Age-Specific Serum Total and Free Estradiol Concentrations in Healthy Men in US Nationally Representative Samples

[madman]

Purpose: To report age-specific serum estradiol concentration in nonsmoking, lean US men without comorbidities. We provide concentrations from 30 and 15 to 20 years ago given previously described declines in serum estradiol in US men over time.

Methods: We used data from the Third National Health and Nutrition Examination Survey (NHANES III; 1988 to 1991) and continuous NHANES (1999 to 2004). Serum estradiol and SHBG were previously measured by competitive electrochemiluminescence immunoassays. Free estradiol was estimated from estradiol, SHBG, and albumin. By age, we calculated median concentrations overall and for nonsmoking, lean (body mass index ,25 kg/m2 and waist ,102 cm) men without diabetes, cardiovascular disease, or cancer.

Results: Overall, respective total estradiol medians for men ages 20 to 39, 40 to 59, and $60 years old were 37.0, 33.9, and 33.5 pg/mL in NHANES III and 31.3, 30.5, and 27.0 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective total estradiol medians were 32.0, 32.1, and 32.0 pg/mL in NHANES III and 29.1, 22.7, and 26.1 pg/mL in continuous NHANES. Overall, respective free estradiol medians were 0.82, 0.72, and 0.64 pg/mL in NHANES III and 0.67, 0.61, and 0.47 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective free estradiol medians were 0.64, 0.67, and 0.62 pg/mL in NHANES III and 0.58, 0.42, and 0.40 pg/mL continuous NHANES.

Conclusion: We report US nationally representative serum estradiol concentrations in healthy men, which could be used for targeting estradiol during testosterone supplementation and for general good health.





In conclusion, we assessed the age-specific distributions of total and free estradiol in NHANES III and 1999 to 2004. Our goal was to report typical estradiol levels in a nationally representative population of healthy men to support the implementation of clinical guidelines for serum estradiol concentrations for men with symptomatic testosterone deficiency who are candidates for testosterone supplementation, and for men in general for good health. With respect to the former use, we envision that consensus guideline developers might need this information. With respect to the latter use, clinical consensus would be needed to define the array of estrogen-associated health states that should be considered and how their relative harms and benefits should be included when optimizing target serum estradiol levels for good health in general based on never-smoking, lean men without comorbidities. Given the recognized racial and ethnic variability in circulating estradiol levels, more work is needed, including by future measurement of estradiol concentrations in existing samples from more recent NHANES surveys, to report with precision population specific estradiol levels.

 

[Cataceous]

Should we expect these values to be somewhat inflated due to the use of ECLIA?

 

[madman]

Should we expect these values to be somewhat inflated due to the use of ECLIA?

I would say so!


*We provide information at two time points, about 30 years and 15 to 20 years ago, given the previously reported but unexplained decline in serum estradiol concentration in men in the United States [11].




Symptoms accompanying testosterone deficiency are often treated with testosterone supplementation. Such treatment could lead to higher estradiol levels via peripheral aromatization of testosterone to estradiol in adipose tissue [1], especially in men with excess body fat. Increases in circulating estradiol as a result of testosterone supplementation may be clinically important for at least two reasons. First, gynecomastia, which has a prevalence of one- to two-thirds of men overall [2] and #70% in men 50 to 69 years old [3], can be exacerbated by replacement testosterone. Indeed, the recent American Urological Association (AUA) Clinical Practice Guidelines for the Evaluation and Management of Testosterone Deficiency recommended that estradiol levels be measured in men with breast symptoms or gynecomastia before supplemental testosterone therapy or during therapy if breast symptoms or gynecomastia developed [4]. However, neither the AUA [4] nor the Endocrine Society [5] recommends measuring estradiol levels before prescribing testosterone for other men being considered for supplementation. Second, elevated circulating estradiol levels have been associated with altered inflammatory and immune responses in men [6], including higher concentrations of circulating proinflammatory markers [7]


The typical laboratory reference range for serum estradiol in men is 10 to 40 pg/mL [8]. However, serum estradiol ranges have not been established for optimal health for older men, such as those without common chronic diseases, who are not overweight or obese, and who do not smoke, all factors that can influence these levels. Age-specific estradiol ranges for healthy men could be useful as clinical targets for men receiving testosterone supplementation. In addition, age-specific estradiol ranges, both low and high, could be used as targets for overall well-being among men, given that estradiol has beneficial effects in men as they age, including reducing the risk of osteopenia [9]


To support the implementation of clinical guidelines for serum estradiol concentrations for men with symptomatic testosterone deficiency who are candidates for testosterone supplementation, and for men in general for good health, we report total and estimated free estradiol concentrations in nationally representative samples of younger, middle-aged, and older nonsmoking, lean men without common chronic diseases. Given the known racial and ethnic differences in estradiol concentration in men [10], we also report estradiol concentrations by race and ethnicity. We provide information at two time points, about 30 years and 15 to 20 years ago, given the previously reported but unexplained decline in serum estradiol concentration in men in the United States [11].

