American Journal of Epidemiology

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Am J Epidemiol 2003; 157:25-31.
Copyright © 2003 by Johns Hopkins Bloomberg School of Public Health

ORIGINAL CONTRIBUTIONS

Endogenous Hormones and Carotid Atherosclerosis in Elderly Men

A. W. van den Beld^1,2,, M. L. Bots², J. A. M. L. L. Janssen¹, H. A. P. Pols¹, S. W. J. Lamberts¹ and D. E. Grobbee²

¹ Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
² Julius Center for Health Sciences of Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

Received for publication October 2, 2001; accepted for publication July 22, 2002.

	ABSTRACT

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The aging process is characterized by a number of gradual changes in circulating hormone concentrations as well as a gradual increase in the degree of atherosclerosis. The authors studied whether serum hormone levels are related to atherosclerosis of the carotid artery in independently living, elderly men. In 1996, 403 men (aged 73–94 years) were randomly selected from the general population of Zoetermeer, the Netherlands. Carotid artery intima-media thickness was determined. Serum concentrations of testosterone; estrone; estradiol; dehydroepiandrosterone and dehydroepiandrosterone sulfate; insulin-like growth factor I (IGF-I) (total and free) and its binding proteins IGFBP-1, IGFBP-2, and IGFBP-3; and leptin were measured. After the authors adjusted for age, serum testosterone, estrone, and free IGF-I were inversely related to intima-media thickness. The strength of these relations was as powerful in subjects with as in those without prevalent cardiovascular disease. Serum estradiol; dehydroepiandrosterone sulfate; total IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3; and leptin showed no association. These findings suggest that endogenous testosterone, estrone, and free IGF-I levels may play a protective role in the development of atherosclerosis in aging men.

aging; atherosclerosis; cardiovascular diseases; hormones; men

Abbreviations: Abbreviations: DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; IMT, intima-media thickness; SE, standard error.

	INTRODUCTION

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Cardiovascular disease is the prime cause of death among the elderly in industrialized countries, and it is a major determinant of chronic disability (1). The burden of atherosclerosis especially afflicts the increasing older part of the population. Most hormone levels decrease with age, coincident with the age-associated increase in atherosclerotic disease. Consequently, a role in the pathogenesis of cardiovascular disease has been suggested for several hormonal systems.

In men, a beneficial effect of testosterone and of dehydroepiandrosterone sulfate (DHEAS) on cardiovascular risk factors has been described (2–6). Furthermore, in women, substantial evidence exists for a protective role of endogenous sex hormones and of estrogen therapy in the development of atherosclerosis (7–13). Recent data have suggested that the insulin-like growth factor (IGF)/IGF binding protein (IGFBP) system is related to cardiovascular risk factors and the degree of atherosclerosis in an elderly population (14, 15).

However, most of these studies were performed among relatively young subjects and concentrated on the relation between hormones and cardiovascular risk factors. We studied whether serum hormone levels are related to atherosclerosis, as measured by intima-media thickness (IMT) of the carotid artery, in a population of independently living, elderly men.

	MATERIALS AND METHODS

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Subjects
A group of 403 independently living men, aged 73–94 years, participated in this 1996 study. Participants were recruited by sending letters of invitation to the oldest male inhabitants of Zoetermeer, a medium-sized town in the midwestern part of the Netherlands. All participants provided informed consent, and the study was approved by the Medical Ethics Committee of the University Hospital Rotterdam.

Participants were judged sufficiently healthy to participate in the study if they were physically and mentally able to visit the study center independently. No additional health-related eligibility criteria were used. A number of participants were taking medications for chronic illnesses, including hypertension (n = 98), angina pectoris (New York Heart Association class 1–3) or a recent myocardial infarction (n = 85), mild congestive heart failure (n = 28), chronic obstructive pulmonary disease (n = 40), and diabetes mellitus (n = 33). We were not informed about one subject’s medical history and parameters of atherosclerosis, although information was available on his serum hormone levels and other parameters measured in this study (not mentioned in this manuscript). Therefore, this subject was excluded from our analyses.

We divided the cohort by the presence (n = 139) or absence (n = 263) of prevalent cardiovascular disease. Presence of cardiovascular disease was defined as having symptoms of or being treated for angina pectoris, congestive heart failure, or intermittent claudication or as having a medical history of myocardial infarction or cerebrovascular accident. Subjects with hypertension were not included in this group, since hypertension is regarded as a risk factor for cardiovascular disease and not as cardiovascular disease itself. In addition, we divided the cohort by use (n = 123) or no use (n = 279) of cardiovascular drug therapies. Cardiovascular drug therapy was defined as using one or more of the following drugs: angiotensin-converting enzyme inhibitors, calcium antagonists, diuretics, ß-inhibitors (any of these four drugs were not included if they were used only to lower hypertension), glycosides, nitrates, amiodarone, cholesterol-lowering drugs, and anticoagulants.

