Low testosterone level is an independent determinant of endothelial dysfunction in men.

We investigated whether a low plasma testosterone level is related to endothelial dysfunction in men with coronary risk factors. One hundred and eighty-seven consecutive male outpatients (mean age+/-SD: 47+/-15 years) who underwent measurement of flow-mediated vasodilation (FMD) of the brachial artery using ultrasonography were enrolled. The relationship between plasma hormones and FMD was analyzed. Total and free testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were significantly correlated with %FMD (r=0.261, 0.354 and 0.295, respectively; p<0.001), while estradiol and cortisol were not. %FMD in the highest quartile of free testosterone was 1.7-fold higher than that in the lowest quartile. Multiple regression analysis revealed that total and free testosterone were related to %FMD independent of age, body mass index, hypertension, hyperlipidemia, diabetes mellitus and smoking (beta=0.198 and 0.247, respectively; p<0.01), and were independent of age, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, fasting plasma glucose, smoking and nitroglycerin-induced dilation (beta=0.196 and 0.227, respectively; p<0.01). DHEA-S was not significantly related to %FMD in multivariate analysis. In conclusion, a low plasma testosterone level was associated with endothelial dysfunction in men independent of other risk factors, suggesting a protective effect of endogenous testosterone on the endothelium.     

Plasma lipids and osteoporosis in postmenopausal women

Many clinical studies have shown that osteoporosis is associated with atherosclerosis and cardiovascular death. Although both high plasma levels of low density lipoprotein cholesterol (LDL-C) and low plasma levels of high density lipoprotein cholesterol (HDL-C) are known to be risk factors for atherosclerosis, it is unclear whether such lipid derangements are also associated with the pathogenesis of osteoporosis. In this study, we evaluated the relationships between plasma levels of total C, LDL-C, HDL-C, or triglyceride (TG) versus bone mineral density (BMD) at the lumbar spine, femoral neck, radius, or total body as well as the presence of vertebral fractures in 214 Japanese postmenopausal women (age range, 47-86 years, mean 62.7). Multiple regression analysis was performed between BMD at each skeletal site versus each lipid level adjusted for age, years after menopause, body mass index (BMI), and %fat. Plasma LDL-C levels were significantly and inversely correlated with the absolute values of both one-third radial (1/3R) and distal radial (UDR) BMD (p<0.01), and tended to be inversely correlated with the absolute values of L-BMD (p=0.051). In contrast, plasma HDL-C levels were significantly and positively correlated with the absolute values of L, 1/3R and UDR BMD (p<0.05). On the other hand, plasma TG levels were significantly lower in women with vertebral fractures than in those without fractures (97.0+/-36.5 vs. 126.4+/-65.8 mg/dl, mean+/-SD, p<0.05). When multivariate logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and each lipid level adjusted for age, years after menopause, BMI, and %fat as independent variables, TG alone was selected as an index affecting the presence of vertebral fractures (odds ratio: 0.51, 95% confidential interval: 0.29-0.89 per SD increase, p<0.05). Our study showed that plasma LDL-C and HDL-C levels were inversely and positively correlated with both R- and L-BMD values, respectively, while low plasma TG levels were associated with the presence of vertebral fractures in postmenopausal women. Thus, plasma lipids might be related to bone mass and bone fragility, and might be the common factor underlying both osteoporosis and atherosclerosis.     

Flow-mediated dilation and gender in patients with coronary artery disease: arterial size influences gender differences in flow-mediated dilation

BACKGROUND: The risk of atherosclerosis and its complications differs between male and female subjects. This is probably associated with gender differences in endothelial function as reflected by endothelium-dependent vasodilation. The aim of the study was to compare flow-mediated dilatation (FMD) in males and females with coronary artery disease (CAD), and to determine factors that might potentially influence FMD. METHODS: Ninety-six patients with stable CAD (CCS II-III): 76 males (mean age: 57.7 +/- 10 years) and 20 postmenopausal females (mean age: 60.1 +/- 10 years) were included into the study. Clinical data, pharmacotherapy, concomitant diseases, and FMD were all assessed. FMD was measured with high-resolution ultrasound as the percent change of brachial artery diameter (BAd) after a 3-minute occlusion (%FMD), and following the administration of 0.4 mg sublingual nitroglycerin (%NTG-MD). RESULTS: The percentage of FMD was significantly decreased (P < 0.05), and BAd was significantly larger (P < 0.001) in males as compared to females. Clinical data, pharmacotherapy, and concomitant diseases were comparable in the study groups.In all subjects examined, %FMD was related to BAd (r =-0.415, P < 0.001) and the percentage of ejection fraction (EF%) (r = 0.325, P < 0.01) in the univariate analysis, and to BAd only (r =-0.343, P < 0.01) in the multivariate analysis. The percentage of nitroglycerine-mediated vasodilatation (NTG-MD) correlated negatively with BAd (r =-0.430, P < 0.001), and positively with EF% (r = 0.334, P < 0.01) in the univariate analysis, and with BAd (r =-0.288, P < 0.05) in the multivariate analysis. Index %FMD x BAd was comparable for male and female subjects. CONCLUSIONS: Males and postmenopausal females with CAD show differences in endothelium-dependent vasodilatation that seem to secondarily result from differences in the BAd. Objective comparison of %FMD is only possible between patients with the same brachial artery size.     

