic Black populations, US men had higher E2, FE, and Bio E than HK men. After adjustment for age and ethnicity, in all participants, US men had higher average concentrations of E2 [39.0 (95% CI 38.6–39.4) versus 28.3 (95% CI 28.3–28.4) pg/ml], FE [72.9 (95% CI 72.7–73.7) versus 56.8 (95% CI 56.6–56.9) ng/dl], and Bio E [17.9 (95% CI 17.7–18.1) versus 14.9 (95% CI 14.8–14.9) pg/ml] than HK men. Further adjustment for height or body mass index (BMI) did not change the results. American Journal of Human Biology

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Fig. 1. Mean total (a), free (b) and Bio E (c) for men aged 18–29 years in HK compared with US (error bars: 95% CI). MA: Mexican Americans; NHB: non-Hispanic Black; and NHW: non-Hispanic White.

age (data not shown). Moreover, ideally the two samples should relate to the same time period, although a secular trend, even over 30 years, is unlikely to account for such a large difference. Second, free and Bio E was calculated, rather than measured, according to the law of mass action described by Sodergard et al. (Sodergard et al., 1982). However, the calculation shows high validation and reli-

ability (Rinaldi et al., 2002). Third, immunoassay rather than the gold-standard MS-based method was used to measure estradiol; however, the same technique was used in both samples. Although the MS-based method provides more accurate measurements, immunoassay is generally valid (Khosla et al., 2008), useful, and widely used in clinical practice, especially for large population-based American Journal of Human Biology

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Fig. 1. (Continued)

research. Moreover, the current study compares two sets of data where different assays were used in different laboratories—one was Roche Diagnostics and the other Ortho Vitros. Although both are based on chemiluminescent immunoassays, there could be some differences between products supplied from different sources. Furthermore, we could not control for interassay variability in the present study as no specimens were used as control and tested simultaneously in these two laboratories. Therefore, interassay variability could not be ruled out. The average percentage difference in total estradiol between these two samples was 28%, which was unlikely explained by the interassay variation (usually less than 15%; Wang et al., 2004). Further studies using the same method in a same laboratory are needed to confirm our results. Fourth, the analysis was based on a single measurement and may not perfectly reflect estradiol concentrations averaged over time. Hence, we could not assess differences in the hormones trajectories with age. There could be some variation in estradiol concentrations across short periods of time. In addition, two single samples from the US and HK populations may be less representative. However, we chose a sample in self-reported good health matched on age with the US men from the NHANES III. Moreover, measuring estradiol in young adults minimizes any confounding by age or underlying illness, and thus more accurately reflect lifelong endogenous estrogen exposure. In conclusion, we have shown much lower total, free, and Bio E among young healthy Chinese men than US men. Including two strictly age-matched samples, our findings could be an important initial step in understanding different patterns of diseases between Western and Asian populations, such as low prevalence of prostate cancer and ischemic heart disease, but high prevalence of central obesity and diabetes in China. American Journal of Human Biology

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ESTRADIOL CONCENTRATIONS National Center for Health Statistics. 1994. Plan and operation of the third national health and nutrition examination survey, 1988–94, series 1: programs and collection procedures. Vital Health Stat 1:1–407. Rinaldi S, Geay A, Dechaud H, Biessy C, Zeleniuch-Jacquotte A, Akhmedkhanov A, Shore RE, Riboli E, Toniolo P, Kaaks R. 2002. Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations. Cancer Epidemiol Biomarkers Prev 11(Pt 1):1065–1071. Rohrmann S, Platz EA, Selvin E, Shiels MS, Joshu CE, Menke A, Feinleib M, Basaria S, Rifai N, Dobs AS, Kanarek N, Nelson WG. 2011. The prevalence of low sex steroid hormone concentrations in men in the Third National Health and Nutrition Examination Survey (NHANES III). Clin Endocrinol 75:232–239. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. 2007. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297:1465–1477. Salonia A, Abdollah F, Capitanio U, Suardi N, Briganti A, Gallina A, Colombo R, Ferrari M, Castagna G, Rigatti P, Montorsi F. 2012. Serum sex steroids depict a nonlinear u-shaped association with high-risk prostate cancer at radical prostatectomy. Clin Cancer Res 18:3648–3657. Salonia A, Gallina A, Briganti A, Suardi N, Capitanio U, Abdollah F, Bertini R, Freschi M, Rigatti P, Montorsi F. 2011. Circulating estradiol, but not testosterone, is a significant predictor of high-grade prostate cancer in patients undergoing radical prostatectomy. Cancer 117:5029–5038.

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Schooling C, Leung G. 2010. A socio-biological explanation for social disparities in non-communicable chronic diseases: the product of history? J Epidemiol Community Health 64:941–949. Sodergard R, Backstrom T, Shanbhag V, Carstensen H. 1982. Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem 16: 801–810. Veldhuis JD, Bae A, Swerdloff RS, Iranmanesh A, Wang C. 2005. Experimentally induced androgen depletion accentuates ethnicity-related contrasts in luteinizing hormone secretion in asian and caucasian men. J Clin Endocrinol Metab 90:1632–1638. Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. 2004. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 89:534–543. Xu L, Freeman G, Cowling BJ, Schooling CM. 2013. Testosterone therapy and cardiovascular events among men: a systematic review and metaanalysis of placebo-controlled randomized trials. BMC Med 11:108. Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, Zimmet P, Son HY. 2006. Epidemic obesity and type 2 diabetes in Asia. Lancet 368:1681– 1688. Yusuf S, Reddy S, Ounpuu S, Anand S. 2001. Global burden of cardiovascular diseases: Part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation 104:2855–2864.

American Journal of Human Biology

Estradiol concentrations in young healthy US versus Chinese men.

The role of estrogens among men has rarely been explicitly considered. We examined differences in total, free, and bioavailable estradiol (Bio E) betw...
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