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From the * Department of Internal Medicine and
Biomedical Sciences, Section of Geriatrics, University of Parma, Italy; the
Clinical Research Branch and #
Laboratory of Cardiovascular Science, National
Institute on Aging, Baltimore, Maryland; the
Tuscany Regional Health Agency, Florence,
Italy; the Geriatric Rehabilitation Unit,
Azienda Sanitaria di Firenze (ASF)–Florence, Italy; the ||
Department of Medicine, Division of
Endocrinology, Johns Hopkins University School of Medicine, Bayview Medical
Center, Baltimore, Maryland; the ¶ Department of
Geriatric Medicine and Metabolic Diseases II, University of Naples, Italy; and
the ** Laboratory of Epidemiology, Demography, and
Biometry, National Institute on Aging, National Institutes of Health,
Bethesda, Maryland.
| Correspondence to: Marcello Maggio, Department of Internal Medicine and Biomedical Sciences, Section of Geriatrics, University of Parma, via Gramsci 14 43100 Parma, Italy; or Marcello Maggio or Luigi Ferrucci, National Institute on Aging (NIA), National Institutes of Health (NIH) NIA-ASTRA unit at Harbor Hospital, 3001 S Hanover Street, Baltimore, MD 21225 (e-mail: marcellomaggio2001{at}yahoo.it; ferruccilu{at}grc.nia.nih.gov). |
| Received for publication June 24, 2008; accepted for publication December 1, 2008. |
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Abstract |
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 Top Abstract Aim of the studyMaterials and MethodsResultsDiscussionReferences |
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Key words: Androgen, andropause
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Aim of the study |
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TopAbstractAim of the studyMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractAim of the studyMaterials and MethodsResultsDiscussionReferences |
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Overall, 1260 persons (543 men and 726 women) aged 65 years and older were randomly selected from the population registry and were eligible for the study. Of these, 1154 consented to participate in the InCHIANTI Study and 1055 donated a blood sample.
This analysis is limited to 459 male participants. Of these, 452 (83% of the 534 men who donated blood sample; age range, 65–96) had complete data on E2, testosterone, sex hormone–binding globulin (SHBG), fasting insulin, interleukin-6 (IL-6), and albumin and complete set of parameters for the diagnosis of MS. The Italian National Institute of Research and Care of Aging Institutional Review Board ratified the study protocol (Ferrucci et al, 2000), and all participants received a full description of the study and consented to participate.
Definition of MS
In accordance with the National Cholesterol Education Program's Adult
Treatment Panel III (ATP-III) criteria, the diagnosis of MS was established as
the presence of 3 or more of the following: fasting blood glucose levels 
126 mg/dL, fasting serum triglycerides 150 mg/dL, serum high-density
lipoprotein (HDL)–cholesterol < 40 mg/dL, blood pressure 130/85
mmHg (or the use of anti-hypertensive medications) and waist circumference
> 102 cm (Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults,
2001).
Components of MS
Waist circumference was measured at the midpoint between the lower rib
margin and the iliac crest (normally umbilical level). Weight and height were
measured according to standard techniques. Body mass index (BMI) was
calculated as weight (kg) divided by height (m2). Baseline blood
pressure was recorded with a standard mercury sphygmomanometer. All blood
pressure measurements were performed with the participant in a supine position
on 3 occasions separated by intervals of 2 minutes, and the average of the
last 2 measures was used in the analysis.
Blood Assays
Fasting blood samples were drawn between 7:00 and 8:00 AM and
were stored at –80°C until analysis. E2 was measured by
ultrasensitive RIA (DSL-4800 Diagnostic Systems Laboratories, Webster, Texas)
and in the same batch with a minimum detectable concentration (MDC) of 2.2
pg/mL. Intra-assay coefficients of variation (CVs) and means for 4 different
concentrations were 8.9% (5.3 pg/mL), 6.5% (24.9 pg/mL), 7.6% (40.4 pg/mL),
and 6.9% (92.6 pg/mL). The interassay CVs and correspondent means were 7.5%
(5.3 pg/mL), 9.7% (28.0 pg/mL), 8.0% (42.3 pg/mL), and 12.2% (108.7 pg/mL),
respectively. Total testosterone and dehydroepiandrosterone sulfate (DHEA-S)
were assayed with the use of commercial kits (Diagnostic Systems
Laboratories). For testosterone, MDC was 0.03 nmol/L; intra-assay and
interassay CVs for 3 different concentrations were less than 9.6% and 9.1%,
respectively. For dehydroepiandrosterone (DHEAS), MDC was 1.7 µg/dL; intra-
and interassay CVs for 3 different concentrations ranged between 4.1% and 5.3%
and between 4.6% and 7.0%, respectively. SHBG was measured by a
radioimmunoassay (Diagnostic Products Corporation, Los Angeles, California)
with a MDC of 0.04 nmol/L and interassay and intra-assay CVs for 3
concentrations of less than 6.9% and 3.6%, respectively. Concentrations of
free E2 were calculated with the mass action equations described by Sodergard
et al (1982). Concentration of
free testosterone was calculated by the Vermeulen formula
(Vermeulen et al, 1999).
