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Bone and Mineral Unit, Oregon Health & Science University (E.O., L.C.L., L.M.M., K.P., J.B.), Portland, Oregon 97239; University of California, San Diego (E.B.-C.), San Diego, California 92103; University of Pittsburgh (J.C.), Pittsburgh, Pennsylvania 15213; Minneapolis Veterans Affairs Medical Center and University of Minnesota (K.E.), Minneapolis, Minnesota 55401; and California Pacific Medical Center (S.C.), San Francisco, California 94115
Address all correspondence and requests for reprints to: Eric Orwoll, M.D., CR113, Oregon Health & Science University, 3181 SW Sam Jackson Park, Portland, Oregon 97239. E-mail: orwoll{at}ohsu.edu.
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Abstract |
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Objective: The purpose of these studies was to assess sex steroid levels in a large cohort of older men.
Design: We conducted a cross-sectional cohort evaluation.
Setting: Community-dwelling men were studied at six academic medical centers in the United States.
Participants: The Osteoporotic Fractures in Men Study is a prospective cohort of men aged at least 65 yr. In these studies, a randomly selected stratified subsample of 2623 participants was analyzed.
Main Outcome Measures: We assessed levels of total and free testosterone and estradiol and SHBG.
Results: Age was inversely associated with free testosterone and free estradiol levels (P for trend = 0.001 for both). Notably, at any age, there was substantial variation in levels of each hormone. Free testosterone levels were lower in men with greater body mass index, lower SHBG, and poorer self-reported health status and in those of Asian race. Free estradiol concentrations were lower in men with lower body mass index and higher SHBG levels. Free estradiol and free testosterone were modestly correlated (r = 0.20; P < 0.001), but at any level of free testosterone, there was considerable variation in free estradiol levels.
Conclusions: This is the largest cohort of older men in which sex steroid levels are available, and it demonstrates that testosterone and estradiol, and their free fractions, tend to decline with age even among older men. However, substantial variation is also present. The relationships between sex steroid levels and their consequences in aging are likely to be complex.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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To some extent, an understanding of the relationships between sex steroid levels and aging, and the opportunity to design intervention studies to examine the benefits of testosterone supplementation, has been limited by a dearth of studies of aged men. Most reports of sex steroid levels with aging involved middle-aged men, often highly selected, nonrepresentative of the general population, and geographically limited (12, 13, 14, 15, 16). Few men older than age 65 yr have been studied despite the fact that many of the adverse effects postulated to be caused by sex steroid insufficiency generally occur relatively late in life. Moreover, the associations between aging and gonadal function in men are based primarily on studies in which total testosterone was the major outcome variable assessed. There is less information available concerning bioavailable and free testosterone levels. Similarly, it has become apparent that estrogen probably has important effects in older men, and there is even less information about estradiol in older men.
The Osteoporotic Fractures in Men Study (MrOS), a prospective cohort study of men aged at least 65 yr, is designed to identify risk factors for fractures and for other aging-related conditions. Here we report the distribution of total, free, and bioavailable testosterone and estradiol concentrations, as well as of SHBG levels, at baseline in a sample of 2623 participants. These results expand the information available concerning variation in sex steroids among older U.S. men and should serve as the foundation for additional longitudinal studies of the effects of sex steroids on important outcomes as well as set the stage for trials of sex steroid administration in elderly men.
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Subjects and Methods |
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The design of the MrOS has been described (17). Briefly, the MrOS cohort consists of 5995 community-dwelling, ambulatory U.S. men aged 65 yr or older. Participants were intended, to the extent possible with a volunteer cohort, to be representative of the population of older men in the communities from which they were recruited. Eligibility criteria were 1) ability to walk without the assistance of another, 2) absence of bilateral hip replacements, 3) ability to provide self-reported data, 4) anticipated residence near a study site for the duration of follow-up, 5) absence of a medical condition that would result in imminent death, and 6) ability to understand and sign an informed consent.
Approximately 1000 participants were recruited at each of six academic medical centers: University of Alabama at Birmingham, Alabama; University of California, San Diego, San Diego, California; University of Minnesota, Minneapolis, Minnesota; Oregon Health & Science University, Portland, Oregon; University of Pittsburgh, Pittsburgh, Pennsylvania; and Stanford University, Palo Alto, California. Recruitment efforts focused on community mailings and were supplemented with a variety of community outreach and educational activities (18). At the baseline clinic visit, participants completed questionnaires regarding medical history, current medication use, and lifestyle characteristics (17). Height and weight were measured, and fasting morning serum was collected. The Institutional Review Board at each center approved the study protocol, and written informed consent was obtained from all participants.
