Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy

OBJECTIVE: Several effects of melatonin are modulated by gonadal steroids and are reduced in ageing women. Administration of melatonin reduces internal carotid artery pulsatility index (PI), and blood pressure in young individuals. Whether these effects are conserved in postmenopausal women and are influenced by hormone replacement therapy (HRT), was herein investigated. DESIGN: Randomised, double-blind placebo controlled study. PATIENTS: Twenty-three postmenopausal women of which 11 were unreplaced with HRT and 12 on the oestrogenic phase of continuous transdermal estradiol (50 microg/day) plus cyclic medroxyprogesterone acetate (5 mg/day x 12 days every 28 days). MEASUREMENTS: Internal carotid PI, by colour Doppler, and supine blood pressure were evaluated 90, 180 and 240 minutes following the oral administration of melatonin (1 mg) or placebo. Levels of nitrites/nitrates (NOx), the stable derivatives of nitric oxide, were also evaluated in samples collected 90 minutes following the administration of placebo or melatonin. RESULTS: In women not on replacement therapy melatonin was ineffective. In HRT-treated women, melatonin reduced internal carotid artery PI (P = 0.005). The effect was maximal within 90 minutes, and maintained for at least 240 minutes, with melatonin levels in the nocturnal physiological range. Systolic and diastolic blood pressures were reduced of 8 mmHg (P = 0.038) and 4 mmHg (P = 0.045), respectively, while NOx levels were significantly increased (P = 0.024). CONCLUSIONS: The circulatory response to melatonin is conserved in postmenopausal women with but not without hormone replacement therapy. Maintenance of the cardiovascular response to melatonin, may be implicated in the reduced cardiovascular risk of postmenopausal women with hormone replacement therapy.     

Influence of 17beta-oestradiol on blood pressure of postmenopausal women at high vascular risk.

OBJECTIVES: It remains an unsolved issue whether hormone replacement therapy (HRT) lowers blood pressure. This randomized trial examined the effect of 17beta-oestradiol combined cyclically with gestodene on blood pressure of postmenopausal women who were not on antihypertensive medication. All subjects had an increased risk for adverse vascular events as indicated by intima-media thickness of carotid arteries and standard risk factors. DESIGN AND SETTING: Two hundred and twenty-six postmenopausal women were randomized to oral treatment for 48 weeks with 1 mg of 17beta-oestradiol per day continuously, plus 0.025 mg gestodene on days 17-28 of each 4-week cycle (HRT 1), or plus gestodene in each third cycle only (HRT 2), or no HRT. According to predefined criteria, four subjects in HRT 1, 12 in HRT 2 and 13 in no HRT who were started on antihypertensive medication were excluded from the analysis. Thirty subjects ended participation prematurely for other reasons. Resting blood pressure was measured at baseline and after 12, 22 and 48 weeks. RESULTS: During treatment diastolic blood pressure changed significantly in both HRT groups compared to no HRT, by -3.7 +/- 9.8 mmHg, -3.0 +/- 8.8 mmHg and 1.0 +/- 9.9 mmHg at week 48 in groups HRT 2, HRT 1 and no HRT, respectively (P = 0.008 for HRT 2 versus no HRT, P = 0.027 for HRT 1 versus no HRT). The higher the diastolic blood pressure was at beginning the greater was the decrease. The decrease of systolic blood pressure was not significantly different between groups. CONCLUSIONS: For postmenopausal women with high cardiovascular risk but without antihypertensive medication, long-term treatment with 17beta-oestradiol combined with gestodene lowers diastolic blood pressure.     

Effect of hormone replacement therapy on age-related increase in carotid artery intima-media thickness in postmenopausal women