Plasma insulin level was determined with a double-antibody, solid-phase
radioimmunoassay (intra-assay CV = 3.1% + 0.3%; Sorin Biomedica, Milan,
Italy). Cross-reactivity with human proinsulin was 0.3%
(Maggi et al, 2006). Serum
glucose level was determined by using an enzymatic colorimetric assay (Roche
Diagnostics, Mannheim, Germany) and a Roche-Hitachi 917 analyzer. Serum IL-6
was measured by high-sensitivity enzyme-linked immunosorbent assay (ELISA;
Biosource, Camarillo, California). A commercial enzymatic test was used to
measure serum HDL cholesterol and triglyceride concentrations (Roche
Diagnostics). The interassay CV was less than 3.8% for HDL cholesterol and
less than 2.5% for triglycerides (Maggio
et al, 2006).
Assessment of Covariates
Information on physical activity was collected by a modified version of a
standard questionnaire and coded as hours per week
(Ainsworth et al, 1993). Daily
alcohol (g) intake was estimated by the European Prospective Investigation
Into Cancer and Nutrition Food Frequency Questionnaire
(Pisani et al, 1997). Smoking
was assessed by self-report and expressed as pack-years (packs smoked per day)
x (years of smoking). Social demographic variables included educational
level.
Statistical Analysis
Because of skewed distributions, log-transformed values for total and free
E2, SHBG, IL-6, DHEAS, free testosterone, and insulin were used in the
analyses. Differences in hormonal levels and other parameters among
participants with and without MS were tested using age-adjusted linear
regression models and Mantel-Haenszel chi-square tests when appropriate. Free
E2 levels were also divided into quartiles to better describe their
relationship with MS. Differences in the prevalence of MS according to
specific free E2 quartiles were formally tested by Pearson chi-square
tests.
A fully adjusted logistic regression analysis was used to test the hypothesis that higher free and total E2 levels were associated with a significantly higher probability of having MS, after adjusting for potential confounders (age, smoking, alcohol consumption, physical activity, log IL-6, log insulin; model 1). To evaluate the association of E2 and MS independently of other hormone precursors of E2 and body composition measurements, we additionally adjusted logistic regression models for total testosterone, DHEAS, and SHBG (model 2) and then for BMI (model 3). Logistic regression analysis was also used to test the relationship between log(total E2) and log(free E2) (predictors) and each component of MS (outcome) after adjusting for all the covariates used in model 1.
The SAS 8.2 statistical package (SAS Institute Inc, Cary, North Carolina) was used for all analyses.
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Results |
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TopAbstractAim of the studyMaterials and MethodsResultsDiscussionReferences |
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Mean age of the sample was 75 (range, 65–96) years. Total and free E2 were not significantly affected by age (Figures 1 and 2), whereas testosterone was significantly lower with older age (data not shown). Age of participants showed no significant effect with MS for both total E2 (β ± SE, –0.002 ± 0.11, P = .9) and free E2 (–0.002 ± 0.007, P = .73). The age trend for total E2 (0.044 ± 0.04, P = .30) and free E2 (–0.01 ± 0.002, P = .62) also were not statistically significant in participants without MS.
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Figure 3 shows the number and percentage of participants with and without MS according to free E2 quartiles. The percentage of participants with MS was progressively and significantly higher across quartiles of free E2 (P < .001 for trend). Similar results were found with total E2 (P = .002 for trend; data not shown). Figure 4 shows age-adjusted levels of sex hormones for categories of number of ATP-III MS criteria (0, 1, and 3 or more). Interestingly, total and free E2 increased with increasing number of MS criteria, mirroring changes in testosterone.
