Association of Plasma Dehydroepiandrosterone-Sulfate Levels with Endothelial Function in Postmenopausal Women with Coronary Risk Factors

69 Hypertens Res Vol.31 (2008) No.1 p.69-74 Original Article Association of Plasma DehydroepiandrosteroneSulfate Levels with Endothelial Function in Postmenopausal Women with Coronary Risk Factors Masahiro AKISHITA1), Masayoshi HASHIMOTO2), Yumiko OHIKE1), Sumito OGAWA1), Katsuya IIJIMA1), Masato ETO1), and Yasuyoshi OUCHI1) Age-related decline of plasma dehydroepiandrosterone-sulfate (DHEA-S) levels may be associated with the risk of cardiovascular disease in women. We investigated whether plasma DHEA-S levels are related to endothelial function in postmenopausal women with coronary risk factors. One hundred and fifteen postmenopausal women (mean age ± SD: 57 ± 5 years; range: 48–65 years) who underwent measurement of flowmediated vasodilation (FMD) of the brachial artery using ultrasonography were enrolled. Plasma hormone levels were determined in the morning after a 14-h fast, and the relationship between hormone levels and FMD was analyzed. DHEA-S was significantly correlated with %FMD (r = 0.392, p < 0.001), while estradiol, total testosterone and cortisol were not. %FMD in the highest quartile of DHEA-S was 1.8-fold higher than that in the lowest quartile (5.3 ± 1.3 vs. 2.9 ± 2.0 [means ± SD], p < 0.01). Multiple regression analysis revealed that DHEA-S was related to %FMD independent of age, body mass index, hypertension, hyperlipidemia, diabetes mellitus and smoking (β= 0.344, p < 0.01), and was itself independent of age, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and smoking (β= 0.291, p < 0.05). In conclusion, plasma DHEA-S levels were weakly but significantly related to endothelial function in postmenopausal women independent of other coronary risk factors, suggesting a protective effect of DHEA on the endothelium. (Hypertens Res 2008; 31: 69–74) Key Words: endothelium, vasodilation, risk factor, man, nitric oxide Introduction Plasma levels of dehydroepiandrosterone-sulfate (DHEA-S), the most abundant circulating steroid that is secreted from the adrenal cortex, decline with advancing age in men and women (1, 2). The age-related decrease in DHEA-S concentrations has often been associated with the pathological processes of aging, such as osteoporosis, depression and dementia (3, 4). A number of studies have investigated the link between DHEA-S and cardiovascular disease, though with inconsistent results (5–7). Among them, Haffner et al. have shown that low DHEA-S levels predicted ischemic heart disease mortality in diabetic women (8). The association of low DHEA-S levels with carotid artery atherosclerosis (9), obesity (10) and decreased diurnal blood pressure variability (11) also suggests a vasoprotective role of DHEA(-S) in women. Furthermore, experimental studies showing endothe- From the 1)Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and 2)Department of General Internal Medicine, Kobe University School of Medicine, Kobe, Japan. This study was supported by Health and Labour Sciences Research Grants (H17-Choju-046) from the Ministry of Health, Labour and Welfare of Japan, by the Gerontology Small Research Grant Program from the Division of Project Coordination, The University of Tokyo and by grants from the NOVARTIS Foundation for Gerontological Research and the Yamaguchi Endocrine Research Association. Address for Reprints: Masahiro Akishita, M.D., Ph.D., Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7–3– 1 Hongo, Bunkyo-ku, Tokyo 113–8655, Japan. E-mail: Received March 14, 2007; Accepted in revised form August 5, 2007. 70 Hypertens Res Vol. 31, No. 1 (2008) Table 1. Characteristics of Study Subjects (n = 115) Age, years 57 ± 5 Body mass index, kg/m2 23.3 ± 4.0 Risk factors Hypertension, n (%) 35 (30) Hyperlipidemia, n (%) 71 (62) Diabetes mellitus, n (%) 20 (17) Current smoker, n (%) 17 (15) Hemodynamic and vascular measurements Systolic blood pressure, mmHg 123 ± 17 Diastolic blood pressure, mmHg 70 ± 10 %FMD 4.8 ± 2.4 %NTG 14.0 ± 4.5 Carotid IMT, mm 0.92 ± 0.22 Blood chemistry and hormones Total cholesterol, mmol/L 5.72 ± 1.01 HDL cholesterol, mmol/L 1.66 ± 0.42 Triglycerides, mmol/L 1.18 ± 0.65 Fasting plasma glucose, mmol/L 5.42 ± 1.22 Hemoglobin A1c, % 5.5 ± 1.0 Estradiol, pmol/L 35 ± 26 Testosterone, nmol/L 0.85 ± 0.43 DHEA-S, μmol/L 2.28 ± 1.07 Cortisol, nmol/L 316 ± 121 [48–65] [17.6–35.0] [93–170] [52–100] [0.0–12.7] [4.1–22.5] [0.46–1.45] [3.73–8.96] [0.77–2.87] [0.36–3.49] [4.00–10.43] [4.3–9.6] [18–160] [0.21–2.01] [0.37–5.02] [110–728] Values except risk factors are expressed as mean ± SD [range]. %FMD, percent flow-mediated dilation of brachial artery; %NTG, percent nitroglycerin-induced dilation of brachial artery; IMT, intima-media thickness of common carotid artery; HDL, high-density lipoprotein; DHEA-S, dehydroepiandrosterone-sulfate. lium-dependent (12) and -independent (13) vasodilating effects of DHEA(-S) led us to hypothesize that postmenopausal women with low plasma DHEA-S levels would have impaired vasomotor function. To test this hypothesis, we conducted a cross-sectional survey of 115 postmenopausal women by examining flow-mediated dilation (FMD) of the brachial artery and plasma sex hormones, and showed that low DHEA-S levels were associated with endothelial dysfunction. Methods Subjects One hundred and fifteen postmenopausal women who underwent examination of vasomotor function of the brachial artery and intima-media thickness (IMT) of the carotid artery in our department were enrolled. The subjects were referred to our department to check their cardiovascular disease or risks. All of them were in chronic stable condition. A history was taken, and physical examination and laboratory tests were performed in all subjects. Subjects with a history of cardiovascu- lar disease, including stroke, coronary heart disease, congestive heart failure and peripheral arterial disease, malignancy, overt endocrine disease or administration of steroid hormones, were excluded. The postmenopausal status of each subject was confirmed by the fact that at least 12 months had passed since her last menses and by the measurement of follicular stimulating hormone and estradiol. The characteristics of the study subjects are shown in Table 1. Seventy-three percent of the subjects had one or more classical coronary risk factors, such as hypertension, hyperlipidemia, diabetes mellitus or current smoking. Hypertension, hyperlipidemia and diabetes mellitus were considered to be present based on the published diagnostic criteria (14–16) or if the subjects were taking any medications for these diseases. Eighty-six percent of the hypertensive subjects were treated: 75% with calcium antagonists, 19% with angiotensin-converting enzyme inhibitors, 10% with diuretics and 7% with β blockers. Eighty-six percent of the hyperlipidemic subjects were treated with statins, an (...truncated)