Amelioration of vascular endothelial dysfunction in obstructive sleep apnea syndrome by nasal continuous positive airway pressure--possible involvement of nitric oxide and asymmetric NG, NG-dimethylarginine.

BACKGROUND: Asymmetric NG,NG-dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase and its plasma concentration is elevated in patients with cardiovascular risk factors, including hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia. Obstructive sleep apnea syndrome (OSAS) has been attracting attention as a risk factor for cardiovascular disorders because it often accompanies hypertension, obesity, glucose impairment, and dyslipidemia, all of which are factors in metabolic syndrome and risk factors for cardiovascular disease. METHODS AND RESULTS: In the present study, flow-mediated vasodilatation (FMD) of the brachial artery and plasma concentrations of ADMA were measured before and after nasal continuous positive airway pressure (nCPAP) therapy, which abrogates apnea, in 10 male patients aged 36-69 years old, who were given a diagnosis of OSAS by polysomnography. The percent FMD (%FMD) improved significantly from 3.3+/-0.3% to 5.8+/-0.4% (p<0.01) and 6.6+/-0.3% (p<0.01), before, 1 week, and 4 weeks after nCPAP, respectively. At the same time, the plasma NOx concentrations, metabolites of NO, tended to increase, but the plasma ADMA concentration decreased inversely to %FMD and NOx. A negative correlation between %FMD and plasma ADMA concentration, and a positive correlation between %FMD and plasma NOx concentrations were observed. CONCLUSION: Nasal CPAP improves endothelial function, in part by the decreasing ADMA concentration, thereby potentiating NO production.     

Transdermal 17 beta-estradiol combined with oral progestogen increases plasma levels of insulin-like growth factor-I in postmenopausal women.

In order to evaluate the effect of postmenopausal estrogen replacement therapy on the plasma levels of the insulin-like growth factor-I (IGF-I) 12 postmenopausal women aged 44 to 59 years were studied. The control group consisted of 15 healthy premenopausal women aged 20-44 years. In the postmenopausal women the plasma levels of IGF-I, gonadotrophins and sex hormones were determined before and after 3 and 6 months cyclic replacement therapy with transdermal 17 beta-estradiol (E2 100 micrograms patches applied twice weekly) combined with oral chlormadinone acetate (2 mg daily for 7 days in each cycle). Basal levels of estradiol (E2), IGF-I, dehydroepiandrosterone sulphate (DHEA-S), testosterone and androstenedione were lower, but gonadotropin levels were higher in postmenopausal than in premenopausal women. In all the women studied age was inversely correlated with IGF-I levels (r = -0.793, p less than 0.001) and with DHEA-S concentrations (r = -0.435, p less than 0.02). In postmenopausal women transdermal estradiol administration restored the circulating E2 levels to the early follicular range and increased the IGF-I levels (from 76.4 +/- 9.2 micrograms/l to 141.8 +/- 20.8 micrograms/l; p less than 0.01). Transdermal estradiol decreased gonadotrophin levels without changes in concentration of DHEA-S, testosterone, androstenedione and SHBG. In postmenopausal women before and during replacement therapy a positive correlation was found between estradiol and IGF-I concentrations (r = -0.439, p less than 0.01). These results suggest that cyclic replacement therapy with transdermal 17 beta-estradiol in combination with chlormadinone acetate given orally increase the plasma levels of IGF-I in postmenopausal women.     

Serum DHEA-S level is associated with the presence of atherosclerosis in postmenopausal women with type 2 diabetes mellitus

We investigated the relationship between serum dehydroepiandrosterone-sulfate (DHEA-S) and insulin-like growth factor-I (IGF-I) to various parameters for atherosclerosis in type 2 diabetes. The levels of DHEA-S and IGF-I are known to decrease with aging and thereby might be associated with an increased risk of cardiovascular disease. One hundred forty-eight men and 106 postmenopausal women with type 2 diabetes were assessed in a cross-sectional study. Serum DHEA-S and IGF-I concentrations were measured and brachial-ankle pulse wave velocity (baPWV) and ultrasonographically-evaluated intima-media thickness (IMT) were assessed. Although simple regression analysis showed that log(DHEA-S) and IGF-I in men and log(DHEA-S) in women were significantly and inversely correlated with baPWV and IMT, only log(DHEA-S) in women was still significantly and inversely correlated with these atherosclerotic parameters after multiple regression analysis was adjusted for age, duration of diabetes, BMI, HbA(1C), systolic blood pressure, LDL-Cholesterol (C), serum creatinine, and smoking (Brinkman index). Serum DHEA-S level seemed to be associated with atherosclerosis in diabetic postmenopausal women independent of age, body stature, diabetic status, and other atherosclerotic risk factors, and might be a useful addition to other parameters for assessing the risk of atherosclerosis in this population.     