MrOS participants whose serum was used for the measurement of sex steroids were selected using a stratified sampling design. Strata were clinic site (each of six sites), race (white or nonwhite), and availability of a complete set of skeletal imaging procedures (to be used in future analyses of the effects of sex steroids on skeletal change). Within each stratum, participants were sampled with known probability. All nonwhite participants were sampled, and those with complete skeletal imaging were oversampled. The sample target was 2643 participants, and a sample of 2623 (99%) was achieved.
Laboratory methods
Serum was prepared immediately after phlebotomy and stored at –70 C. All samples remained frozen until assayed. Assays were performed at the Oregon Health & Science University General Clinical Research Center by a single technician. Pooled serum controls were included in every assay. Total testosterone was assayed using a solid-phase 125I RIA (Diagnostic Products Corp., Los Angeles, CA) with a detectable range of 10–1600 ng/dl, interassay coefficient of variation (CV) of 8.2%, and intraassay CV of 5.4%; total estradiol by ultrasensitive RIA (Diagnostic Systems Laboratory Inc., Webster, TX) with a detectable range of 2.5–750 pg/ml, interassay CV of 13.3%, and intraassay CV of 8.5%; SHBG by immunometric assay (Diagnostic Products) with a detectable range of 0.2–180 nM, interassay CV of 5.3%, and intraassay CV of 3.3%; and albumin using a Beckman LX 20 analyzer (Beckman-Coulter Instruments, High Wycombe, UK United Kingdom) with an interassay CV of 3.4% and intraassay CV of 1.6%.
Duplicate aliquots from each participant’s serum were assayed and the two results averaged. Samples for testosterone were repeated (in duplicate) when there was a 40% or greater difference between initial assay duplicates. Estradiol measures were repeated when the difference between duplicates was greater than 100% and the means of the duplicates were less than 15 pg/ml or when the mean of the duplicates was greater than 15 pg/ml and there was a 40% difference between replicates. Results from the repeat analyses were averaged with the original results, and 235 of 2623 (8.9%) estradiol samples met repeat criteria and 21 of 2623 (0.8%) testosterone samples met repeat criteria. Estradiol values in two samples fell below the standard curve and were reported as half the lowest standard (i.e. 1.25 pg/ml).
Measures of free and non-SHBG-bound (bioavailable) testosterone, and of free and bioavailable estradiol, were calculated using the mass action equations described by Sodergard et al. (19). In these equations, the possible binding of other steroids to SHBG was disregarded. Free and non-SHBG-bound (bioavailable) estradiol was calculated taking the concentration of testosterone into account. The association constants of testosterone and estradiol used in the equations were taken from Vermeulen et al. (20).
Statistical analyses
Crude means and SDs were calculated. The distributions of sex steroids and SHBG were found to be roughly normal. Pearson partial correlations and least-squared means were adjusted for stratification variables (clinic site, race, and availability of imaging of skeletal sites) to account for any variation present because of the sampling scheme (21).
Multivariate regression models included the stratification variables and additional covariates measured at the baseline examination: age, race, body mass index (BMI), current alcohol consumption, smoking status, and health status. For multivariate analyses examining total and free testosterone levels, estradiol was not included as a predictor in the models because testosterone serves as the major precursor of estradiol in men. SHBG was included as a predictor in multivariate regression models of sex steroids. Trend analyses were performed for sex steroids using linear contrasts after categorization into quintiles. Standardized regression coefficients (standardized to SD) for the continuous variables (age, BMI, alcohol consumption, and sex steroid concentrations) from the multivariate models are reported to facilitate the comparison of the strength of association. With the exception of the demonstration of the sex steroid levels in the entire cohort, men treated with androgens or GnRH agonists were excluded from all analyses.
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Results |
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The average age of the study sample was 73 yr (Table 1
), and 389 (15%) were age 80 or older. Approximately 75% were Caucasian. Most reported themselves to be in excellent or good health compared with their peers. There were few current smokers, but a large proportion had smoked in the past. Alcohol consumption was four drinks per week on average. With the exception of race, distributions of these characteristics were not significantly different from those in the entire MrOS cohort.
