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Endogenous Androgens and Carotid Intimal-Medial Thickness in Women

Department of Internal Medicine (G.P.B., M.S., A.M., G.F.A., C.O.B., A.S.) and Department of Experimental Pathology (R.C.), Medical Biotechnology, Infertility and Epidemiology, and Institute of Clinical Physiology C.N.R., University of Pisa, 56100 Pisa, Italy

Address correspondence and requests for reprints to: Dr. Giampaolo Bernini, Dipartimento di Medicina Interna, University of Pisa, Via Roma 67, 56100 Pisa, Italy.

	Abstract

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The influence of endogenous androgens on atherosclerotic disease in women is unknown. In this study involving 101 pre- and postmenopausal females, we evaluated the relationship between serum androgen levels and both carotid artery intimal-medial thickness (IMT) and major cardiovascular risk factors. In addition to evaluation of blood pressure, body mass index, and waist-to-hip ratio, serum dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A), total testosterone (TTS), free testosterone (FTS), insulin, cholesterol (total and high density lipoproteins), triglycerides, and glucose were measured. All women underwent carotid ultrasonography. Spearman correlation coefficients showed that serum DHEA-S and A levels were negatively related (P < 0.03–0.0004) to several IMT measures. Higher tertiles of DHEA-S, A, and FTS corresponded to significantly lower measures of carotid thickness. DHEA-S, and all androgens were inversely related to age (P < 0.03 or less), showing no unfavorable association with major cardiovascular risk factors. In contrast, serum DHEA-S was negatively associated with WHR (P < 0.02), while A was negatively associated with body mass index (P < 0.02). Stepwise multiple regression analysis indicated that A and FTS showed an inverse association with IMT measures (P < 0.05–0.001).

In conclusion, our data indicate that in women serum DHEA-S and androgens decline with age and that normal hormonal levels are not associated with major cardiovascular risk factors. They also show that higher DHEA-S and androgen concentrations are related to lower carotid wall thickness; for A this association is independent of cardiovascular risk factors. Our results suggest that, in the physiological range, DHEA-S and androgens in women are correlated with lower risk of carotid artery atherosclerosis.

	Introduction

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SEVERAL studies show that endogenous estrogens protect against the atherosclerotic process and that estrogen replacement therapy reduces cardiovascular morbidity and mortality in women (1, 2). In contrast, the role of endogenous androgens in healthy women remains unclear.

Androgen receptors have been found on vascular smooth muscle cells and endothelial cells (3). In isolated female rabbit aorta and coronary artery, testosterone (TS) has induced endothelium-independent relaxation (4). Serum total TS (TTS) and androstenedione (A) levels are lower in women with coronary heart disease than in controls (5). In addition, in vitro (6, 7, 8, 9, 10) and animal studies (11, 12) have indicated that dehydroepiandrosterone (DHEA) and its sulfate derivative DHEA-S may hinder the development of cardiovascular disease. Moreover, decreased DHEA-S levels have been found in women with coronary heart disease (5), and an inverse correlation between DHEA-S and cardiovascular mortality (13, 14) has been reported in post-menopausal women. Taken together, these data suggest that normal androgen levels in females do not exert an unfavorable effect on cardiovascular disease.

To our knowledge the relationship between DHEA-S or androgen levels in women and carotid artery thickness, an indicator of atherosclerosis and coronary artery disease (CAD) (15, 16, 17, 18), has never been explored. For this reason we evaluated whether normal serum DHEA-S, free testosterone (FTS), TTS, and A levels are associated with carotid thickness or with major cardiovascular risk factors in women.

	Materials and Methods

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Subjects

Our subjects were obtained through open enrollment of women employed at or visiting our Institution. No inpatients were included. The study design was approved by the local Ethical Committee. Informed consent was obtained for each subject. We excluded women with irregular menses or abnormal hormonal profiles (for age and/or menstrual status), as well as women who were taking hormones or drugs (fibrins, statins, antihypertensives) potentially affecting the thickness of arterial walls. Following these criteria, out of 112 candidates, 101 women were included in the study. Fifty-three were normal menstruating (at least 10 cycles within the previous 12 months), and 48 were in stable (at least 1 yr) menopause. Thirty-three were present or former smokers; 68 had never smoked. Thirty-seven subjects had blood pressure over 140/90 mm Hg, and 21 showed low density lipoprotein-cholesterol (LDL-CHO) of more than 160 mg/dL. Participants discontinued any medications for at least 3 weeks before entering the study. All subjects were asked to maintain their usual diets and levels of physical activity.

Experimental design

On the day of the study, participants presented to our Institution between 0800 and 0900 h after at least a 14-h fast. After a clinical history and physical examination, body mass index (BMI, Kg/m²), waist-to-hip ratio (WHR), and blood pressure were obtained. Blood pressure was measured by mercury sphygmomanometer following the guidelines of the Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (19). Blood samples were obtained for determination of serum DHEA-S, TTS, FTS, A, total cholesterol (T-CHO), HDL-CHO, triglycerides, glucose, and insulin. In menstruating women samples were taken during the follicular phase (within 10 days of menses). Finally, all subjects underwent bilateral carotid ultrasonography.