Association of depressive symptoms with coagulation factors in young healthy individuals

BACKGROUND: Depression has been reported to be an independent risk factor for coronary heart disease (CHD). We investigated the association of depressive symptoms with lipids and coagulation factors in young individuals free of CHD. METHODS: We recruited 1073 young healthy individuals candidates for military academies (mean age=18.4+/-0.8 years, males 762) in whom the presence of depressive symptoms was assessed by using the depression scale of Minnesota Multiphasic Personality Inventory test. Total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein (a), fibrinogen, factors VII, VIII and X were measured. RESULTS: The depression score ranged from 22 to 90. The participants were divided into quartiles according to the depression score. Three hundred twenty-two subjects were classified in the upper quartile (score>48) and 269 in the lower quartile (score<37) of the depression score. Factor VII (102.95+/-24 versus 98.5+/-20%) and X levels (92+/-11 versus 89.7+/-10%) were significantly higher in individuals in the upper quartile compared to the lower quartile of the depression score. In a logistic regression model with factor VII as dependent variable (upper versus lower quartile) and depression score, age, gender, body mass index, exercise and smoking as predictor variables, depression was an independent predictor of factor VII levels with an adjusted odds ratio for high levels of factor VII of 1.05 (95% confidence interval 1.008-1.09, p=0.01). Factor VII levels were associated with triglycerides (r=0.21, p=0.001) while factor X with triglycerides (r=0.22, p<0.001) and cholesterol levels (r=0.12, p<0.001). CONCLUSIONS: Depressed mood is associated with a hypercoagulant profile as it is expressed by the higher levels of coagulation factors VII and X. This might partially explain the higher propensity for CHD of people with depressive symptoms.     

Lipoprotein (a) is associated with endothelial function in healthy postmenopausal women

BACKGROUND: Lipoprotein (a) (Lp(a)) is an independent risk factor for atherosclerotic cardiovascular disease. The atherogenic potential of Lp(a) may be by impairment of endothelial function. Objectives. We investigated the relation of Lp(a) plasma levels to endothelium dependent and independent dilatation of the brachial artery in healthy postmenopausal women. METHODS: One hundred and five healthy postmenopausal women aged 52-67 years were included in the study. Endothelial function was assessed non-invasively by measuring percent lumen diameter change in the brachial artery after reactive hyperemia and sublingual nitroglycerine spray. RESULTS: Flow mediated dilatation was inversely related to the plasma logLp(a) level. Mean change per unit logLp(a) increase:-2.83% (95% CI: -5.22--0.43). Elevated Lp(a) (>239 mg/l) (upper quartile) was associated with an impaired flow mediated vasodilatation (2.4%+/-1. 2) compared to Lp(a) < or =239 mg/l (5.2%+/-0.7). Adjustment for other cardiovascular risk factors did not change the magnitude of the association. Nitroglycerine-induced vasodilatation was not significantly lower in the high Lp(a) level group, compared to the group with normal levels of Lp(a) (< or =239 mg/l) (8.0+/-1.2 vs. 11.4%+/-0.8). CONCLUSION: Elevated lipoprotein (a) levels are associated with an impaired endothelial function in healthy postmenopausal women, independent of conventional risk factors for cardiovascular disease. Since Lp(a) may be pathogenetically important for early vascular damage, elevated Lp(a) levels might contribute to the increased cardiovascular risk seen in postmenopausal women.     