The aim of this study was to determine the changes in carotid artery intima-media thickness as measured by B-mode ultrasound in postmenopausal women receiving hormone replacement therapy (HRT) or not. One hundred and fifty-nine healthy postmenopausal women aged 45-65 years were recruited from our menopause clinic. All the selected women were free of cardio-vascular diseases and had no cardio-vascular risk factors. None of the women were receiving lipid-lowering or antihypertensive drugs. Because carotid artery intima-media thickness was shown to be strongly and positively correlated with age in women aged 55 years and older but not before, women were divided into four groups according to age (<55 vs. > or =55 years) and use of HRT (current users vs. never users). All the treated women received non-oral 17beta-estradiol with a non-androgenic progestin and had started HRT within the first year after menopause. Scanning of the right common carotid artery was performed with a B-mode ultrasound imager and thickness of the intima-media complex as well as luminal diameter of the artery were determined using an automated computerized procedure. Within each age group (i.e. <55 or > or =55 years), women had comparable demographic characteristics and only differed by HRT use. Long-term treated women had significantly lower total cholesterol levels than untreated women (P=0.005). Triglycerides, low-density lipids (LDL)-cholesterol and high-density lipids (HDL)-cholesterol levels, systolic and diastolic blood pressure were not significantly different between users and non-users. In women <55 years, no significant difference in carotid intima-media thickness was found between current users (mean 2.5+/-1.4 years) and non users. In older women, the mean values of carotid intima-media thickness were significantly smaller in current users (mean 6.9+/-3.3 years) than in never treated women: 0.50+/-0.05 versus 0.56+/-0.07 mm, P<0.0001. Carotid artery intima-media thickness was significantly correlated to age in never users (r=0.5, P<0.0001) but not in women who were currently receiving HRT (r=0.2, ns). These findings suggest an apparent protective effect of long-term HRT on age-related thickening of the intima-media of the right common carotid artery. This may contribute to explain the apparent cardio-protective effect of HRT after the menopause.     

Hormone replacement therapy and interrelation between serum interleukin-6 and body mass index in postmenopausal women: a population-based study

Postmenopausal women are at increased risk to develop osteoporosis, coronary artery disease, heart failure, and hypertension. Interleukin-6 (IL-6) may be a pathogenetic element in these disorders. Serum IL-6 levels increase during aging and seem to be related to increased body fat mass. In the present retrospective study we aimed to investigate the role of hormone replacement therapy (HRT) on serum IL-6 levels and the interrelation of IL-6 and body fat mass. Parameters were assessed in a population-based sample of postmenopausal women (n = 302) and, for comparison, 245 men of the same age. Women with HRT (n = 92) had significantly lower serum IL-6 levels compared to subjects without HRT, which was independent of age, antihypertensive therapy, smoking habits, and blood pressure (1.5 +/- 0.1 vs. 2.9 +/- 0.6 pg/mL; P = 0.017). In women without HRT, the body mass index (BMI) was correlated with serum IL-6 levels (P < 0.001). Multivariate analysis controlling simultaneously for the effects of blood pressure and heart rate confirmed the positive correlation (P = 0.001). However, in subjects with HRT no such correlation between IL-6 and BMI was demonstrated, which was confirmed after controlling covariates. In male subjects, BMI correlated with serum IL-6 (P = 0.009), which was, however, blunted after controlling for blood pressure and heart rate, probably indicating an influence of the sympathetic nervous system on this interrelation. In conclusion, women receiving HRT display lower serum IL-6 levels and a blunted interrelation of IL-6 and BMI. As IL-6 may be a pathogenetic factor in age-related diseases, HRT-related inhibition of IL-6 secretion could be an important element for the favorable effects of HRT in postmenopausal women.     

Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized, controlled trial

OBJECTIVES: The study objective was to clarify in a randomized, controlled, observer-blind trial whether hormone replacement therapy (HRT) improves elastic properties of the common carotid artery in women with signs of subclinical atherosclerosis, especially in subgroups with increased risk, and whether less progestin enhances the effect. BACKGROUND: Previous observational studies have yielded conflicting results on the influence of HRT on central arteries. Some studies reported improvement of distensibility by estrogen alone or in the subgroup of smokers. METHODS: A total of 321 postmenopausal women were randomized to 1 mg 17beta-estradiol plus 0.025 mg gestodene for 12 days every month (HRT 1), or 1 mg 17beta-estradiol plus 0.025 mg gestodene for 12 days every third month (HRT 2), or no-HRT, during 48 weeks. In 173 women, distensibility of the common carotid artery was determined before and after therapy by M-mode ultrasound and brachial blood pressure measurement. RESULTS: Change of distensibility was small and similar in the three treatment groups. In the subgroup of current smokers, HRT 2 (low progestin) increased distensibility by 32% (HRT 2: 8.2+/-11.7; HRT 1:0.6+/-6.0; no HRT: -1.8+/-6.8 x 10(-3)/kPa, p = 0.025 for no-HRT vs. HRT 2). In the subgroups with elevated blood pressure, high low density lipoprotein (LDL) cholesterol, or high age, no effect of HRT was detected. CONCLUSIONS: This randomized intervention study demonstrates that long-term HRT with estrogen and progestin does not substantially influence distensibility of central arteries. Yet, in currently smoking postmenopausal women, HRT with low progestin seems to improve distensibility; this merits further study in a specifically designed trial.     