 

[madman]

A. Total Estradiol

For all men, the respective median total estradiol concentrations among men 20 to 39, 40 to 59, and $60 years old were 37.0, 33.9, and 33.5 pg/mL in NHANES III and 31.3, 30.5, and 27.0 pg/mL in NHANES 1999 to 2004 [18]. For lean men without comorbidities, medians were similar to those for all men in both NHANES III and NHANES 1999 to 2004: respective median total estradiol concentrations were 37.5, 33.2, and 34.5 pg/mL in NHANES III and 32.4, 29.6, and 29.8 pg/mL in NHANES 1999 to 2004. For nonsmoking men, total estradiol concentrations were generally slightly lower than for all men: the respective median total estradiol concentrations were 33.8, 32.2, and 32.6 pg/mL in NHANES III and 29.7, 26.5, and 26.6 pg/mL in NHANES 1999 to 2004 [18]. For nonsmoking, lean men without comorbidities in NHANES III, median total estradiol concentrations were similar to those for all men except 20- to 39-year-old men, whereas in NHANES 1999 to 2004, medians were lower for middle-aged and older men, although the median appeared similar for men 20 to 29 years old: the respective median total estradiol concentrations were 32.0, 32.1, and 32.0 pg/mL in NHANES III and 29.1, 22.7, and 26.1 pg/mL in NHANES 1999 to 2004.

a BMI ,25 kg/m2 and WC ,102 cm.
b Without congestive heart failure, heart attack, stroke, diabetes, or cancer.
c Never or former smokers.








B. Estimated Free Estradiol

The analysis for estimated free estradiol was based on the 1445 men (98.8%) in NHANES III and 973 men (99.8%) in NHANES 1999 to 2004 who additionally had SHBG concentrations available. For all men, the respective median free estradiol concentrations among men 20 to 39, 40 to 59, and $60 years old were 0.82, 0.72, and 0.64 pg/mL in NHANES III and 0.67, 0.61, and 0.47 pg/mL in NHANES 1999 to 2004 [18]. For lean men without comorbidities, free estradiol concentrations were slightly lower than for all men in both NHANES III and NHANES 1999 to 2004: the respective medians were 0.78, 0.67, and 0.65 pg/mL in NHANES III and 0.64, 0.54, and 0.48 pg/mL in NHANES 1999 to 2004. For nonsmoking men, free estradiol concentrations were generally lower than concentrations for all younger and middle-aged men in NHANES III and middle-aged men in NHANES 1999 to 2004, whereas for older men free estradiol concentrations were similar in both NHANES III and NHANES 1999 to 2004: the respective medians were 0.75, 0.70, and 0.62 pg/mL in NHANES III and 0.68, 0.57, and 0.46 pg/mL in NHANES 1999 to 2004 [18]. For nonsmoking, lean men without comorbidities, median free estradiol concentrations were lower than for all men in both NHANES III and NHANES 1999 to 2004, except for older men in NHANES III, whose concentrations were similar: respective medians were 0.64, 0.67, and 0.62 pg/mL in NHANES III and 0.58, 0.42, and 0.40 pg/mL in NHANES 1999 to 2004. Given that free estradiol was calculated with SHBG, we also provide distributions for SHBG in an online repository [18].

a BMI ,25 kg/m2 and WC ,102 cm.
b Without congestive heart failure, heart attack, stroke, diabetes, or cancer.
c Never or former smokers.

 

[madman]

One purpose of our report is to inform the monitoring of serum estrogen in men receiving testosterone supplementation. Although the literature on the influence of testosterone supplementation on estrogen levels is not extensive, the influence of testosterone supplementation on estradiol levels is supported by the fact that some men who receive testosterone therapy develop estrogen-related symptoms such as gynecomastia and by direct measurements of their serum estradiol concentrations. For example, in a 2015 study by Tan et al. [19], of 34,016 men treated for low testosterone across 35 US sites, 20.2% had high estradiol levels, defined as .42.6 pg/mL as measured by electrochemiluminescence immunoassay.