Imaging of carotid arteries

Carotid ultrasonography was performed by a Biosound 2000 II s.a. (Esaote Biomedica, Indianapolis, IN) high-resolution ultrasound unit equipped with an 8-MHz transducer. All scans were performed by the same operator, trained and certified with regular quality control. Patients were examined in the supine position; each carotid wall and segment was explored to identify the thickest intimal-medial sites. Three segments were identified on each side: the distal 1.0 cm of the common carotid proximal to the bifurcation, the bifurcation itself, and the proximal 1.0 cm of the internal carotid artery. The far and near walls of each segment were examined. Intimal-medial thickness (IMT) was measured using the technique of Pignoli et al. (20). The reader identified and captured frames that demonstrated the maximum IMTs at the near and far wall within each segment. The selected maximum IMTs were calculated in pixels and then converted to millimeters. To quantify carotid artery wall thickness, the following measures were chosen: mean of the maximum wall thickness of 2 sites (far wall of the left and right side) for common carotid (MEAN CC); the maximum of 2 sites (far wall of the left and right side) for common carotid (MAX CC); mean of the maximum of 4 sites (far wall of the left and right side) for common carotid and bifurcation (MEAN CB); mean of the maximum of all 12 sites (4 sites at each of the three segments), or of at least 4 sites for each side (MEAN TOT); the maximum of all 12 sites (4 sites at each of the three segments), or of at least 4 sites for each side (MAX TOT). Because of anatomical variation and neck girth and/or adiposity, it was not always possible to obtain all 12 measurements in each subject.

Assays

T-CHO, HDL-CHO, triglycerides, and glucose were measured immediately after collection. Serum T-CHO and HDL-CHO were evaluated using an enzymatic method (Menarini, Firenze, Italy). LDL-CHO was calculated by the formula [T-CHO - (HDL-CHO + triglycerides/5)]. Glucose was measured by the standard method. Blood for the other samples (DHEA-S, androgens, and insulin) was immediately centrifuged and frozen at -20 C. Hormones were assayed in duplicate and in the same run using specific commercial radioimmunological kits. Intraassay and interassay covariance analyses were as follows: DHEA-S (Radim, Roma, Italy), 6.8% and 8.1%; TTS (Medical System, Genova, Italy), 6% and 7.8%; FTS (Diagnostics Systems Laboratories, Inc., Webster, TX), 5% and 8.3%; A (Sorin, Saluggia, Italy), 7.1% and 10.8%. DHEA-S was assayed rather than DHEA because the former shows no diurnal fluctuation and little intra-individual variation over a period of 6 months (21). The fasting glucose/insulin ratio (G/I as mg/dL-µU/mL)) was used as a measure of insulin resistance (22).

Statistics

Results are shown as average, standard deviation, standard error, and range for all variables. Because IMT measures and hormone levels showed a slightly skewed distribution, analyses were performed using untransformed and log-transformed data, no difference being found. In this paper only untranformed data are shown in tables and figure. Spearman correlation coefficients (r) were used as a measurement of association. Stepwise multiple regression analysis was carried out to test the joint effect of different variables on IMT parameters of carotid arteries. In stepwise regression model, log-transformed IMT measures were the dependent variables; log-transformed hormones and major risk factors for cardiovascular disease were the independent variables. Smoking was included in the model as a variable coded as 1 (for present or past smoking) or 0 (for no smoking history). Menopausal status was entered in the model coded as 1 (for menopause) or 0 (for premenopause). When indicated, covariance analysis and the unpaired t test were also used. P levels less than 0.05 were considered statistically significant.

	Results

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General data, laboratory profiles, and carotid thickness measures for all subjects are reported in Table 1. The broad range of parameters demonstrates the presence of a wide range of subjects, including those with obesity, hypertension, and hypercholesterolemia. In contrast, all subjects showed hormonal values within the normal range for our laboratory.

Analysis of the relationship between hormones and IMT measures for all 101 women (Table 2) revealed that DHEA-S was negatively correlated with MEAN CC (P < 0.01), MAX CC (P < 0.03), and MEAN CB (P < 0.02). Serum A was negatively correlated with all IMT measures (P < 0.03 or less). No association between IMT parameters and TTS or FTS was found. Evaluation of MEAN CC values (mean ± SE) for age-adjusted DHEA-S and A tertiles as well as that of MEAN CB values (mean ± SE) for age-adjusted FTS tertiles showed that higher hormonal tertiles corresponded to significantly lower IMT measures (Figure 1). In postmenopausal women A was negatively correlated with MEAN CC (P < 0.03), MAX CC (P < 0.03), MEAN CB (P < 0.05) and MEAN TOT (P < 0.01), while FTS showed an inverse correlation with MEAN CB (P < 0.03). No such correlations were found in the premenopausal subgroup.