Effects of raloxifene on carotid blood flow resistance and endothelium-dependent vasodilation in postmenopausal women

Raloxifene is one of the most important selective estrogen receptor modulators currently employed for the treatment of postmenopausal osteoporosis. However, it has also been suggested that this compound affects the vascular system. We evaluated both carotid blood flow resistance and endothelium-dependent vasodilation in 50 healthy postmenopausal women randomly assigned to receive, in a double blind design, either raloxifene (60 mg per day; N=25 subjects) or placebo (N=25 subjects) for 4 months. Indices of carotid blood flow resistance, such as the pulsatility index (PI) and resistance index (RI), as well as the flow-mediated brachial artery dilation were measured both at baseline and at the end of treatment. Changes in PI were -1.86+/-2.24 and -2.15+/-2.22% after placebo and raloxifene treatment, respectively, with no significant differences between groups. Changes in RI were -0.77+/-1.72 and -1.81+/-1.54% after placebo and raloxifene treatment, respectively, with no significant differences between groups. At the end of the treatment period, the increments in artery diameter measured after the flow stimulus were 10.79+/-2.39 and 6.70+/-1.23% for placebo and raloxifene, respectively, with no significant differences between groups. These results demonstrate no significant effects of raloxifene on either carotid blood flow resistance or brachial artery flow-mediated dilation in postmenopausal women.     

Temporal changes in clinic and ambulatory blood pressure during cyclic post-menopausal hormone replacement therapy

OBJECTIVE: Post-menopausal hormone replacement (HRT) might protect against cardiovascular disease, possibly by arterial vasodilation and reduced blood pressure. Progestogens are needed to avoid endometrial disease but vascular effects are controversial. The objective was to assess temporal changes in blood pressure (BP) by two measurement techniques during a cyclic hormone replacement regimen. DESIGN AND METHODS: Sixteen healthy and normotensive post-menopausal women (age 55 +/- 3 years) were studied in a placebo-controlled, randomized crossover study, and were randomized to 17beta-oestradiol plus cyclic norethisterone acetate (NETA) or placebo in two 12-week periods separated by a 3-month washout Clinic blood pressure was measured sitting by the same observer with a mercury manometer at four visits in each period. Twenty-four hour ambulatory blood pressure was measured at baseline and in the ninth weeks of treatment in both periods. RESULTS: Clinic systolic and diastolic BP were reduced after 10 days of oestradiol (-5.1 and -3.2 mmHg respectively, P < or = 0.05). After 9 weeks of cyclic HRT, prior to progestogen addition, clinic BP returned to baseline. During addition of NETA, diastolic blood pressure was again reduced (-3.6 mmHg, P= 0.037). Mean 24 h ambulatory systolic and diastolic blood pressures were significantly lower than clinic measurements (-15.7 and -5.9 mmHg, P < 0.001) but were unaffected by HRT. CONCLUSIONS: Clinic blood pressure is reduced during a cyclic HRT regimen but the reduction varies with the HRT regimen, which might explain the diversity in previous BP findings during HRT. Norethisterone acetate might possess additive blood pressure-lowering effects in postmenopausal women.     

The effect of hormonal replacement therapy on the vascular reactivity and endothelial function of healthy individuals and individuals with type 2 diabetes