Seventy subjects smoked at the time of the investigation, whereas 281 subjects did not but had smoked previously. Fifty-one subjects had never smoked.

Height and weight were measured with participants in the standing position but not wearing shoes. Body mass index was calculated as weight in kilograms divided by the square of height in meters. Waist circumference was measured at the level of the umbilicus, and hip circumference was measured at the level of the greater trochanter. The average of two readings was used in the analyses. Waist/hip ratio, which represents a measure of upper body adiposity, was calculated from these two measurements.

Measures of atherosclerosis
To determine carotid artery IMT as a quantitative measure of generalized atherosclerosis (16), ultrasonography of the left and right common carotid artery and the bifurcation was performed with a 7.5-MHz linear array transducer (ATL Ultramark IV; Advanced Technology Laboratories, Inc., Bothell, Washington). A careful search was conducted for all interfaces of the near and far walls of the distal common carotid artery and the far wall of the carotid bifurcation (17). The actual IMT measurements were performed off-line, as described previously (18). A composite measure that combined mean common carotid artery IMT and mean carotid bifurcation IMT (z score) was obtained by averaging these two measurements after standardization (subtraction of the mean and division by the standard deviation).

The common carotid artery, carotid bifurcation, and internal carotid artery were also evaluated for the presence (yes/no) of atherosclerotic lesions on both the near and far walls of the carotid arteries. Plaques were defined as a focal widening relative to adjacent segments, with protrusions into the lumen composed of only calcified deposits or a combination of calcification and noncalcified material (17). The size of the lesions was not quantified. Presence of the number of plaques was used as an indicator of the presence of atherosclerosis. Serum total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglyceride concentrations were measured by using commercially available radioimmunoassay kits.

Hormone measurements
Blood samples were collected in the morning after an overnight fast. Serum concentrations of total testosterone (nmol/liter) and sex hormone-binding globulin (nmol/liter) were measured by radioimmunoassay using commercial kits (Diagnostic Systems Laboratories, Inc., Webster, Texas). For total testosterone and sex hormone-binding globulin, the intra-assay coefficients of variation were 8.1 percent and 3.0 percent, respectively, and the interassay coefficients of variation were 10.5 percent and 4.4 percent, respectively. Serum concentrations of estrone (nmol/liter), estradiol (pmol/liter), DHEA (nmol/liter), and DHEAS (µmol/liter) were also measured by radioimmunoassay using commercial kits (Diagnostic Systems Laboratories, Inc.); the intra-assay coefficients of variation were 5.6 percent, 5.3 percent, 3.8 percent, and 2.1 percent, respectively, and the interassay coefficients of variation were 10.2 percent, 8.1 percent, 8.6 percent, and 5.1 percent, respectively.

Dissociable free IGF-I was measured with a commercially available, noncompetitive, two-site immunoradiometric assay (Diagnostic Systems Laboratories, Inc.). Total IGF-I was measured by an IGFBP-blocked radioimmunoassay (Medgenix Diagnostics, Fleurus, Belgium), as described previously (19); the intra-assay and interassay coefficients of variation were 6.1 percent and 9.9 percent, respectively. IGFBP-1, IGFBP-2, and IGFBP-3 were all measured with radioimmunoassays (Diagnostic Systems Laboratories, Inc.), as described previously (20–23); the intra-assay coefficients of variation were 3.4 percent, 2.9 percent, and 1.9 percent, respectively, and the interassay coefficients of variation were 8.1 percent, 10.3 percent, and 9.2 percent, respectively. Insulin was measured by a commercially available radioimmunoassay (Farmacia, Threibel, Germany); the intra-assay and interassay coefficients of variation were 8.0 percent and 13.7 percent, respectively. Leptin (µg/liter) was also measured by radioimmunoassay (Lilly Research Laboratories, Giessen, Germany).

Data analyses
In this paper, results are expressed as mean (standard deviation), unless otherwise stated. Relations between variables were assessed by using linear regression for continuous variables and are described as the linear regression coefficient (ß) and its standard error as well as the 95 percent confidence interval. Since an association was present between several hormone concentrations and age, multiple regression analysis was used to adjust for age as well as to assess the independent contribution of different variables to the dependent variable. We used a paired t test to compare continuous characteristics. Differences between groups were stated together with the 95 percent confidence interval.