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Free and Total E2 and Components of MS
In the age-adjusted analysis, log(total E2) and log(free E2) were
positively associated with triglycerides (OR, 2.11; 95% CI, 1.24–3.60;
P = .006 and OR, 2.63; 95% CI, 1.64–4.21; P <
.0001, respectively), hypertension (OR, 1.64; 95% CI, 1.04–2.57;
P = .03 and OR, 1.51; 95% CI, 1.05–2.19; P = .02,
respectively), and waist circumference (OR, 1.93; 95% CI, 1.03–3.64;
P = .04 and OR, 2.24; 95% CI, 1.29–3.87; P = .004,
respectively). In the age-adjusted analysis, log(total E2) and log(free E2)
were not associated with HDL-cholesterol (OR, 0.93; 95% CI, 0.52–1.67;
P = .81 and OR, 0.79; 95% CI, 0.49–1.27; P = .33,
respectively) or fasting glucose (OR, 0.79; 95% CI, 0.44–1.41;
P = .41 and OR, 0.79; 95% CI, 0.49–1.27; P = .33,
respectively).
After adjustment for age, total E2 levels were significantly and positively associated with BMI (age-adjusted: b, 0.20; SE, 0.088; P = .0225).
Additionally, total and free E2 levels were significantly higher in obese
than nonobese men. Total E2 levels were 9.2 ± 6.2 pmol/L
(
± SD) in nonobese and 10.1
± 6.2 pmol/L ( ± SD) in
obese older men (age-adjusted P = .0479). Free E2 levels were 0.37
± 0.43 pmol/L ( ± SD)
in nonobese and 0.43 ± 0.32 pmol/L
( ± SD) in obese older men
(age-adjusted P = .042).
In the fully adjusted analysis, log(total E2) and log(free E2) were still positively associated with triglycerides (OR, 1.77; 95% CI, 1.02–3.07; P = .04 and OR, 2.33; 95% CI, 1.43–3.78; P = .0007) and log(free E2) (OR, 2.00; 95% CI, 1.12–3.58; P = .02), but not log(total E2) (OR, 1.65; 95% CI, 0.84–3.22; P = .14), was still associated with waist circumference; both log(total E2) and log(free E2) were almost associated with hypertension (OR, 1.55; 95% CI, 0.96–2.50; P = .07 and OR, 1.43; 95% CI, 0.97–2.11; P = .07, respectively). Neither log(total E2) nor log(free E2) was associated with HDL-cholesterol (P = .81 and P = .33, respectively) and fasting glucose (P = .17 and P = .25, respectively) in the multivariate analysis.
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Discussion |
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TopAbstractAim of the studyMaterials and MethodsResultsDiscussionReferences |
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E2 and Age
In contrast to some studies (Simon et
al, 1992; Ferrini and
Barrett-Connor, 1998; Van den
Beld et al, 2000; Vermeulen et
al, 2002; Bjornerem et al,
2004; Orwoll et al,
2006), but in accordance with others
(Belanger et al, 1994;
Muller et al, 2003), both
total and free fractions of E2 did not significantly change with age
irrespective of MS.
E2 and Presence of MS
Because this is the first study to our knowledge to evaluate the
relationship between E2 and MS in a population of older men, our results
cannot be compared with other studies in the literature. In contrast to our
study, Muller et al (2005)
failed to detect a significant association between E2 and MS in adult men,
although E2 levels were positively associated with central obesity and
triglycerides. However, the younger age of the study population
( = 60 y) and lack of information on
the free fraction of E2 makes that study hardly comparable to ours
(Muller et al, 2005). Kiel et
al (1989) found strong
relationships of total and free E2 with total and HDL-cholesterol. However,
fasting insulin, alcohol consumption, and physical activity (all factors known
to influence E2 levels) were not included as confounders in their multivariate
analysis (Kiel et al,
1989).
The role of E2 in men and its influence on features of MS are still unclear. Conditions of estrogen deficiency, such as congenital aromatase deficiency, are associated with impaired glucose and lipid metabolism (Goodman-Gruen and Barrett-Connor, 2000). On the other hand, in accordance with other studies, we found that obese men have higher total and free E2 levels than nonobese men (Schneider et al, 1979). The discrepancy between these 2 different conditions remains unclear.