Estrogens protect healthy women from cardiovascular disease. However, epidemiological data suggest that women with diabetes are denied the cardioprotection associated with estrogens. Whether or not hormonal replacement therapy (HRT) confers cardiovascular benefits in postmenopausal women with diabetes is not known. The aim of this study was to examine the effects of HRT on the microvascular reactivity and endothelial function of individuals with and without diabetes. We studied the following groups of individuals: premenopausal healthy women [n = 28, age 41 +/- 8 yr (mean +/- SD)], premenopausal women with type 2 diabetes (n = 16, age 43 +/- 6 yr); postmenopausal healthy women (n = 12, age 57 +/- 4 yr), postmenopausal women with diabetes (n = 17, age 62 +/- 5 yr); postmenopausal healthy women on HRT (n = 13, age 51 +/- 5 yr), postmenopausal women with diabetes on HRT (n = 11, age 57 +/- 7 yr). We used laser Doppler flowmetry to measure forearm cutaneous vasodilatation in response to iontophoresis of 1% acetylcholine (endothelium dependent) and 1% sodium nitroprusside (endothelium independent). The endothelium-dependent vasodilation was significantly higher in premenopausal healthy women (180 +/- 67%; increase over baseline) compared to premenopausal diabetic women (87 +/- 41%; P < 0.001). endothelium-dependent vasodilation was also higher in postmenopausal healthy women on HRT (143 +/- 52) compared with postmenopausal diabetic women on HRT (86 +/- 61), postmenopausal healthy women without HRT (104 +/- 43), and postmenopausal diabetic women without HRT (74 +/- 28; P < 0.001). A similar pattern of responses was observed in the endothelium-independent vasodilation (premenopausal healthy women, 126 +/- 56; premenopausal diabetic women, 88 +/- 26; postmenopausal healthy women on HRT, 121 +/- 37; postmenopausal diabetic women on HRT, 88 +/- 41; postmenopausal healthy women without HRT, 84 +/- 36; and postmenopausal diabetic women without HRT, 73 +/- 36; P < 0.001). Soluble intercellular adhesion molecule (sICAM) was also measured among all the women with diabetes. Premenopausal women with diabetes (248.9 +/- 56 ng/ml) and postmenopausal women with diabetes on HRT (257.7 +/- 49 ng/ml) had lower sICAM levels compared with the postmenopausal diabetic women without HRT (346.4 +/- 149 ng/ml; P < 0.05). We conclude that menopausal status and type 2 diabetes are associated with impaired microvascular reactivity. HRT substantially improves microvascular reactivity in postmenopausal healthy women. In contrast, the effect of HRT on the microvascular reactivity of postmenopausal diabetic women is less apparent. However, the use of HRT among women with diabetes is associated with lower sICAM levels, suggesting an attenuation in endothelial activation.     

Effect of transdermal hormone replacement therapy on carotid artery wall thickness and levels of vascular inflammatory markers in postmenopausal women.

Carotid intima-media thickness (IMT) and vascular inflammatory markers have been shown to be involved in atherosclerosis. This study was designed to investigate the effect of transdermal hormone replacement therapy (HRT) on carotid IMT and vascular inflammatory markers in postmenopausal women and to explore the interrelationship between the change in carotid IMT and the changes in vascular inflammatory markers. Thirty-five postmenopausal women (mean age 57.0+/-7.7 years) received transdermal HRT (continuous 17beta-estradiol patch [36 microg/day] plus cyclic oral medroxyprogesterone acetate [2.5 mg/day, for 12 days/ month]) for 12 months, and 32 controls (mean age 58.0+/-7.5 years) did not. Carotid IMT, assessed by ultrasound, and circulating vascular inflammatory markers, i.e., C-reactive protein (CRP), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, E-selectin, monocyte chemoattractant protein (MCP)-1, and matrix metalloproteinase (MMP)-9 were measured before and after 12 months of treatment. In the HRT group, carotid IMT decreased significantly (p<0.01), from 0.71+/-0.13 mm to 0.65+/-0.12 mm, and the ICAM-1, VCAM-1, E-selectin, and MCP-1 levels decreased significantly (p<0.01 for all), but the CRP and MMP-9 levels remained unchanged. Carotid IMT and vascular inflammatory markers were unchanged in the control group. In the HRT group, the change in carotid IMT was significantly correlated with the change in serum E-selectin (r=0.38, p<0.05), but not with the changes in other vascular inflammatory markers. These results suggest that transdermal HRT reduced carotid artery wall thickness, and that the reduction may have been induced by an antiatherosclerotic effect combined with the direct effect of estrogen and decreased levels of estrogen-induced E-selectin.     

Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen

The gender difference in cardiovascular disease has been partly attributed to higher androgenic hormone levels. Although testosterone in women may not affect lipids, it remains unknown whether it negates favorable estrogenic effects on endothelial function. We have investigated the effects of testosterone implant therapy on arterial reactivity encompassing endothelial-dependent and -independent vasodilation in women using hormone replacement therapy (HRT). B-mode ultrasound measurements of resting brachial artery diameter, following reactive hyperemia [endothelium-dependent flow- mediated dilation (FMD)] and following glyceryl trinitrate (GTN) (endothelium-independent dilation), were recorded in 33 postmenopausal women stabilized on HRT (>6 months), at baseline, and 6 weeks after a testosterone implant (50 mg), with 15 postmenopausal nonusers of HRT serving as controls. In the brachial artery, baseline resting diameter was similar (0.40 +/- 0.01 vs. 0.41 +/- 0.01 cm, P = 0.5). In the treated group, testosterone levels increased (0.99 +/- 0.08 to 4.99 +/- 0.3 nmol/L, P < 0.001), associated with a mean 42% increase in FMD (6.4% +/- 0.7 to 9.1% +/- 1.1, P = 0.03). The control group did not change (8.1% +/- 1.4 to 5.6% +/- 1.0, P = 0.4). ANOVA of repeated measures (P = 0.04) and mean change (P = 0.02) in FMD both demonstrated significantly greater improvement with testosterone compared with controls. GTN induced vasodilation increased with testosterone treatment (14.9% +/- 0.9 to 17.8% +/- 1.2, P = 0.03). Our preliminary data indicate that parenteral testosterone therapy improves both endothelial-dependent (flow-mediated) and endothelium-independent (GTN-mediated) brachial artery vasodilation in postmenopausal women using long-term estrogen therapy. The mechanisms underlying these potentially beneficial cardiovascular effects require further investigation.     