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The means (± SD) of total and free testosterone and estradiol, albumin, and SHBG are shown in Table 1
, and the population distributions of total sex steroid levels and SHBG are in Fig. 1. The distributions of free and bioavailable fractions followed similar patterns (data not shown). There was a wide range of total testosterone levels, including a small (n = 58; 2.2%) and distinct subset of men with very low testosterone levels (<100 ng/dl or 3.4 nmol/liter). The majority of these participants (n = 50; 86%) had a history of prostate cancer treated with androgen ablation therapy. When these participants were excluded, the distribution of each variable was essentially normal. This small group of men with prostate cancer and men with a self-reported history of androgen use (n = 33) were not included in subsequent analyses. Total estradiol levels were also variable, but the range was somewhat less broad than with total testosterone, and there was no obvious subgroup with very low levels.
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). There was a similarly wide variation apparent in the relationship between free testosterone and free estradiol levels (r = 0.20) (Fig. 2). Serum free estradiol levels in the men with free testosterone levels in the lowest quartile ranged from 0.26–4.95 pmol/liter (0.07–1.35 pg/ml), whereas free estradiol levels in the men with free testosterone levels in the highest quartile ranged from 0.12–7.75 pmol/liter (0.03–2.11 pg/ml). Bioavailable and free steroid levels were highly correlated (estradiol and testosterone, r = 0.93 and r = 0.84, respectively). Subsequent analyses are reported for free sex steroid levels, but analyses with bioavailable levels yielded equivalent results.
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The relationships between sex steroid levels, age, and other baseline measures are shown in Table 3 and Fig. 3. Both testosterone and estradiol concentrations were lower in older men, a trend that was more marked in levels of free steroids (test for trend: total estradiol, P < 0.001; free estradiol, P < 0.001; free testosterone, P < 0.001) with a particularly low association between age and total testosterone (test for trend, P = 0.27). On the other hand, increasing age was associated with higher SHBG levels (Fig. 3E). Although aging was associated with lower sex steroid and higher SHBG levels, the correlation coefficients with age were modest (Table 3), and there was a considerable variability in levels at any age. Figure 4 shows the proportion of men that have total testosterone levels less than 100 ng/dl, 200 ng/dl, and 300 ng/dl as a function of 5-yr increments of age. The proportion of men with the lowest levels of testosterone progressively increases with advancing age. Approximately 3% of men 65 yr and older had total testosterone levels less than 200 ng/dl (6.9 nmol/liter), although nearly 17% of men had levels less than 300 ng/dl (10.5 nmol/liter). It has been suggested that levels of bioavailable estradiol less than 40 pmol/liter may be deleterious for bone mass in men (22, 23), and 43% of the MrOS population fell below that level (34% in men 65–69 yr and 64% in men >80 yr).
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). Body weight followed the same trend (data not shown). Total and free testosterone levels were slightly higher in men who rated their health status as excellent/good compared with those who rated it as fair/poor/very poor and were slightly higher in current smokers (although there was a very weak negative correlation between testosterone levels and pack years of cigarette consumption) (Table 3). SHBG levels were slightly higher in these two groups as well. Estradiol levels did not differ by health or smoking status, but levels were associated (free and total) with higher reported current alcohol consumption. No sex steroid measure was related to the CAGE index of alcohol dependence (not shown) (44, 45).
Mean sex steroid levels differed by racial categories (Table 4). Total testosterone and age-adjusted testosterone did not differ significantly by race; however, after adjusting for both BMI and age, there were racial differences (P < 0.001). Total testosterone levels were lower in Asian men and higher in African-American and Hispanic men. Free testosterone levels differed significantly by race (unadjusted P < 0.001; age- and BMI-adjusted P < 0.001) following the same trends as for total testosterone. No significant differences in total estradiol by race category were found (unadjusted P = 0.29; age- and BMI-adjusted P = 0.55). Unadjusted free estradiol differed slightly by race (P < 0.03) with whites having the lowest free estradiol concentration; however, after adjusting for age and BMI, the differences by race category diminished. SHBG concentrations differed by race category (unadjusted P < 0.02; age- and BMI-adjusted P < 0.001) with Asian men having the lowest SHBG concentration and African-American and white men having the highest mean concentrations.