DHEA-S levels in hypopituitaric patients with severe GH deficiency are strongly reduced across lifespan. Comparison with IGF-I levels before and during rhGH replacement

Both IGF-I and DHEA-S undergo an age-related decrease and their decrease could be involved in age-related changes in body composition, structure functions and metabolism. On the other hand, it is well known that mean IGF-I levels are clearly reduced in hypopituitaric patients with GH deficiency (GHD) while data about dehydroepiandrosterone sulfate (DHEA-S) levels in hypopituitarism are scanty. We evaluated DHEA-S and IGF-I levels and their relationship in 90 patients with panhypopituitarism (HYPOPIT) with severe GHD [49 women and 41 men; age, mean+/-SE: 47.9+/-1.49 yr, range: 20-80 yr, BMI: 26.4+/-0.6 kg/m2; 21 with childhood-onset (CO) and 69 with adult-onset (AO) HYPOPIT]. DHEA-S and IGF-I levels were also evaluated in 24 HYPOPIT with GHD after 3-month recombinant human GH (rhGH) replacement. Data in HYPOPIT were compared with those in a large group of healthy controls (NS, 233 women and 103 men, aged 20-80 yr; all subjects were within +/-15% of their ideal body weight). In NS both DHEA-S levels and IGF-I were gender-independent while showed a strong, inverse correlation with age (r=-0.6; p<0.001 and r=-0.56; p<0.0001, respectively). Nevertheless, no relationship was found between DHEA-S and IGF-I levels in NS. In HYPOPIT, age-adjusted mean DHEA-S and IGF-I levels were clearly lower than those in NS (2.3+/-0.4 vs 16.0+/-0.7 microg/l, p<0.005; 71.1 +/- 4.5 vs 170+/-4.7 microg/l, p<0.005). IGF-I levels in CO-HYPOPIT were lower (p<0.01) than those in AO-HYPOPIT (49.6+/-4.8 vs 77.0+/-5.4 microg/l), while DHEA-S levels were similar in both subgroups (2.6+/-0.7 vs 2.3+/-0.4 microg/l). In HYPOPIT both DHEA-S and IGF-I were independent of age and gender while there was a trend toward a positive association between each other (r=0.45; p<0.003). Analyzing individual levels in HYPOPIT with respect to age-adjusted normal ranges, IGF-I levels were below normal in 84, 62 and 0% between 20-40, 40-60 and 60-80 yr, respectively. On the other hand, DHEA-S levels were below normal in 84, 86 and 67% between 20-40, 40-60 and 60-80, respectively. In HYPOPIT rhGH treatment strikingly increased IGF-I levels (150+/-3.2 vs 85.3+/-4.1 microg/l, p<0.005) while did not modify DHEA-S levels (1.7+/-0.2 vs 1.6+/-0.2 microg/l). In conclusion, our results demonstrate that DHEA-S and IGF-I are negatively and independently associated to age in physiological conditions but not in hypopituitaric patients in whom both are strikingly reduced. Both DHEA-S and IGF-I levels in HYPOPIT show some overlap with those in normal subjects; thus the assay of these parameters is not diagnostic for hypopituitarism. DHEA-S reduction in HYPOPIT does not depend on IGF-I as indicated also by evidence that GH replacement restores IGF-I but does not modify DHEA-S levels.     

Smoking is associated with dose-related increase of intima-media thickness and endothelial dysfunction

Cigarette smoking is firmly established as a risk factor for atherosclerosis. However, the exact mechanism causing smoking-related damage to the arterial wall and its relation to the atherosclerotic process is not known. Also unknown is the time delay between the start of smoking and the sequence of functional and morphologic changes occurring in the arterial wall caused by smoking and their interrelationship. Therefore, the aim of this study was to evaluate the acute and chronic effects of smoking on endothelium-dependent (flow-mediated) dilation (FMD) of the peripheral arteries, the effects of dose and duration of chronic smoking on intima-media thickness (IMT) of the carotid arteries, and their interrelationship. The study encompassed two groups of smokers. In group A there were 40 subjects of both sexes, who smoked on average 17.6 +/- 6.5 cigarettes per day, for 5 to 15 years (mean 8.95 +/- 4.0 years), mean age 28.1 years. Group B consisted of 42 smokers of both sexes who smoked 21.15 +/- 8.2 cigarettes/day for more than 15 years (mean 21.15 +/- 3.4 years), mean age 39.5 years. The control group consisted of 40 healthy subjects without major risk factors of atherosclerosis, mean age 29.1 years. By means of high-resolution ultrasound the brachial artery diameter was measured at rest and during reactive hyperemia (after release of a forearm tourniquet) and the flow-mediated, endothelium-dependent dilation was calculated. The IMT of the carotid arteries was determined in all subjects by use of B-mode ultrasonography. Resting blood flow in the brachial arteries was significantly less in the smokers' groups than in controls (78.8 +/- 31.9 vs 134.9 +/- 45.0 mL/min, p<0.0001). This decrease was much more evident in female than in male smokers. Female smokers also had significantly smaller brachial artery diameter at rest. In smokers the FMD of the brachial artery was reduced (11 +/- 4% vs 7 +/- 4%, p<0.004) and the mean IMT was significantly greater than in controls (0.68 +/- 0.13 vs 0.59 +/- 0.04 mm, p<0.001). Impairments of FMD and IMT increase were related to the duration and to the number of cigarettes smoked. In all subjects IMT was significantly correlated with total and LDL cholesterol, fibrinogen, lipoprotein(a) concentration, body mass index, and age of the subjects, but multivariate analysis showed that only total dose smoked and fibrinogen concentration were independently related to IMT. The results of this study show that smoking is associated with dose-related impairment of FMD and increased IMT of the carotid arteries. Impairment of FMD occurs in smokers very early and is the earliest detectable event, preceding morphologic changes of the vessel wall. Some harmful effects of smoking on the vessel wall are gender related.     