Ascorbic acid selectively improves large elastic artery compliance in postmenopausal women

The compliance of large elastic arteries in the cardiothoracic region decreases with advancing age/menopause and plays an important role in the increased prevalence of cardiovascular diseases in postmenopausal women. We determined whether oxidative stress contributes to the reduced large elastic artery compliance of postmenopausal women. Carotid artery compliance was measured during acute intravenous infusions of saline (baseline control) and supraphysiological doses of the potent antioxidant ascorbic acid in premenopausal (n=10; 23+/-1; mean+/-SE) and estrogen-deficient postmenopausal (n=21; 55+/-1 years) healthy sedentary women. Carotid artery compliance was 56% lower in postmenopausal compared with premenopausal women during baseline control (P<0.0001). Ascorbic acid infusion increased carotid artery compliance by 26% in postmenopausal women (1.11+/-0.07 to 1.38+/-0.08 mm2/mm Hgx10(-1); P<0.001) but had no effect in premenopausal women (2.50+/-0.25 versus 2.43+/-0.20 mm2/mm Hgx10(-1)). Carotid artery diameter, blood pressure, and heart rate were unaffected by ascorbic acid. In the pooled population, the change in arterial compliance with ascorbic acid correlated with baseline waist-to-hip ratio (r=0.56; P=0.001), plasma norepinephrine (r=0.58; P=0.001), and LDL cholesterol (r=0.54; P=0.001). These results suggest that oxidative stress may be an important mechanism contributing to the reduced large elastic artery compliance of sedentary, estrogen-deficient postmenopausal women. Increased abdominal fat storage, sympathetic nervous system activity, and LDL cholesterol may be mechanistically involved in oxidative stress-associated suppression of arterial compliance in postmenopausal women.     

Regular exercise,hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women

OBJECTIVE: Carotid arterial compliance is reduced with age in sedentary estrogen-deficient women, contributing to the development of cardiovascular disorders. We determined the effects of regular aerobic exercise, hormone replacement therapy (HRT), and their interaction on carotid arterial compliance using a combination of cross-sectional and intervention study designs. METHODS: Cross-sectionally, we studied three groups of healthy postmenopausal women (50-80 years): 20 sedentary not taking HRT; 24 sedentary taking HRT; and 14 endurance-trained not taking HRT; and 11 sedentary premenopausal controls (20-37 years). In the intervention study, 12 sedentary postmenopausal women (58+/-3 years) who were taking HRT were studied before and after participation in a 3-month aerobic exercise (walking) program. Carotid arterial compliance was measured via simultaneous common carotid artery ultrasound imaging and applanation tonometry. RESULTS: Cross-sectional study. Carotid arterial compliance was lower (P<0.001) in all three postmenopausal groups compared with premenopausal women. Among the postmenopausal groups, arterial compliance was 33-43% higher in the sedentary HRT and endurance-trained women than in their sedentary estrogen-deficient peers. Intervention study. Arterial compliance increased (P<0.05) by approximately 40% to levels that were no longer different than premenopausal women. CONCLUSIONS: HRT use and regular aerobic exercise are associated with augmented carotid arterial compliance in healthy postmenopausal women. Moderate, short-term aerobic exercise can restore carotid arterial compliance in previously sedentary postmenopausal women taking HRT.     