View larger version (16K): [in this window] [in a new window]   Figure 1. MEAN CC values (mean ± SE) for tertiles of DHEA-S (up) and of A (middle), and MEAN CB values (mean ± SE) for tertiles of FTS (down). Higher tertiles of hormones showed significantly lower values of IMT measures. Hormone levels were age-adjusted.

	Discussion

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The present study shows that, in women, serum concentrations of DHEA-S, TTS, FTS, and A are inversely related to age and that this finding is seen also in premenopausal women. Thus our findings confirm recent observations indicating that, with aging, independently of menopause, reduced synthesis of the precursor steroid DHEA-S by adrenals (23) leads to a fall in the formation of androgens in blood circulation and in peripheral target tissues (24).

In males, normal levels of circulating androgens have a beneficial effect on CAD (25), but the situation is less clear in females. Therefore, we used carotid artery thickness, an established gauge of atherosclerosis and CAD (15, 16, 17, 18), to study the relationship between androgen levels in females and carotid atherosclerosis.

Except for age, the present data show that in both pre- and postmenopausal females neither total nor free TS is associated with major cardiovascular risk factors. Furthermore, a significant inverse relationship between carotid IMT and FTS was observed, and this association proved to be independent of the other cardiovascular risk factors, except for age. Our data indirectly support recent evidence that plasma TS is lower in women with CAD than in those with normal coronary anatomy (5). In addition, reduced TTS levels have been shown to be predictors of ischemic heart disease mortality in women (14).

Our study also shows an inverse and independent association between A and several IMT measures of carotid arteries and no unfavorable relationship with cardiovascular risk factors. Such results are consistent with those of Barrett-Connor et al. (26), who reported no positive relation between A and cardiovascular risk factors in postmenopausal women. Our data also agree with findings showing lower A concentrations in women with CAD when compared to women with normal coronary anatomy (5).

Finally, this study enabled us to confirm (27) no adverse impact of DHEA-S on cardiovascular risk factors and also to show a significant inverse, though not independent, relationship between serum DHEA-S and carotid IMT. The effect of DHEA-S suggested by our results may be compatible with decreased DHEA-S levels seen in women with CAD (5). An inverse relationship seems to exist between DHEA-S and cardiovascular mortality in older women (13).

Because androgens (e.g. DHEA-S) begin their progressive decline in the middle of the third decade, independent of menopause (24, 28, 29), the statistical evaluation of our data was performed in the entire group. The analysis allowed us to consider our subjects as points along a continuum of declining androgenicity. However, after the menopause, the hormonal status of the women dramatically changes. The concentration of estrogens abruptly decreases, while the influence of androgens now predominates. For this reason we also analyzed our pre and postmenopausal groups separately. We obtained similar results in menopausal women. The larger range of carotid thickness in this group probably permits the effect of androgens to be seen more clearly. In addition, the androgen impact may be more evident in menopause because it is no longer obscured by the presence of estrogens.

Taken together, our data show that androgens, when present in the normal range in females, exert a positive influence on carotid artery walls. Many in vitro and in vivo data point to a protective effect of androgens on the vasculature. Testosterone induces endothelium-independent relaxation in isolated rabbit coronary artery and aorta of both sexes (4). Dihydrotestosterone inhibits human umbilical vascular smooth muscle cells proliferation and stimulates endothelial replication, showing a role of androgens in vascular protection and remodeling responses to vascular injury (30). DHEA-S increases lipolysis (6), inhibits the growth (7) and differentiation (31) of fibroblasts, blocks human aortic smooth muscle cell proliferation (8) and human platelet aggregation (9), and exhibits a dose-dependent relaxation of rat tail artery (10). In addition, animal studies have shown that DHEA prevents the development of aortic atherosclerosis in cholesterol-fed rabbits (11) and inhibits accelerated coronary atherosclerosis in the heterotopic rabbit model of cardiac transplantation (12). Finally, in women, lipid profile is not altered by DHEA administration (32), and combined estrogen and androgen replacement therapy does not modify lipid concentration in comparison to that observed with estrogen alone (33, 34).

Though this evidence points to the involvement of androgens per se in the cardiovascular protection of normal women, it cannot be ruled out that the apparent benefit results from tissue conversion of androgens to estrogens via the aromatase pathway (35).

In conclusion, our data indicate that serum DHEA-S and androgen levels decline with age and that normal hormonal concentrations have no apparent negative effects on cardiovascular risk factors in women. Moreover, we show that higher DHEA-S, A, and FTS values are associated with lower carotid wall thickness, and that the association of A is independent of the major cardiovascular risk factors. These results seem to suggest that higher, but physiological, androgenicity in women may have a direct role in antagonizing the development of carotid atherosclerosis.

Received November 10, 1998.

Revised February 24, 1999.

Revised April 1, 1999.

Accepted April 1, 1999.

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