Sex steroids and plasma lipoprotein levels in healthy women: The importance of androgens in the estrogen-deficient state

The role of endogenous estrogens and androgens and their potential interaction in atherosclerosis is not well understood. Therefore, we investigated the effects of natural menopause and endogenous sex steroids on triglycerides (TG), a major risk factor for cardiovascular disease in women. Fasting lipid and lipoprotein concentrations, postheparin lipase activities, kinetic indicators of triglyceride lipolysis, and various hormone levels, including dehydroepiandrostenedione-sulfate (DHEA-S), (bioavailable) testosterone, and androstenedione, were determined in 18 premenopausal and 18 postmenopausal women, matched for age and body composition. Fasting plasma TG were 0.69 +/- 0.29 mmol/L in postmenopausal women and 0.73 +/- 0.33 mmol/L in premenopausal women (difference not significant [NS]). Approximately 30% of all plasma TG were present in the very-low-density lipoproteins (VLDLs) in both groups. No differences were found between groups in plasma lipolytic potential of TG-rich lipoproteins. Univariate analysis revealed that VLDL-TG concentrations were strongly related to insulin (r = 0.84, P =.0001) and androstenedione (r = 0.65, P =.004) in postmenopausal women. Multivariate analysis of potential determinants of VLDL-TG showed that insulin, androstenedione, and bioavailable testosterone were independent variables, explaining 87% of the variability (r = 0.93, P =.0001) in postmenopausal women. In contrast, in premenopausal women, the only identified predictor of fasting VLDL-TG in univariate and multivariate analysis was insulin (r = 0.72, P =.001). Our results show that the association of androgens with TG varied depending on androgen concentrations, the relative androgenic potential, and most importantly on hormonal milieu. Endogenous androgens were only related to plasma VLDL-TG in the estrogen-deficient state.     

Menopause is associated with reduced protection from postprandial lipemia

Deficiency of endogenous estrogens has been associated with a higher incidence of coronary heart disease (CHD) in women. We investigated whether natural menopause is associated with reduced protection from postprandial lipemia, which represents a risk indicator of CHD. Twenty-three postmenopausal women (mean age, 50+/-1 [SD] years; body mass index, 24.6+/-2.8 kg/m(2)) and 21 premenopausal women matched for age and body mass index (age, 49+/-1 years; body mass index, 24. 1+/-2.6 kg/m(2)) underwent an oral vitamin A fat-loading test. Vitamin A is a marker of the metabolism of chylomicrons and chylomicron remnants. All women were normolipidemic, were in good health, were nonsmokers, and used no medication. Postprandial lipids and vitamin A were measured at hourly intervals up to 12 hours. In postmenopausal women, plasma total cholesterol and LDL cholesterol concentrations were significantly higher. Fasting plasma triglyceride (TG) concentrations were 1.14+/-0.57 mmol/L in postmenopausal women and 0.88+/-0.33 mmol/L in premenopausal women (P=NS). In the postprandial phase, postmenopausal women had higher plasma TG (13.0+/-6.1 versus 9.5+/-3.3 mmol x L(-1) x h(-1); P=0.024) and vitamin A (54.1+/-22.9 versus 35.9+/-9.6 mg x L(-1) x h(-1); P=0. 001) responses. To correct for the possible confounding effect of fasting TG, 13 postmenopausal women were carefully matched with 19 premenopausal women. Although fasting TG levels were identical (0. 72+/-0.20 versus 0.73+/-0.21 mmol/L), differences in postprandial vitamin A (45.3+/-14.5 versus 33.0+/-7.7 mg x L(-1) x h(-1); P=0.006) and incremental TG (ie, after subtraction of baseline TG) (3.2+/-1.8 versus 2.3+/-1.0 mmol x L(-1) x h(-1); P=0.023) persisted between postmenopausal and premenopausal women. Natural menopause is associated with aggravated postprandial lipemia in women matched for age and body mass index. Higher postprandial lipemia potentially explains the relation of TGs and CHD mortality risk in postmenopausal women.     