Hormone replacement therapy improves membrane fluidity of erythrocytes in postmenopausal women: an electron paramagnetic resonance investigation

BACKGROUND: Many studies have shown that hormone replacement therapy (HRT) might provide protection against the development of hypertension and arteriosclerosis in postmenopausal women. However, the precise mechanism underlying its benefits is unclear. This question was addressed in an electron spin resonance (EPR) study of membrane function of erythrocytes in postmenopausal women. The purpose of this study was to investigate the effects of HRT on membrane fluidity of erythrocytes in postmenopausal women by means of the EPR and spin-labeling method. METHODS: The healthy postmenopausal women were randomly divided into the HRT group (n = 14) receiving the conjugated estrogen with medroxyprogesterone for 3 months and the non-HRT control group (n = 14). We measured membrane fluidity of erythrocytes in postmenopausal women before and after the trial period. RESULTS: The HRT group showed a significant decrease in blood pressure (BP) after treatment (systolic BP 145.7 +/- 5.5 v 123.3 +/- 5.1 mm Hg, n = 14, mean +/- SEM, P <.05). The order parameter (S) for 5-nitroxide stearate in the EPR spectra of erythrocyte membranes decreased significantly in the HRT group (S: 0.718 +/- 0.002 v 0.695 +/- 0.002, n = 14, P <.01). The finding indicated that HRT increased the membrane fluidity of erythrocytes and improved the microviscosity of the cell membranes in postmenopausal women. CONCLUSIONS: These results are consistent with the hypothesis that HRT might have a beneficial effect on the membrane rheologic behavior of erythrocytes and the microcirculation in postmenopausal women.     

Hormone replacement therapy use is associated with a lower occurrence of carotid atherosclerotic plaques but not with intima-media thickness progression among postmenopausal women. The vascular aging (EVA) study

BACKGROUND: Information on the impact of hormone replacement therapy (HRT) on carotid atherosclerosis is limited. Moreover, transdermal estrogens have not been investigated. METHODS: We examined association of HRT use with ultrasonographically assessed carotid atherosclerotic plaque occurrence and mean common carotid artery intima-media thickness (CCA-IMT) progression. Within the Vascular Aging (EVA) Study, a community-based cohort, 815 postmenopausal women aged 59-71 have been followed during 4 years. Among these women, 166 had already used HRT. RESULTS: Women who had ever used HRT experienced a lower occurrence of plaques (8.6 versus 19.1%, P=0.003). After adjustment for the main cardiovascular risk factors, odds-ratio for plaque occurrence was 0.41 (95% confidence interval 0.21-0.78, P=0.01) among ever users of HRT compared with never users. When transdermal route of estrogen administration was used, adjusted odds-ratio was 0.66 (95% confidence interval 0.47-0.99, P=0.04). The progression of IMT, which was measured at a plaque-free site and adjusted on initial levels of CCA-IMT did not differ between ever and never users of HRT. It was 0.011 mm per year among ever users and 0.012 mm per year among never users (P=0.61). CONCLUSION: These data suggest that HRT use may prevent the development of atherosclerotic plaques in postmenopausal women, especially when estrogens are administered by transdermal route.     

Insulin sensitivity, insulin secretion, and glucose tolerance versus intima-media thickness in nondiabetic postmenopausal women

To study the association between insulin sensitivity and secretion vs. early manifestations of atherosclerosis, we performed a 5-yr prospective study in 84 nondiabetic, postmenopausal women, aged 58.7 +/- 0.4 yr (mean +/- SD). Insulin sensitivity was measured with the euglycemic, hyperinsulinemic clamp, and insulin secretion was measured as the acute response to iv arginine (5 g). Early atherosclerosis was studied by ultrasonography of the right carotid artery. Mean intima-media thickness (IMT), determined 1 cm proximal to the bifurcation, was 0.81 +/- 0.14 mm at baseline and increased by 0.012 +/- 0.014 mm/yr over the 5 yr (P < 0.001). The maximal IMT, determined in the carotid bifurcation, was 1.42 +/- 0.42 mm at baseline and increased by 0.035 +/- 0.049 mm/yr (P < 0.001). Neither basal IMT nor the increase in mean or maximal IMT correlated to insulin sensitivity or secretion. In contrast, both baseline IMT and the progression in IMT over the 5-yr follow-up (both mean common carotid artery IMT and maximal bifurcation IMT) correlated with systolic blood pressure and low-density lipoprotein cholesterol. We conclude that carotid intima-media thickness is not related to insulin sensitivity or secretion in nondiabetic, postmenopausal women. Instead, the strongest association is seen with systolic blood pressure and low-density lipoprotein cholesterol levels.     

Gender differences in the timing of arterial wave reflection beyond differences in body height.

