Sandra Zoncu

Estradiol-17β reduces blood pressure and restores the normal amplitude of the circadian blood pressure rhythm in postmenopausal hypertension

After menopause, both systolic (SBP) and diastolic (DBP) blood pressure (BP) become higher in women than in men of the same age, suggesting that estrogen deficiency may influence the age-related increase in BP. We studied 30 postmenopausal women (mean age, 55 +/- 5.7 years; time from menopause, 2-5 years) affected by mild hypertension with no target-organ complications by means of 24-h BP monitoring. None of the group were undergoing estrogen replacement therapy or taking antihypertensive drugs. According to a randomized, double-blind protocol, subjects received patches of transdermal estradiol-17beta (E2) or a matched placebo, with crossover after a 7-day washout period. In 12 patients the 24-h peak-to-trough variation in SBP and DBP amounted to less than 10% (nondippers). Administration of E2 significantly decreased 24-h SBP and DBP in the whole cohort (P < .05). Furthermore, E2 restored the expected reduction in BP during nighttime in the nondipper subgroup. It is well known that estrogen replacement therapy protects against the development of both cardiovascular diseases and stroke. Our data suggest that this activity could be attributed, at least in part, to the activity of E2 in preserving physiologic circadian fluctuation of BP.

Effects of Acute Administration of Transdermal Estrogen on Postmenopausal Women With Systemic Hypertension

We studied 16 postmenopausal women with mild to moderate hypertension according to a randomized, double-blind protocol. They received patches of transdermal estradiol-17beta rated to deliver 100 mg/day of substance or matched placebo. A 24-hour ambulatory blood pressure (BP) monitoring was performed at baseline and after drug administrations. Our data show that estradiol-17beta exerts beneficial effects, both in lowering elevated BP levels and in maintaining a uniform BP control over 24 hours. Estrogen replacement therapy could be considered when significant changes in BP occur during the postmenopausal period.

Effects of acute administration of natural progesterone on peripheral vascular responsiveness in healthy postmenopausal women

Peripheral vascular responses to acute administration of natural progesterone were studied in 12 postmenopausal women (mean +/- SD age 50.3 +/- 4.8 years) with no evidence of cardiovascular disease. According to a randomized, double-blind protocol, all subjects were given natural progesterone as a vaginal cream, able to produce a rapid peak and decay of plasma hormone concentrations, or matched placebo, with crossover after a 1-week washout period. Forearm blood flow and peak flow after ischemic stress (ml/100 ml/min), local vascular resistance (mm Hg/ml/100 ml/min), venous volume (ml/100 ml), and venous compliance (ml/100 ml/mm Hg) were measured by strain-gauge venous occlusion plethysmography at baseline and after progesterone or placebo administration. Plasma norepinephrine concentrations were determined by high-performance liquid chromatography with electrochemical detection. Progesterone sharply decreased forearm blood flow (p <0.01) through an increase in local vascular resistance (p <0.01). Measures of venous function remained unchanged. Although the hormone increased circulating norepinephrine concentrations (p <0.05), there were no significant changes in mean arterial pressure or heart rate. Furthermore, progesterone reduced the local vasodilator capacity, shown by a decrease in forearm delta flow (difference between peak flow and basal flow, p <0.05). Compared with the well-known effect of estrogen, progesterone exerted an opposite action on peripheral vascular responsiveness. Peripheral circulatory changes may be attributed to a direct activity of progesterone on the arterial wall and may in part reflect a modulation of the hormone on peripheral sympathetic tone. Consideration must be given to the hypothesis that the addition of progestin may attenuate the beneficial effects of unopposed estrogen replacement therapy in postmenopausal women.

Menopause induced by oophorectomy reveals a role of ovarian estrogen on the maintenance of pressure homeostasis