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In multivariate analyses (Tables 5 and 6) in which age, race, BMI, SHBG, smoking status, alcohol consumption, and health status were considered, 38% of the variance in total testosterone was explained, primarily by the strong positive association with SHBG. Higher age, higher BMI, and worse health status were associated with slightly lower total testosterone levels. Only 18% of the variation in free testosterone concentrations was explained by the variables considered here; age, BMI, SHBG, and free estradiol were each weakly related to free testosterone levels. Increasing levels of BMI positively, but slightly, influenced free estradiol. A larger proportion of free estradiol levels were related to free testosterone (positively) and SHBG (negatively) levels. The associations between free testosterone, SHBG, and free estradiol levels are shown in Fig. 5. Men with the highest free testosterone and lowest SHBG levels had free estradiol levels approxi-mately 3-fold higher than those with the lowest free testosterone and highest SHBG concentrations. The relationships between free testosterone and free estradiol, and between SHBG and estradiol, were linear. The concentrations of SHBG were slightly higher with greater age, were positively related to total testosterone levels, and were negatively associated with free estradiol levels.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Testosterone levels, particularly levels of free testosterone, were lower in men of greater age. The rate of decline (approximately 10% per decade based on multivariate models) is similar to that reported in other cross-sectional and longitudinal studies (13, 15). Many older men had total testosterone levels less than those in young men. The expected range of free testosterone in young men is not well established, but because the reduction in free testosterone levels with age is more pronounced than it is for total testosterone, the proportion of older men with free testosterone levels falling below the young normal range would be expected to be greater. Nevertheless, there was broad variation in the levels of sex steroid concentrations in older men, and only a modest amount of the variability in levels was explained by age. Many older men have levels considered normal for young men. The level of testosterone that represents sufficiency is unknown and may vary among individuals and between tissues (muscle, bone, adipose, neural, etc.).
There is little information concerning estradiol levels in older men. In MrOS, estradiol concentrations were lower as age increased, and the correlation between age and free or total estradiol was stronger than between age and testosterone levels. This decline in estradiol levels (particularly free or bioavailable levels) is similar to some reports (12, 14, 24, 25, 26, 27), but other studies have noted stable (5, 28, 29) or even rising (30) estradiol levels with age. The reasons for these differences are unclear. As we observed with testosterone, there was a wide range of serum estradiol levels, and there is very little information concerning what level of estradiol is optimal. Some data suggest that there is a threshold level of bioavailable estradiol (40 nmol/liter) below which the rate of loss in bone density is accelerated (22, 23). In our population, 43% had estradiol levels in the range postulated to be related to bone loss.
By virtue of aromatase activity, testosterone serves as the major precursor of estradiol in men (31). In fact, men with the highest free testosterone concentrations had approximately twice the free estradiol levels as men with the lowest levels of free testosterone. However, the simple correlation between free estradiol and free testosterone was relatively modest, indicating that circulating free testosterone is but one determinant of estradiol levels. It is possible that differences in aromatase activity, either genetic or otherwise, may have contributed to this finding (32). In addition, the clearance rate of estradiol may exert an important influence, and polymorphisms in the gene coding for the estrogen-degrading enzyme catechol-O-methyltransferase are associated with variation in estradiol levels (33).
SHBG binding would be expected to reduce the availability of testosterone for aromatization, and a very robust relationship was seen among free estradiol, free testosterone, and SHBG. However, higher SHBG levels were related to lower estradiol levels independent of free testosterone, suggesting that either SHBG has effects on estradiol levels over and above its testosterone-binding properties or that SHBG is actually a surrogate for other variables that may affect both SHBG and estradiol levels. These relationships are very similar to those recently reported by de Ronde et al. (7) and emphasize the physiological importance of SHBG binding to testosterone.
Body composition has been related to male sex steroid physiology in several ways (34). In the current studies, increasing BMI was related to lower total and free testosterone levels, higher total and free estradiol levels, and slightly higher levels of SHBG. These relationships are known from previous studies (35), although they have not been so clearly demonstrated, and whereas univariate correlations suggested a reasonably strong relationship between BMI and sex steroid levels, multivariate analyses indicated the direct effect of BMI was minimal.