	RESULTS

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Mean age of the population was 77.8 years (range, 73–94 years). Descriptive values of the measures of atherosclerosis, as well as general characteristics, are presented in table 1. Descriptive values of the hormone levels are presented in table 2. Mean IMT of the carotid bifurcation (ß = 0.05 (standard error (SE), 0.01) mm/year, p = 0.001) and combined IMT of the carotid artery (ß = 0.05 (SE, 0.02) mm/year, p = 0.01) were both directly associated with age. In our population, serum total testosterone and insulin were not significantly associated with age. Serum estradiol, estrone, DHEA, and DHEAS were significantly inversely related to age (respectively, ß = –1.99 (SE, 0.80) (pmol/liter)/year, ß = –4.90 (SE, 0.50) (pmol/liter)/year, log-transformed ß = –0.02 (SE, 0.006) (nmol/liter)/year, and ß = –0.04 (SE, 0.01) (µmol/liter)/year; all, p < 0.01). In addition, serum IGF-I, IGFBP-3, and leptin concentrations were inversely related to age (respectively, ß = –0.85 (SE, 0.41) (nmol/liter)/year, p = 0.04; ß = –0.07 (SE, 0.01) (µmol/liter)/year, p < 0.001; and ß = –0.02 (SE, 0.01) (nmol/liter)/year, p = 0.04). IGFBP-1 and IGFBP-2 levels were positively related to age (respectively, log-transformed ß = 0.03 (SE, 0.006) (nmol/liter)/year and ß = 0.03 (SE, 0.004) (µmol/liter)/year; both, p < 0.001).

View this table: [in this window] [in a new window]   TABLE 1. Baseline characteristics of 403 ambulatory elderly Dutch men studied regarding serum hormone levels and carotid atherosclerosis, Zoetermeer, the Netherlands, 1996

 

View this table: [in this window] [in a new window]   TABLE 2. Serum hormone concentrations in 403 ambulatory elderly Dutch men studied regarding an association with carotid atherosclerosis, Zoetermeer, the Netherlands, 1996

 
Atherosclerosis and gonadotropic and adrenal hormones
Serum estradiol, DHEA, and DHEAS concentrations were not related to combined IMT of the carotid artery. In addition, no relation was found after adjustment for age and body mass index.

However, serum testosterone concentrations were inversely related to mean IMT of the bifurcation and combined IMT after adjustment for age (p = 0.02; table 3). Serum total testosterone concentrations were inversely related to body mass index (ß = –0.17 (SE, 0.05) (nmol/liter)/(kg/m²), p < 0.001). Testosterone levels did not differ between subjects with and those without hypertension or diabetes. Mean serum testosterone concentrations were significantly higher in subjects who had never smoked compared with subjects who had (difference = 1.01 nmol/liter, 95 percent confidence interval: 0.10, 1.91 nmol/liter). The associations between serum testosterone and IMT were independent of body mass index, waist/hip ratio, presence of hypertension and diabetes, smoking, and serum cholesterol levels (total, low density lipoprotein, and high density lipoprotein cholesterol and triglycerides).

View this table: [in this window] [in a new window]   TABLE 3. Regression coefficients* resulting from use of intima-media thickness of the carotid artery (mm) as the dependent variable and endogenous testosterone, estrone, and free insulin-like growth factor I levels (nmol/liter) as the independent variables in a study of 297 elderly men with or without cardiovascular disease, Zoetermeer, the Netherlands, 1996

 
Serum estrone concentrations were also inversely related to mean IMT of the common carotid artery and to combined IMT, after adjustment for age (p = 0.02; table 3, figure 1). Serum estrone levels were positively related to waist/hip ratio (ß = 0.13 (SE, 0.07) (nmol/liter)/1, p = 0.04). Furthermore, subjects with hypertension had significantly higher estrone concentrations compared with subjects without hypertension (difference = 0.01 nmol/liter, 95 percent confidence interval: 0.003, 0.021 nmol/liter). The distribution of estrone concentrations did not differ significantly regarding diabetes and smoking. The association between IMT and estrone concentrations was independent of body mass index, waist/hip ratio, presence of hypertension and diabetes, smoking, and serum cholesterol levels.