OBJECTIVES Following spontaneous menopause women show a greater increase in systolic and diastolic blood pressure than men of the same age. The aim of the present study was to assess the effect of acute ovarian hormone withdrawal and replacement on blood pressure and forearm blood flow. METHODS We studied 18 fertile middle-aged normotensive women (48 +/- 1.5 years, range 46-51 years) 1 week prior and 1 month subsequent to bilateral oophorectomy by means of 24-h blood pressure monitoring and strain-gauge venous occlusion plethysmography. Eighteen subjects who had undergone hysterectomy with ovarian sparing, matched for age and biophysical characteristics, were used as a control group. All women were free from cardiovascular risk factors or disease. RESULTS Oophorectomy increased the mean values of 24 h (P < 0.001), daytime (P < 0.05), and nighttime (P < 0.01) diastolic blood pressure and nighttime systolic blood pressure (P < 0.01). Blood pressure increase was associated with a rise in forearm vascular resistance (P < 0.01). No significant changes in either blood pressure or forearm vascular resistance values were observed in hysterectomized women. In 16 oophorectomized women a 3-month estrogen replacement therapy (ERT) (17beta-estradiol, 100 mcg/day by transdermal patches) brought blood pressure and forearm vascular resistance values to a level comparable to that recorded before intervention. CONCLUSIONS Surgically-induced menopause causes an increase in peripheral vascular resistance and blood pressure suggesting a role of ovarian hormones in the homeostatic pressure modulation. Recovery of the baseline condition after ERT suggests that the accelerated increase in blood pressure after menopause is due to ovarian and above all estrogen insufficiency.

Effect of atorvastatin on endothelium-dependent vasodilation in postmenopausal women with average serum cholesterol levels.

After menopause, most healthy women show an impairment of peripheral vasodilation and an increase of plasma cholesterol levels. Statins have been shown to improve endothelial function in hypercholesterolemic men and women. The present study tests whether atorvastatin (10 mg) influences endothelium-dependent vasodilation in postmenopausal normocholesterolemic women. Twenty-eight healthy, postmenopausal women (mean age 51 +/- 2 years) with serum total cholesterol and low-density lipoprotein cholesterol within the desirable range entered a double-blind, single-crossover study. Postmenopausal women were randomized to receive either atorvastatin (10 mg/day) or placebo for 10 days and then crossed to the complementary treatment. Endothelium-dependent and -independent responses were assessed by means of strain-gauge plethysmography before and after intra-arterial infusion of acethylcholine (ACh) and sodium nitroprusside, in comparison to physiologic saline. The nitric oxide pathway was evaluated by repeating the infusion of ACh during admininstration of L-arginine and (G)-monomethyl-L-arginine (L-NMMA). Serum lipoproteins were not significantly modified by the active treatment. The vasodilation induced by ACh was significantly higher in the atorvastatin-treated women compared with the placebo-treated group (24 +/- 3 vs 13 +/- 2 ml/100 ml tissue/min, p <0.01). In contrast, responses to the endothelium-independent vasodilator sodium nitroprusside were not significantly modified by atorvastatin. The ACh-stimulated vasodilation induced by atorvastatin was additionally potentiated by L-arginine (800 +/- 105% vs 370 +/- 60%, p <0.05) and blunted by L-NMMA. No correlation was found between changes in plasma cholesterol and improvement in forearm blood flow. Our data show that the beneficial effect of atorvastatin on endothelium-dependent vasodilation is independent from changes in the lipid profile.

Lipid profiles and endothelial function with low-dose hormone replacement therapy in postmenopausal women at risk for coronary artery disease: a randomized trial

AIMS To compare the effect of low (0.3 mg) and commonly prescribed (0.625 mg) doses of conjugated equine estrogens (CEE) on brachial artery flow-mediated dilation and lipid profiles. METHODS AND RESULTS Twenty-five postmenopausal women (mean age, 65+/-6 years) at risk for coronary artery disease (CAD) (> or =2 established risk factors) entered a double-blind crossover study. Brachial artery endothelial function was evaluated by means of high-resolution vascular echography. Both CEE doses significantly decreased total cholesterol (-13%, 0.3 mg; -15%, 0.625 mg), low-density lipoprotein-cholesterol (LDL-C) (-15%, 0.3 mg; -16%, 0.625 mg), and lipoprotein(a) (-28%, 0.3 mg; -39%, 0.625 mg) values from baseline levels. Both treatments increased high-density lipoprotein-cholesterol (HDL-C) (5%, 0.3 mg; 7%, 0.625 mg) and triglycerides (3%, 0.3 mg; 8%, 0.625 mg). There was no dose effect for changes in the LDL-C/HDL-C ratio (-21%, 0.3 mg; -23%, 0.625 mg). Both doses improved brachial artery dilation during reactive hyperemia by 63% over baseline. CONCLUSION In women at risk for CAD, low-dose hormone replacement treatment (HRT) improves lipid profiles and brachial artery endothelial function comparably to the most commonly prescribed dose. The benefit:risk ratio of low-dose HRT provides an attractive option for postmenopausal women at risk for CAD.

Comparative vascular effects of hormone replacement therapy and raloxifene in women at increased cardiovascular risk.