OBJECTIVES: The timing of arterial wave reflection affects the shape of the arterial waveform and thus is a major determinant of pulse pressure. This study assessed differences in wave reflection between genders beyond the effect of body height. METHODS: From 1123 elderly (aged 71 +/- 5 years) currently untreated hypertensives, we selected 104 pairs of men and women with identical body height (average 164 +/- 4 cm). All subjects underwent echocardiography, including measurement of aortic arch expansion, automated blood pressure measurements, measurement of ascending aortic blood flow and simultaneous carotid artery tonometry. RESULTS: Women had higher pulse (80 +/- 17 versus 74 +/- 17 mmHg, P < 0.05) and lower diastolic pressure (79 +/- 11 versus 82 +/- 10 mmHg, P < 0.05). Whilst heart rate was similar, women had a longer time to the systolic peak (210 +/- 28 versus 199 +/- 34 ms, P < 0.01) and a longer ejection time (304 +/- 21 versus 299 +/- 25 ms, P < 0.001). Wave reflection occurred earlier in women (time between maxima 116 +/- 55 versus 132 +/- 47 ms, P < 0.05) and augmentation index was higher (36 +/- 11 versus 28 +/- 12%, P < 0.001). Aortic diameter was smaller in women and the aortic arch was stiffer (median Ep 386 versus 302 kN/m2, P < 0.05). Hence, systemic arterial compliance was less in women (0.8 +/- 0.2 versus 1.0 +/- 0.3 ml/mmHg). CONCLUSIONS: We conclude that elderly hypertensive men and women have a different timing of both left ventricular ejection and arterial wave reflection when both genders are matched for body height. Women have smaller and stiffer blood vessels resulting in an earlier return of the reflected wave, which is likely due to an increased pulse wave velocity in women.     

Effect of oral postmenopausal hormone replacement on progression of atherosclerosis : a randomized, controlled trial

-Postmenopausal hormone replacement therapy (HRT) is associated with low cardiovascular morbidity and mortality in epidemiological studies. Yet, no randomized trial has examined whether HRT is effective for prevention of coronary heart disease (CHD) in women with increased risk. The objective of this study was to determine whether HRT can slow progression of atherosclerosis, measured as intima-media thickness (IMT) in carotid arteries. Carotid IMT is an appropriate intermediate end point to investigate clinically relevant effects on atherogenesis. This randomized, controlled, observer-blind, clinical, single-center trial enrolled 321 healthy postmenopausal women with increased IMT in >/=1 segment of the carotid arteries. For a period of 48 weeks, subjects received either 1 mg/d 17ss-estradiol continuously plus 0.025 mg gestodene for 12 days every month (standard-progestin group), or 1 mg 17ss-estradiol plus 0.025 mg gestodene for 12 days every third month (low-progestin group), or no HRT. Maximum IMT in 6 carotid artery segments (common, bifurcation, and internal, both sides) was measured by B-mode ultrasound before and after intervention. HRT did not slow IMT progression in carotid arteries. Mean maximum IMT in the carotid arteries increased by 0.02+/-0.05 mm in the no HRT group and by 0.03+/-0.05 and 0.03+/-0.05 mm, respectively, in the HRT groups (P:>0.2). HRT significantly decreased LDL cholesterol, fibrinogen, and follicle-stimulating hormone. In conclusion, 1 year of HRT was not effective in slowing progression of subclinical atherosclerosis in postmenopausal women at increased risk.     

Hormone-replacement therapy increases serum paraoxonase arylesterase activity in diabetic postmenopausal women

The paraoxonase (PON1) enzyme is associated with high-density lipoproteins (HDL) in the blood and is low in patients with type 2 diabetes. Hormone-replacement therapy (HRT) can increase HDL cholesterol levels, but its effect on serum PON1 arylesterase activity is uncertain. The aim of the present study was to determine the effect of 6 months' HRT with conjugated equine estrogen and medroxyprogesterone acetate on serum PON1 arylesterase activity in postmenopausal women with type 2 diabetes. Serum PON1 activity was measured immediately before and at the end of the second arm of a randomized, placebo-controlled, crossover with washout study originally designed to test the effect of HRT on plasma lipids in diabetic postmenopausal women. Baseline serum PON1 arylesterase activity was significantly (P <.001) lower in the postmenopausal diabetic women (149 +/- 38 micromol/mL/min; n = 47) than values in healthy postmenopausal women (173 +/- 32 micromol/mL/min; n = 51). Serum PON1 activity increased (10%) significantly (P =.009) in diabetic women treated with HRT compared with placebo. A significant (P =.02) interaction between baseline PON1 activity and treatment indicated a greater increase in PON1 activity during HRT in women with lower baseline activities. At baseline, serum PON1 arylesterase activity was correlated significantly with plasma HDL cholesterol levels in diabetic women (r = 0.333, P =.01, n = 47), and the increase in serum PON1 activity was correlated significantly with the change in plasma HDL cholesterol during HRT (r = 0.659, P =.0001, n = 28). These data suggest that serum PON1 activity is abnormally low in postmenopausal women with type 2 diabetes and increases during HRT, particularly in women with lower baseline levels and in those who show a concomitant increase in HDL cholesterol.     