Endogenous sex hormones and risk factors for atherosclerosis in healthy Greek postmenopausal women

OBJECTIVE: To assess the association between endogenous sex hormones and risk factors for atherosclerosis in healthy postmenopausal women. DESIGN: Cross-sectional study in a university menopause clinic. METHODS: Serum sex hormones and lipid-lipoprotein profile, arterial pressure, homocysteine and insulin resistance, measured by the homeostasis model assessment of insulin resistance (HOMA-IR), were assessed in 598 healthy postmenopausal women not on hormone therapy. RESULTS: Compared with women in the lowest testosterone quartile (Q), women in the highest testosterone quartile had higher total cholesterol (Q1: 225.2 +/- 41.3 vs Q4: 246.2 +/- 38.4 mg/dl, P < 0.01), low-density lipoprotein (LDL)-cholesterol (Q1: 146.9 +/- 37.2 vs Q4: 171.8 +/- 35.3 mg/dl, P < 0.001), atherogenic index of plasma (AIP) (Q1: -0.224 +/- 0.238 vs Q4: -0.087 +/- 0.254, P < 0.01), apolipoprotein B (ApoB) (Q1: 100.7 +/- 23.1 vs Q4: 113.9 +/- 23.8 mg/dl, P < 0.001) and higher high-density lipoprotein (HDL)-cholesterol (Q1: 60.7 +/- 14.5 vs Q4: 52.9 +/- 13.0 mg/dl, P < 0.01). Accordingly, women in the highest free androgen index (FAI) quartile had higher AIP (Q1: -0.232 +/- 0.254 vs Q4: -0.078 +/- 0.243, P < 0.001) and ApoB (Q1: 102.4 +/- 25.5 vs Q4: 114.2 +/- 25.8 mg/dl, P < 0.01) and lower HDL-cholesterol (Q1: 62.0 +/- 15.7 vs Q4: 51.9 +/- 11.6 mg/dl, P < 0.001) and apolipoprotein A (Q1: 159.6 +/- 25.6 vs Q4: 147.9 +/- 24.1 mg/dl, P < 0.01) compared with women in the lowest FAI quartile. These differences remained significant after adjustment for age, body mass index (BMI), insulin resistance and social habits. The free estrogen index (FEI) exhibited similar associations to the FAI. HOMA-IR showed an independent positive association with total testosterone (Q1: 2.00 +/- 1.36 vs Q4: 2.66 +/- 1.60, P < 0.01), FAI (Q1: 1.70 +/- 1.12 vs Q4: 3.04 +/- 1.66, P < 0.001) and FEI (Q1: 1.70 +/- 0.91 vs Q4: 3.08 +/- 1.77, P < 0.001). CONCLUSIONS: Increased androgenicity in healthy postmenopausal women is associated with an unfavorable cardiovascular risk profile. High endogenous estradiol is related to a pro-atherogenic lipid profile, an association which may, in part, be mediated by insulin resistance.     

Gender difference in age-related changes in vascular function

PURPOSE: We investigated whether, in a randomly selected population of 55-year-old men and women, there is a relationship between vascular function measured as flow-mediated (endothelium-dependent) and nitroglycerine-mediated (nonendothelium-dependent) dilatation of the brachial artery and conventional risk factors for cardiovascular disease such as gender, smoking, elevated blood-lipids and high blood pressure. The results are compared with those in a young healthy population of 35-year-olds. SUBJECTS: A total of 57 men (73% of the invited males) living in the community and 47 women (62% of the invited females) participated and were compared with a previously studied 35-year-old population (52 men and 56 women). METHODS: Basal brachial artery diameter was measured by high-frequency ultrasound methods. Endothelial function was measured as flow-mediated dilatation (FMD) in response to reactive hyperaemia. The nonendothelium-dependent vasodilatation was measured after administering sublingual nitroglycerine (NTG). RESULTS: Flow-mediated endothelium-dependent dilatation was similar in men and women being 3.1 +/- 2.5% (mean +/- SD) in men vs. 2.6 +/- 2.3% in women. FMD of the brachial artery was negatively correlated with vessel size in both men and women (P < 0.001). Men had larger brachial artery diameter than women (4.6 +/- 0.7 vs. 3.6 +/- 0.4 mm, P < 0.001). There was no difference in FMD or in NTG-induced dilatation in the women receiving oral oestrogen replacement therapy compared with those that did not. The women taking oral oestrogen had lower cholesterol than those not taking oral oestrogen (P=0.04). FMD was not correlated with any of the risk factors. NTG-induced vasodilatation was correlated with the body mass index (BMI) in men (P=0.01) and a combined risk factor score in women (P=0.04). There was a large increase in the number of subjects with cardiovascular risk factors in the 55-year-old men and women compared with the 35-year-olds. The distribution of risk factors was fairly equal amongst men and women. CONCLUSION: There are no correlations between any of the conventional cardiovascular risk factors and FMD in a population of 55-year-olds, but there is a high prevalence of risk factors in the 55-year-old age group. NTG-induced vasodilatation correlated with the BMI in men and a combined risk-factor score in women. FMD-induced vasodilatation is smaller in women at 55 years of age than at 35 years of age. FMD was similar in men at 35 and 55 years of age and in men and women at 55 years of age. The smaller FMD in women at 55 years of age, compared with at 35, could be due to postmenopausal hormonal changes.     