Hormone replacement therapy (HRT) improves endothelial function in postmenopausal women while the effects of raloxifene, a selective estrogen receptor modulator, are still under debate. The aim of this study was to evaluate endothelium-dependent flow-mediated vasodilatation in the brachial artery and plasma levels of nitrite, nitrate and endothelin-1 in 20 postmenopausal women with increased cardiovascular risk treated with either HRT or raloxifene for 4 weeks in a randomized double-blind single cross-over study. Patients had an endothelium-dependent flowmediated dilatation of 4% prior to initiation of the study. Treatment with HRT resulted in a 67% increase in dilatation compared with baseline (from a 7.4% increase to a 12.4% increase, p < 0.01). Raloxifene treatment resulted in no change in vasodilatation from baseline. Endotheliumdependent dilatation was significantly improved by HRT compared with raloxifene treatment (12.4±0.6% vs. 6.1±2.0%; p < 0.01). Compared with baseline values, nitrate plus nitrite levels increased significantly (p < 0.05) with HRT but not with raloxifene. Similarly, endothelin-1 decreased from baseline with both treatments, but only the HRT-induced decrease was statistically significant (p < 0.05). In conclusion, HRT improved endothelial function and reduced plasma levels of endothelin-1 in postmenopausal women at risk of coronary artery disease. These beneficial effects were not shared by raloxifene.

Effects of transdermal estrogen administration on peripheral vascular responsiveness in menopausal women

This study was designed to evaluate the peripheral vascular responses to acute estrogen replacement. According to a cross-over, double-blind study design, we randomized nine healthy postmenopausal women (time lapse from menopause to >1 year; mean age±SD 45.4±11.7 years) to treatment with transdermal patches of estradiol-17β or matched placebo. The estrogen patch was rated to assure a plasma concentration of substance of more than 100 pg/ml after 8–10 hours of treatment. Forearm blood flow (ml/100 ml/minute), local vascular resistance (mmHg/ml/100 ml/minute), venous volume (ml/100 ml), and venous compliance (ml/100 ml/mmHg) were measured in supine resting subjects by the straingauge venous occlusion plethysmography. Plasma concentration of norepinephrine (pg/ml) was quantified by HPLC-ED. Estradiol-17β produced increase in forearm blood flow and decrease in local vascular resistance. The drug reduced circulating norepinephrine concentrations. There were no significant changes in mean arterial pressure or heart rate. Venous volume and venous compliance were both enhanced by estrogen administration. The peripheral circulatory changes are attributed to a direct activity of estradiol-17β on arterial and venous wall and may in part reflect a modulation of estrogen on peripheral sympathetic tone.

Study of myocardial contractility by pulsed wave Doppler tissue imaging does not reveal an inotropic effect of estrogen at physiologic dose.

We studied myocardial contractility by pulsed wave Doppler tissue imaging in 6 postmenopausal healthy women. According to a crossover, double-blind protocol, we randomized patients to treatment with transdermal patches of estradiol-17beta or matched placebo. Estradiol-17beta did not modify local systolic and diastolic functions. Thus, at least when acutely administered, estrogen seems to be unable to determine hemodynamic changes at the myocardial level, in opposition to what occurs in the peripheral vascular system.

Different effect of hormone replacement therapy, DHEAS, and tibolone on endothelial function in postmenopausal women with increased cardiovascular risk

Menopause is associated with an increased cardiovascular risk and with a decrease in endothelial function. Hormone replacement therapy (HRT) improves endothelial function in post-menopausal women (PMW) without established atherosclerosis. New alternative treatments, among which tibolone (T) and DHEAS have been suggested to reduce postmenopausal cardiovascular risk. Although, in vitro animal studies have suggested that T and DHEAS improve endothelial function, their effect in humans has never been tested. The aim of the present study was to compare the effects of HRT (continuous combined 0.625 mg conjugated equine estrogen plus 2.5 mg/d medoxyprogesterone) DHEAS and T on endothelium-dependent flow-mediated vasodilatation (FMD), plasma nitrite, nitrate and endothelin-1 levels in 16 PMW with increased cardiovascular risk in a double-blinded, double-crossover study. Women were randomized and treated for 4 weeks with HRT, T or DHEAS. Brachial artery diameter, FMD, endothelin-1 and plasma nitrite and nitrate levels were measured at baseline and after each treatment phase. Brachial artery diameters remained unchanged after each treatment phase. HRT significantly improved FMD compared to both baseline and to T and DHEAS therapies while no effect of T or DHEAS on FMD was noted. In conclusion, HRT, but neither T nor DHEAS, improves endothelial function and reduces plasma levels of endothelin-1 in PMW at risk of CAD.