Similarity of spontaneous and induced heart rate and blood pressure turbulence

BACKGROUND: Heart rate turbulence (HRT) is a transient tachycardia-bradycardia that follows premature ventricular complexes (PVCs). The physiology of turbulence is studied in the electrophysiology lab using induced premature ventricular stimuli but the reliability of this model for HRT is unknown. OBJECTIVES: To compare heart rate and blood pressure signatures of induced and spontaneous HRT. METHODS: Each patient received 10 ventricular extrastimuli at 1-min intervals. Electrocardiogram and continuous blood pressure results were digitized for 34 electrophysiology patients. RESULTS: Fifteen patients yielded at least one induced and one spontaneous analyzable PVC. Per subject, 3.6+/-2.2 spontaneous and 6.1+/-3.3 induced HRT sequences were detected. Spontaneous and inducible HRT were indistinguishable according to turbulence onset (median -1.7% versus -2.3%, P=0.09), turbulence slope (median 7.1 ms/beat versus 10.0 ms/beat, P=0.73), turbulence tachycardia (median 29 ms versus 22 ms, P=0.97) and turbulence bradycardia (45 ms versus 72 ms, P=0.60). Accompanying blood pressure signatures were indistinguishable according to initial hypotension (-0.5+/-5.9 mmHg versus 12.1+/-5.5 mmHg, P=0.19), hypertension time (7.7+/-3.6 s versus 7.8+/-1.9 s, P=0.93) and turbulence hypertension (13.5+/-5.7 mmHg versus 16.1+/-9.2 mmHg, P=0.19). Baroreflex sensitivities estimated by the spontaneous sequence method were similar for spontaneous and induced turbulence (median 7.5 ms/mmHg versus 7.2 ms/mmHg, P=0.89) and correlated with each other (r2=0.81). Heart rate and blood pressure turbulence induced in the electrophysiology laboratory were similar to those following spontaneous PVCs and induced turbulence was a valid model for study under controlled conditions.     

Ambulatory blood pressure monitoring versus self-measurement of blood pressure at home: correlation with target organ damage

OBJECTIVE: Ambulatory blood pressure (BP) monitoring and home blood pressure measurements predicted the presence of target organ damage and the risk of cardiovascular events better than did office blood pressure. METHODS: To compare these two methods in their correlation with organ damage, we consecutively included 325 treated (70%) or untreated hypertensives (125 women, mean age = 64.5 +/- 11.3) with office (three measurements at two consultations), home (three measurements morning and evening over 3 days) and 24-h ambulatory monitoring. Target organs were evaluated by ECG, echocardiography, carotid echography and detection of microalbuminuria. Data from 302 patients were analyzed. RESULTS: Mean BP levels were 142/82 mmHg for office, 135.5/77 mmHg for home and 128/76 mmHg for 24-h monitoring (day = 130/78 mmHg; night = 118.5/67 mmHg). With a 135 mmHg cut-off, home and daytime blood pressure diverged in 20% of patients. Ambulatory and Home blood pressure were correlated with organ damage more closely than was office BP with a trend to better correlations with home BP. Using regression analysis, a 140 mmHg home systolic blood pressure corresponded to a 135 mmHg daytime systolic blood pressure; a 133 mmHg daytime ambulatory blood pressure and a 140 mmHg home blood pressure corresponded to the same organ damage cut-offs (Left ventricular mass index = 50 g/m, Cornell.QRS = 2440 mm/ms, carotid intima media thickness = 0.9 mm). Home-ambulatory differences were significantly associated with age and antihypertensive treatment. CONCLUSION: We showed that home blood pressure was at least as well correlated with target organ damage, as was the ambulatory blood pressure. Home-ambulatory correlation and their correlation with organ damage argue in favor of different cut-offs, that are approximately 5 mmHg higher for systolic home blood pressure.