Relationships between dehydroepiandrosterone-sulphate and anthropometric, metabolic and hormonal variables in a large cohort of obese women

OBJECTIVE: The aim of the present study was to measure dehydroepiandrosterone-sulphate (DHEA-S) levels in obesity and assess the relationships between DHEA-S and anthropometric, metabolic and hormonal variables. SUBJECTS AND METHODS: We evaluated the serum DHEA-S levels in 217 obese but otherwise normal female subjects (age (mean +/- SEM): 39.4 +/- 0.9, range 18-67 years, body mass index (BMI) = 36.1 +/- 0.4, range 27.1-57.1 kg/m2). RESULTS: DHEA-S levels showed an age-dependent fall similar to that observed in normal women (n = 156, age 46.2 +/- 1.2, range 22-69 years, BMI < 25 kg/m2). Adjusting for age, obese women had mean DHEA-S levels higher than the control group (P < 0.02). In obese patients, DHEA-S levels were directly associated with serum testosterone, androstendione, IGF-I, fT3 levels and 24 h-urinary cortisol. On the other hand, DHEA-S levels were negatively associated with age, total cholesterol, triglycerides levels and systolic blood pressure. No correlation was found with BMI, waist:hip ratio, basal and post-OGTT insulin and glucose, free fatty acids, GH, PRL, fT4, TSH, SHBG levels or diastolic blood pressure. Multiple regression analysis indicated that in obese women, DHEA-S levels were associated negatively to age and positively to testosterone, androstendione and IGF-I levels and daily urinary cortisol. In a subgroup of 20 obese women, DHEA-S levels significantly (P < 0.001) fell after OGTT without any correlation with the insulin response. CONCLUSIONS: The present results show that dehydroepiandrosterone-sulphate levels are not reduced in obesity, being slightly increased, particularly in young adulthood. Dehydroepiandrosterone-sulphate levels are positively and independently associated with androgen, 24-h urinary cortisol and IGF-I levels but do not seem associated with insulin levels or cardiovascular risk indices.     

Endogenous androgens and carotid intimal-medial thickness in women.

The influence of endogenous androgens on atherosclerotic disease in women is unknown. In this study involving 101 pre- and post-menopausal 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.     

Weight and length at birth and their relationship to diabetes incidence and all-cause mortality--a 32-year follow-up of the population study of women in Gothenburg, Sweden

OBJECTIVE: The purpose of the study was to explore the relationship of weight and length at birth to diabetes in adult life and to all-cause mortality. Special attention was taken to potential confounding factors as age, family history, education, socio-economic group, physical inactivity, smoking, blood pressure, serum lipids and obesity. RESEARCH DESIGN AND METHODS: A longitudinal population study consisting of a representative sample of 1381 women aged 38-54 started in Gothenburg, Sweden, in 1968-1969 monitoring for diabetes mellitus and overall mortality over 32 years. Original delivery records were retrieved for 61.2% of the women. Death certificates were obtained for 99.3% the women who died during the 32-year follow-up period. RESULTS: We observed an inverse statistically significant relationship between birth weight and 32-year diabetes incidence independent of age, the highest incidence 16.3% in the lowest quartile of birth weight compared to 9.2% in the highest quartile. The relationship remained when controlling for the following covariates: education, socio-economic group, physical activity, smoking, systolic blood pressure, adult body mass index (BMI), waist-hip ratio, serum triglycerides and cholesterol. When overweight women (BMI> or =25) were excluded from the statistical analyses birth weight was even stronger related to the incidence of diabetes, 12.8% in lowest quartile and 5.7% in the highest quartile of birth weight independent of birth length, education, socio-economic group, physical activity, smoking, systolic blood pressure, body mass index, waist-hip ratio, blood glucose, serum triglycerides and cholesterol. Length at birth was a predictor for diabetes independent of age plus adult body mass index (BMI) and smoking but not independent of age only. No significant associations were observed between birth factors as birth weight and birth length and overall mortality during the 32-year of follow-up. CONCLUSIONS: A low birth weight seems to be a risk factor for diabetes in adult women independent of age and most of the established risk factors for diabetes.     