Risks of supplemental testosterone, including estrogen-associated symptoms, have been discussed extensively in the literature and summarized in consensus practice guidelines [5]. However, other possible consequences of increased estrogen levels, whether caused by testosterone supplementation or other factors, have been not been discussed in the same depth. Some studies have reported that estrogen influences carcinogenesis via genomic and nongenomic processes. For example, estrogens can produce DNA damage after being metabolized to catechols [20, 21]. Of particular interest for older men, evidence from animal studies suggests a synergistic role for estrogens in prostate carcinogenesis [6, 22]. In rats, although prostate cancer can be induced by androgens alone, a higher chance of inducing prostate cancer occurs when the combination of androgens and estrogen is administered [6, 22]. However, a large, pooled analysis of epidemiologic studies on circulating estrogens measured once in middle or older age and prostate cancer risk does not support a link [23]. Nevertheless, elevated estrogens, irrespective of the cause, could generate chronic, systemic inflammation; men with higher estrogens have higher white blood cell counts and C-reactive protein concentrations and consequent adverse effects on health in general [7]. Although it remains unknown whether circulating estradiol levels influence intraprostatic inflammation in men, as has been observed in rodents [24], such a possibility is concerning given that intraprostatic inflammation has been associated with an elevated risk of prostate cancer [25, 26].


We reported medians and distributions of estradiol concentrations in healthy men who participated in the morning sessions of phase I of NHANES in 1988 to 1991 or in continuous NHANES in 1999 to 2004. Although the medians were different, patterns of total and free estradiol concentrations were similar at these two time points. We reported data separately by time point because members of our team previously published that estradiol concentrations, adjusted for BMI, WC, and smoking, decreased between the years of these two surveys among non-Hispanic white and Mexican American men [11]. These declines could be the result of secular changes in the prevalences of factors that directly or indirectly influence serum estradiol, although we could not rule out time differences. However, the samples were assayed in the same laboratory by the same method. As noted above, a small number of the NHANES III samples were reanalyzed when the NHANES 1999 to 2004 samples were assayed, and there was a CV of 15.3%, which was not unexpected for this analyte, which has a low concentration in men [11].

 

[madman]

This study reports on typical estrogen levels in men without common proestrogenic, proandrogenic, or antiandrogenic states in a nationally representative sample of men overall and by race and ethnicity. Other studies have reported estrogen levels by age but not specifically in healthy men. The most extensive of these reports is a cohort of .10,000 men of predominantly European ancestry ages 35 to 100 years old, pooled from three population based studies of community-dwelling men in three Australian cities [36]. In that study, median total estradiol concentrations of men aged ,65, 65 to ,75, 75 to ,85, and $85 years old were 88 pmol/L (24 pg/mL), 77 pmol/L (21 pg/mL), 81 pmol/L (22 pg/mL), and 85 pmol/L (23 pg/mL), respectively. In a study of 572 German men who were blood donors and older sports club members with BMI ,30 kg/m2 and without chronic illness, mean total estradiol levels (mean 6 SD) varied by age decade (20 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, and 70 to 80 years), and were 102.9 6 23.43 (28.03 6 6.38 pg/mL), 94.17 6 18.01 (25.65 6 4.91 pg/ mL), 90.76 6 18.33 (24.72 6 4.99 pg/mL), 81.02 6 15.33 (22.07 6 4.12 pg/mL), 78.82 6 16.33 (21.47 6 4.45 pg/mL), and 80.37 6 17.14 (21.89 6 4.67 pg/mL) pmol/L, respectively [37]. The medians and means in all men and in nonsmoking lean men in NHANES III and in NHANES 1999 to 2004, which measured estradiol by electrochemiluminescence immunoassays, were notably higher than the medians in the Australian study, which measured estradiol by using liquid chromatography–mass spectrometry [36], and the means in the German study, which measured estradiol via radioimmunoassay [37].

 

[madman]

The major strength of our study is the use of NHANES data. Both NHANES III and NHANES 1999 to 2004 used stringent sampling designs, and we applied sampling weights so that the findings can be generalized to the US population. Because of the wealth of information available in NHANES and because factors influencing estradiol had been previously studied in NHANES, to generate typical medians and distributions for healthy men, we were able to make exclusions based on factors observed to influence estradiol. Nevertheless, our study has several aspects that warrant discussion. Although we used data on serum estradiol measured in the same laboratory with the same assay method, mass spectrometry is the current standard method for research. Nevertheless, the laboratory method in the current study is commonly used clinically, and the kits that were used are approved by the US Food and Drug Administration for clinical use. Measurement of serum total estradiol tends to be less precise than that of other hormones because of its low concentration in men. Although we estimated free estradiol, the estimation method used each man’s measured concentration of SHBG and albumin. Because we used existing data, sample sizes were fixed, which led to small counts for some analyses when stratified by race and ethnicity. We were limited to the most prevalent racial and ethnic groups in the NHANES surveys of 1998 to 1991 and 1999 to 2004; thus, we were not able to provide information relevant to Asian men or American Indian/Alaska Native men.

 

[Nelson Vergel]

It would have been a better study if they had estimated T/E2 ratios even with their use of the old E2 test.