View larger version (12K): [in this window] [in a new window]   FIGURE 1. Mean intima-media thickness (mm) based on the combined score for the common carotid artery (CCA) and the bifurcation (BIF), in tertiles of serum estrone concentrations (nmol/liter), Zoetermeer, the Netherlands, 1996. p, significancy of the third toward the first tertile.

 
Serum estrone and testosterone concentrations were significantly positively related (r = 0.28, p < 0.001). We therefore conducted a multiple regression analysis including both estrone and testosterone as the independent variables and IMT of the carotid artery as the dependent variable. The relation with both estrone and testosterone attenuated and became statistically nonsignificant (respectively, ß = –2.31 (SE, 1.39) nmol/mm, p = 0.10 and ß = –0.03 (SE, 0.02) nmol/mm, p = 0.09).

No significant associations were present between serum testosterone, estrone, estradiol, DHEA, or DHEAS concentrations and number of plaques present in the carotid artery.

Atherosclerosis, somatotropic hormones, and insulin and leptin concentrations
Serum total IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, insulin, and leptin concentrations were not significantly related to IMT of the carotid artery. In addition, no relation was found after adjustment for age and body mass index.

Serum free IGF-I was inversely related to mean IMT of the carotid bifurcation after adjustment for age (p = 0.05; table 3, figure 2). However, serum free IGF-I concentrations were not related to body mass index or waist/hip ratio. The distribution of free IGF-I levels did not differ between subjects with or without hypertension, diabetes, or smoking. The relation between serum free IGF-I and IMT was independent of body mass index, waist/hip ratio, presence of hypertension and diabetes, smoking, and serum cholesterol levels.

View larger version (12K): [in this window] [in a new window]   FIGURE 2. Mean intima-media thickness (mm) based on the combined score for the common carotid artery (CCA) and the bifurcation (BIF), in tertiles of serum free insulin-like growth factor I (IGF-I) concentrations (nmol/liter), Zoetermeer, the Netherlands, 1996. p, significancy of the third toward the first tertile.

 
No associations were present between IGF-I (free or total), IGFBP-1, IGFBP-2, IGFBP-3, insulin, and leptin concentrations and number of plaques present in the carotid artery.

IMT, serum hormone levels, and prevalent cardiovascular disease
We hypothesized that the above-described significant relations between serum estrone, testosterone, and free IGF-I concentrations and IMT of the carotid artery are due to cardiovascular disease rather than being the cause of disease. Therefore, we reassessed linear regression between serum hormones and IMT in two groups, namely, with and without prevalent cardiovascular disease. The results of these analyses are shown in table 3. We also performed the same analyses with the two groups using and not using cardiovascular drug therapy. Similar results were found, as described in table 3. In addition, serum testosterone, estrone, and free IGF-I were not differently distributed among subjects with or without cardiovascular disease or cardiovascular drug therapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this study among 403 independently living, elderly men, several associations between circulating hormone levels and ultrasonographic measures of atherosclerosis were observed. Increased wall thickness of the carotid artery was related to lower serum testosterone, estrone, and free IGF-I concentrations in subjects with prevalent cardiovascular disease as well as in subjects free of cardiovascular disease.

Thickening of the intima-media of the carotid artery is generally considered an early marker of generalized atherosclerosis and has been associated with an unfavorable cardiovascular risk profile, other localizations of atherosclerosis (9), and an increased risk of myocardial infarction and stroke (16, 24, 25). The combined carotid artery IMT measurement is more precise compared with only common carotid IMT or carotid bifurcation IMT measurement (24).

Although it is known that testosterone levels influence lipoprotein patterns (3, 26), only a few studies have directly examined the relation between testosterone and markers of atherosclerotic cardiovascular disease. A study by Phillips et al. of 55 men (aged 39–89 years) found an inverse relation between serum testosterone and degree of coronary artery disease (2). We observed that high testosterone concentrations were associated with reduced IMT of the carotid artery. It was not possible to discriminate between cause and effect in this cross-sectional study. Low testosterone levels might lead to an increase in IMT. On the other hand, atherosclerosis could be widespread and have caused a decrease in testicular blood flow and function. Alternatively, blood flow to the pituitary could be impaired, leading to low luteinizing hormone concentrations and a degree of secondary hypogonadism; that is, the hormone changes were the result and not the cause of the findings. In addition, high estrone concentrations were associated with reduced IMT in our population of elderly men. The reason that both estrone and testosterone lost their significant relation with IMT, when adjusted for one another, might be that both hormones have the same precursor, androstenedione, and are therefore linked very strongly. However, the major source of testosterone is direct testicular secretion.