Improvement of endothelial dysfunction in acromegaly after transsphenoidal surgery

Flow-mediated vasodilatation (FMD) is a vascular functional test to detect endothelial dysfunction at the early stage of cardiovascular diseases. Patients with active acromegaly have higher morbidity and mortality due to cardiovascular events. To determine whether active acromegaly is associated with endothelial dysfunction, we studied 17 patients with active acromegaly for measurements of FMD, carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV), and other biochemical parameters before and 3 months after transsphenoidal surgery (TSS). Baseline %FMD in patients with active acromegaly was significantly lower than that in age- and sex-matched control subjects. After TSS, the mean %FMD in acromegaly significantly increased from 5.3% to 7.4%; 12 patients had increased %FMD (responders), whereas 5 patients had decreased or unchanged %FMD (non-responders). However, neither carotid IMT nor baPWV changed after TSS. Serum levels of GH, insulin-like growth factor (IGF)-1, total cholesterol, low-density lipoprotein cholesterol (LDL-C), hemoglobin HA(1C), fasting plasma glucose and insulin levels, and homeostasis model assessment (HOMA)-R significantly decreased, whereas high-density lipoprotein cholesterol significantly increased. Responders had significantly lower baseline %FMD than did non-responders and both insulin levels and HOMA-R significantly decreased in responders, but not in non-responders after TSS. Simple regression analysis revealed that the change of %FMD showed a significant negative correlation with that of LDL-C, but not of IGF-1 or GH, in responders. In conclusion, it is suggested that endothelial dysfunction associated with active acromegaly improves soon after TSS, which is related to LDL-C and/or insulin resistance, but not to excess GH and/or IGF-1 itself.     

Leukocyte count is associated with reduced endothelial reactivity

BACKGROUND: Leukocyte count has been associated with cardiovascular and cerebrovascular disease in several studies. We hypothesized that white blood cell count is associated with endothelial reactivity. METHODS AND RESULTS: Leukocyte count was measured in a sample of stroke-free community participants undergoing brachial artery testing for endothelial reactivity. Flow-mediated dilation (FMD) during reactive hyperemia was assessed in each subject using high-resolution B-mode ultrasound. Multivariate linear regression was used to calculate the effect of leukocyte count on endothelial reactivity after adjusting for potential confounding factors. Mean age of the 868 participants was 66.7+/-8.8 years; 57% were women. Mean leukocyte count was (6.1+/-1.8)x10(9)/L. Each unit increase in leukocyte count was associated with a mean 0.18% decrease in FMD (p = 0.01). After adjusting for other atherosclerosis risk factors, including age, sex, hypertension, diabetes, hyperlipidemia, and smoking, the relationship persisted (mean decrease in FMD per unit leukocyte count = 0.17%, p = 0.02). There was a linear decrease in FMD by quartile of leukocyte count (p = 0.0014). The effect of leukocyte count on FMD was greater for women, those under age 70, and non-diabetics. CONCLUSIONS: Relative elevations in leukocyte count are associated with a reduction in brachial artery endothelial reactivity. These findings are consistent with current hypotheses regarding the inflammatory or infectious etiology of risk of atherosclerosis and stroke, but also suggest interactions with demographic and other risk factors.     

Relation between high-density lipoprotein cholesterol and peripheral vasomotor function

Low levels of high-density lipoprotein (HDL) cholesterol are one of the most common lipid abnormalities in patients with coronary artery disease. Endothelial dysfunction is also highly prevalent in patients with coronary artery disease. We sought to determine whether HDL cholesterol levels are correlated with endothelium-dependent vasomotion in patients being evaluated for atherosclerosis. Peripheral vascular endothelial function was assessed by high-resolution brachial artery ultrasound. Flow-mediated dilation (FMD) during reactive hyperemia was defined as the percent change in arterial diameter following 5-minute arterial occlusion. All patients underwent stress testing with nuclear single-photon emission computed tomographic imaging to determine percent left ventricular ejection fraction and define the presence or absence of coronary artery disease. One hundred fifty-one subjects (87 men, 64 women) were enrolled (average age 58 +/- 11 years). Total cholesterol, HDL cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were 188 +/- 48, 47 +/- 13, 108 +/- 37 and 154 +/- 88 mg/dl, respectively. The mean FMD for the entire group was 9.9 +/- 5.2%. Subjects with an HDL cholesterol of <40 mg/dl (n = 39) had lower FMD (7.4 +/- 3.6%) compared with those with an HDL cholesterol >/=40 mg/dl (11.0 +/- 5.5%, p <0.001). There was a significant correlation between FMD and HDL cholesterol level (linear regression, p <0.001), and in multivariate analysis, HDL cholesterol was an independent predictor of FMD. Peripheral endothelial function was abnormal in subjects with low HDL cholesterol and well-preserved in those with high HDL cholesterol. These data suggest that impaired endothelial function associated with low HDL cholesterol may be an additional, previously unrecognized mechanism contributing to the increased risk of atherosclerosis in these patients.