E2 and Presence of MS: The Role of BMI
Total E2 levels were significantly and positively associated with BMI,
independent of age.
After adjusting for all confounders including BMI, a rough measure of obesity, and body composition, free E2 was still associated with MS, suggesting that the relationship between E2 and MS is only partially explained by BMI and by increased conversion from testosterone via aromatization in adipose tissue.
In previous studies, low total testosterone was associated or was a predictor of MS in men (Laaksonen et al, 2004; Muller et al, 2005; Maggio et al, 2006; Rodriguez et al, 2007). Whether low testosterone levels are linked to increased conversion to E2 levels in older men with MS is not clear, although it has been shown that E2 might operate in reducing testosterone levels through a negative feedback at the hypothalamic and pituitary levels (Hayes et al, 2000).
The relative condition of hypogonadotropic hypogonadism of obese male subjects was reported several years ago and confirmed recently in large studies (Vermeulen et al, 1993; Wu et al, 2008).
E2 and Presence of MS: The Role of the Androgens
In the final model including all the covariates and the hormones, such as
DHEAS, testosterone, and SHBG, the association between total or free E2 and MS
was still significant, suggesting that the role of E2 in MS is not accounted
for by the biological effects of its precursors.
Free and Total E2 and Components of MS
One of the most interesting findings is the association with increasing
number of criteria for MS. This association suggests a dose-response effect of
E2 on MS. In the adjusted analysis, total and free E2 levels were associated
with 3 components of MS, namely hypertension, triglycerides, and waist
circumference, which might also explain the mechanisms by which E2 could have
an effect on diabetes and cardiovascular diseases
(Barrett-Connor and Khaw, 1988;
Philips et al, 1996; Ding et al,
2006). Additionally, in this older male population, we found a
positive association between E2 and IL-6
(Maggio et al, 2009), which
can explain another factor mediating the relationship between E2 and MS. E2
was found to be an independent predictor of the progression of carotid
intimae–media thickness in middle-aged men
(Muller et al, 2004).
Moreover, in older men in the Honolulu-Asia Aging Study with a negative
history for coronary artery disease and cancer, E2 level, but not testosterone
or SHBG, was a strong predictor of stroke
(Abbott et al, 2007). However,
the presence of MS was not investigated in any of these studies.
Limitations and Strengths of the Study
The main limitation of our study is the cross-sectional design, which does
not allow any inference on the causal role of E2 on MS. A mechanism of reverse
causality (i.e., that MS, classically associated with central obesity and
inflammatory status, positively influences E2 levels) cannot be excluded. In
this regard, there is evidence that inflammatory cytokines, also produced in
adipose tissue, stimulate aromatase expression
(Zhao et al, 1996). Secondly,
we did not directly measure free E2; instead, we estimated its levels from
calculations (Barrett-Connor and Khaw,
1988) and lacked information on E2 receptors that might have
provided more details on the E2 pathway
(Muller et al, 2003).
E2 assays were performed 8 years after drawing blood into stored plasma samples and more recently than testosterone, SHBG, and DHEAS. However, the samples used to measure E2 were maintained at –80°C and never thawed before the analysis. Also, even if some decoy of the E2 molecule was observed, it is likely that the relative values between individuals maintained the same rank order. Therefore, we believe that in spite of this limitation, our findings maintain their validity.
However, these limitations are offset by important strengths. This study is the first to evaluate the relationship between E2, including the free fraction, and MS in a large representative sample of older men with complete information on ATP-III criteria for MS; the participants were screened for multiple confounders, such as inflammatory markers, smoking, physical activity, alcohol intake, and fasting insulin levels. Furthermore, we evaluated E2 with ultrasensitive methods. Although weakened by the cross-sectional nature, the results of this study have important clinical and conceptual implications.
Clinical Implications
Because previous epidemiologic studies in older men focused on testosterone
rather than E2, we suggest that further studies should test the relationship
between this parameter and MS in older men. Given the opposite relationship of
testosterone and E2 with MS, future studies should also look at the role of
the testosterone:E2 ratio in MS. The findings, once confirmed in other
populations, raise the possibility that aromatase inhibitor therapy might be a
good therapeutic option in older male participants affected by MS.
In older men, high E2 levels are associated with MS, independent of potential confounders. Whether changes in this hormonal pattern play a role in the development of MS should be further tested in longitudinal studies.
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Footnotes |
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