Few studies have examined the relation between estrogens and atherosclerosis in men (27). In women, estrogen replacement therapy is associated with plaque regression in the carotid artery (10) as well as a delay in thickening of the intima layer of the carotid artery (11). In men, estrogens also may offer some degree of protection against cardiovascular disease by influencing the lipid profile (28, 29). We could not demonstrate an association between endogenous serum estradiol concentrations and measures of atherosclerosis. However, estradiol might have a local effect that cannot be shown in relations between serum estradiol and measures of cardiovascular disease, since estradiol derives from the conversion of testosterone and estrone, which were both related to measures of cardiovascular disease. In addition, estradiol might change the insulin sensitivity of peripheral tissues. Finally, larger intra- and intervariability of the measurement of estradiol might be the underlying reason.

DHEAS has been proposed to be cardioprotective in men (5, 6, 30). However, its role in the etiology and prevention of coronary disease has been challenged (31) because results from other studies have not supported the cardioprotective hypothesis (32). In agreement with Baulieu et al. (33), we did not find supporting evidence for the potential cardioprotective role of DHEAS; in our population, DHEAS concentrations were not associated with IMT or number of plaques in the carotid artery.

Recently, data have suggested that the IGF/IGFBP system is related to atherosclerosis in the elderly population (14, 15). Several studies have demonstrated that growth-hormone-deficient adults have increased IMT (34) and a high prevalence of hypertension (35). High levels of fasting serum free IGF-I have been associated with a reduced number of atherosclerotic plaques, symptomatic cardiovascular disease, and lower serum triglyceride levels (15). In the present study, free IGF-I, rather than total IGF-I, was independently related to mean IMT of the carotid bifurcation, suggesting that the easily dissociable IGF-I fraction might be able to act on the vascular wall. In diabetic and nondiabetic populations, higher IGFBP-1 levels have been associated with an advantageous cardiovascular risk profile (15, 36). IGFBP-1 and IGFBP-2 are capable of both inhibition and augmentation of IGF-I bioactivity (37). No significant relations were observed between IGFBP-1 and IGFBP-2 and atherosclerosis in our elderly population.

It is well established that leptin is positively associated with fat mass, insulin resistance, and insulin levels (38). Whether leptin itself, apart from fat mass and insulin levels, is a cardiovascular risk factor is subject to debate (39). Leptin levels in our population were not related to measures of atherosclerosis.

As has already been touched on briefly, an important question is whether the elevated levels of testosterone, estrone, and free IGF-I that were inversely related to carotid intima-media wall thickness are cause or effect. In an attempt to answer this question, we subdivided the cohort according to the presence or absence of prevalent cardiovascular disease. Although power to infer conclusions was limited, we were able to show that the associations between IMT and testosterone, IMT and estrone, and IMT and free IGF-I in subjects free of symptomatic cardiovascular disease were as powerful as those in subjects with prevalent cardiovascular disease. This finding was illustrated by the same direction of the linear regression coefficient as well as by the fact that we found no significant difference between these associations. Similar results were obtained for subjects using and those not using cardiovascular drug therapy. These results suggest that the findings are not due to cardiovascular disease but hint that low hormone levels are indeed a cause of disease. Of course, follow-up studies, and preferably intervention studies, should be performed to confirm these preliminary conclusions.

In summary, testosterone, estrone, and free IGF-I concentrations appear to be linearly inversely related to atherosclerosis, as measured by the IMT of the carotid artery in elderly men. The fact that the associations were as strong in the group free of cardiovascular disease as in the group with prevalent disease suggests that testosterone, estrone, and free IGF-I levels may play a protective role in the development of atherosclerosis in aging men.

	ACKNOWLEDGMENTS

 
The authors thank Hanneke van Meurs for performing all ultrasonographic measurements of the carotid artery. They gratefully acknowledge the contribution of Dickie Mooi-weer-Boogaert and Inge Harmsen to data collection. Andro Medical Research, Rotterdam facilitated the investigation by offering assistance and its study center in the city of Zoetermeer. Finally, the cooperation of the city board and the general practitioners of the city of Zoetermeer is acknowledged.

	NOTES

 
Correspondence to Dr. Annewieke W. van den Beld, Department of Internal Medicine, Room D433, Erasmus University Medical Center Rotterdam, 40 Dr. Molewaterplein, 3015 GD Rotterdam, the Netherlands (e-mail: vandenbeld{at}inw3.azr.nl).

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