These analyses have a number of strengths. To our knowledge, this study is the largest available evaluation of sex steroid levels in older men. Many of the men studied here are over 80 yr, a segment of the male population that is underrepresented in the available literature but that is increasing steadily. This is also one of the few reports of the distribution of estradiol levels in older men. Well controlled assay methods were used to overcome recognized problems regarding the precision of sex hormone measures (36) and to ensure a high level of confidence in the reliability of the data. An extensive evaluation of the mass action equations was undertaken to ensure the assumptions inherent in the calculations were reasonable and consistently applied, and these calculations yield values that compare well to direct assays of free steroid levels. (37)
There are also weaknesses inherent in these studies, including the cross-sectional design. On the other hand, the large sample size available provides an opportunity to confidently detect associations that can be tested in studies of longitudinal design. Second, the most appropriate methods for the measurement of serum sex steroid concentrations remain controversial. The accurate measurement of sex steroid levels is difficult, and there remains no universally accepted approach (38, 39). It is clear that the use of RIA to measure serum concentrations of estradiol and testosterone, particularly when they are present in low concentrations, yields somewhat different results than do measurements done with non-immunoassay-based techniques such as mass spectrometry (40) (considered the reference standard) or with RIA performed on extracted samples (36). Concern about assay technique is probably less relevant for the measurement of testosterone levels in men, where concentrations are relatively high and inaccuracy using RIA-based methods is low (40). However, estradiol levels in men are low, and some degree of inaccuracy may have resulted by the use of RIAs. Nonetheless, more stringent assay quality control measures were used here than in published comparisons of estradiol measurement methods, and our approach should have reduced imprecision. To whatever extent inaccuracy resulted from the use of RIAs, the true strengths of the relationships reported here between estradiol and other variables may have been underestimated. The assessment of free testosterone levels can be performed in several ways, including by equilibrium dialysis and by calculation from mass action equations (used in the current studies). The two methods give very comparable results (20, 41). Mass action equations also provide calculated bioavailable (albumin-bound plus free) steroid levels. Bioavailable steroid levels in serum can also be assessed by methods involving the precipitation of SHBG-bound steroids followed by the assay of nonprecipitated levels. The two approaches yield similar results, and bioavailable levels are highly correlated with free levels (20, 42). Finally, in the current studies, sex steroid measures were performed on a single morning sample rather than multiple or pooled specimens. Assays on single samples are accurate representations of testosterone levels in older men (43), and thus the results we obtained are likely to be a reasonable reflection of sex hormone levels on the morning of collection. How much variation there is in steroid levels over a longer sampling period is unclear (other parts of the day or over months and years). Finally, despite the fact that our cohort encompasses considerable variety in essential traits and is similar to representative cohorts (e.g. NHANES; http://www.cdc.gov/nchs/about/major/nhanes/Anthropometric%20Measures.htm), the results from the population we have studied may not be generalizable to broader populations of older men.
In conclusion, increasing age in older men is associated with lower levels of total and free estradiol and testosterone, but the variability in sex steroid levels in the population is remarkable. Many older men have levels of sex steroids similar to those reported in young men. Testosterone levels were lower in men with fair/poor health, higher BMI, and lower SHBG levels. Both free testosterone (positively) and SHBG (negatively) were related to free estradiol levels, and men with low free testosterone and high SHBG levels have considerably reduced free estradiol concentrations. Nevertheless, these variables (and others related to body mass and lifestyle) explained only a small fraction of the variation in estradiol levels. The modest correlation between testosterone and estradiol reflects considerable interindividual heterogeneity in the relationship between these two fundamentally important gonadal hormones. Longitudinal evaluations are needed to verify these findings and to determine the relationships of sex steroids to health outcomes in older men.
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Acknowledgments |
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Footnotes |
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First Published Online December 20, 2005
Abbreviations: BMI, Body mass index; CV, coefficient of variation; MrOS, Osteoporotic Fractures in Men Study.
Received August 12, 2005.
Accepted December 13, 2005.
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S. Khosla Sex Hormone Binding Globulin: Inhibitor or Facilitator (or Both) of Sex Steroid Action? J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 4764 - 4766. [Full Text] [PDF]
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H. J. Litman, S. Bhasin, C. L. Link, A. B. Araujo, J. B. McKinlay, and for the Boston Area Community Health Survey Invest Serum Androgen Levels in Black, Hispanic, and White Men J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4326 - 4334. [Abstract] [Full Text] [PDF]
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E. Orwoll, L. C. Lambert, L. M. Marshall, J. Blank, E. Barrett-Connor, J. Cauley, K. Ensrud, S. R. Cummings, and for the Osteoporotic Fractures in Men Study Group Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med, October 23, 2006; 166(19): 2124 - 2131. [Abstract] [Full Text] [PDF]
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J. P. Bilezikian What's Good for the Goose's Skeleton is Good for the Gander's Skeleton. J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1223 - 1225. [Full Text] [PDF]
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