The acute effects of sublingual estradiol on left ventricular diastolic function in normotensive and hypertensive postmenopausal women

AIM: limited information is available on estrogen influences on diastole. We aimed to investigate the acute effects of a single dose of sublingual 17beta-estradiol on left ventricular diastolic function in postmenopausal women. METHODS: the study included 28 women aged 55.6 +/- 6 (15 normotensive and 13 hypertensive), who underwent Doppler echocardiography and estradiol plasma levels determination before and 60 min after sublingual administration of 4 mg of 17beta-estradiol. RESULTS: there were no modifications in heart rate. Both systolic and diastolic blood pressure dropped significantly in the hypertensives and remained unchanged in normotensives. Estradiol levels were 1790 +/- 869 pg/ml in the normotensives and 2664 +/- 1490 in the hypertensives (P < 0.05). Peak early velocity, in the population as a whole, increased from 84 +/- 18 to 91 +/- 18 cm/s and the early-to-atrial velocity ratio from 1.1 +/- 0.4 to 1.4 +/- 0.6 (P < 0.0001 for both). Both acceleration and deceleration rates increased significantly (P < 0.0001). These changes were shared by all the patients. In addition, the hypertensive patients, who presented a baseline pattern characterized mainly by a grossly increased peak atrial velocity with reduction in the early-to-atrial velocity ratio, demonstrated a decrease in peak atrial velocity from 92 +/- 12 to 78 +/- 10 cm/s (P < 0.0001), associated with significant reductions in deceleration time (P < 0.0001) and pressure half time (P < 0.005). Therefore, the typical picture of impaired ventricular relaxation was favorably changed after estradiol administration. CONCLUSIONS: the sublingual administration of estradiol induces acute modifications in left ventricular diastolic function in postmenopausal women, with improvement in the age-related left ventricular relaxation pattern, and that these beneficial changes are more pronounced in hypertensive that in normotensive women.     

Endothelin-1 and nitric oxide levels are related to cardiovascular risk factors but are not modified by estradiol replacement in healthy postmenopausal women. A cross-sectional and a randomized cross-over study

OBJECTIVE: To evaluate whether in healthy postmenopausal women endothelial substances such as endothelin-1 (ET-1) and nitric oxide are related to cardiovascular risk factors and can be influenced by estradiol replacement. DESIGN: A cross-sectional evaluation and a randomized, double-blind, placebo-controlled study with cross-over. METHODS: In 20 healthy postmenopausal women it was investigated the relation of ET-1 and NOx with age, BMI, 24-h blood pressure, lipid and glucose metabolism, and coagulation parameters. In addition, in the same women, the role played by estrogens on circulating ET-1 and stable derivatives of nitric oxide (nitrite/nitrates) was investigated by administering for 2 months transdermal estradiol (50 microg/day) vs. placebo. RESULTS: ET-1 and NOx were inversely related to each other (r=0.458; P=0.016). Multivariate analysis of regression showed that ET-1 levels were related directly to LDL-cholesterol (r=0.585; P=0.0005) and protein C (r=0.516; P=0.0008), and inversely to insulin (r=0.488; P=0.0065). The ratio NOx/ET-1 was directly related to HDL-cholesterol (r=0.441; P=0.005). The above relations were not influenced by estradiol. Indeed, in comparison to placebo, transdermal estradiol, besides reducing nocturnal systolic (P=0.002) and diastolic (P=0.03) blood pressure, did not modify ET-1 or NOx levels, as well as, any of the parameters considered. CONCLUSIONS: The relation of several cardiovascular risk factors with ET-1 and NOx/ET-1 suggests a primary role for these endothelial products in the determination of the cardiovascular risk of women. The present data do not support a role for transdermal estradiol in modifying ET-1 or NOx levels of healthy postmenopausal women.     

The effect of hormone replacement therapy on diastolic left ventricular function in hypertensive and normotensive postmenopausal women

Objectives: To evaluate the effect of hormone replacement therapy (HRT) on left ventricular diastolic function in a group of hypertensive and normotensive postmenopausal women. Methods: Left ventricular diastolic function at rest was evaluated by M-mode, two-dimensional and Doppler echocardiography in 19 postmenopausal women with normal blood pressure and 11 postmenopausal women with mild hypertension, before treatment and during 12 months of HRT. Transdermal estradiol was used in women with a surgical menopause and a sequential regimen of transdermal estradiol and peroral medroxyprogesterone acetate in women with a spontaneous menopause. The parameters assessed were: body mass index, heart rate, ejection fraction of the left ventricle (EF), septal (SW) and posterior wall (PW) dimensions, left ventricular end-systolic (LVsd) and end-diastolic (LVdd) dimensions and volumes (ESV, EDV), total diastolic time (DT), duration of the early (Ei) and of the late (Ai) filling phase, peak velocity of the early (E) and late mitral flow (A), A/E velocity ratio and systolic and diastolic blood pressure. Quantitative data were analyzed using unpaired t-test, MANOVA and multiple regression analysis where appropriate. Results: Hypertensive postmenopausal women had significantly higher SW (P<0.05), PW (P<0.05), A/E (P<0.05) and A (P<0.001) than normotensive postmenopausal women, before therapy. After 12 months of HRT a significant decrease in SW, PW, LVsd, ESV and increase in EF, DT, Ei and E was observed in both hypertensive and normotensive postmenopausal women. Heart rate slowed and systolic pressure decreased significantly only in normotensive postmenopausal women on HRT. Conclusion: HRT of 12 months' duration does not deteriorate left ventricular diastolic function of both hypertensive and normotensive postmenopausal women. Improvement in some parameters of diastolic function could be partially explained by the decrease in heart rate and systolic pressure, induced by therapy.     

Determinants of the effect of estrogen on the progression of subclinical atherosclerosis: Estrogen in the Prevention of Atherosclerosis Trial

OBJECTIVE: To determine the extent to which the estrogen-induced changes in lipids and markers of carbohydrate metabolism explain the beneficial effect of estrogen therapy on the progression of carotid artery intima-media thickness (IMT) in postmenopausal women. DESIGN: A randomized, double-blind, placebo-controlled, single-center trial enrolling 222 postmenopausal women 45 years and older without cardiovascular disease and with low-density lipoprotein (LDL) cholesterol levels of 3.37 mmol/L or greater (> or = 130 mg/dL). Intervention was unopposed micronized 17beta-estradiol versus placebo. Measurements were made using high-resolution B-mode ultrasonography to measure carotid artery IMT at baseline and every 6 months on-trial. RESULTS: Progression of carotid IMT was inversely related to on-trial high-density lipoprotein (HDL) cholesterol (P = 0.04) and was directly related to on-trial LDL-cholesterol (P = 0.005). Compared with placebo, women randomized to estradiol showed a higher mean on-trial HDL-cholesterol level and a lower mean on-trial LDL-cholesterol level. In contrast, fasting glucose, insulin, and hemoglobin A1C were lowered and insulin sensitivity increased with estradiol therapy, but the changes were not related to carotid IMT progression. On-trial HDL-cholesterol and LDL-cholesterol were significant independent determinants of carotid IMT progression, jointly explaining 30% of the treatment effect of unopposed estrogen on the progression of carotid IMT. CONCLUSION: Unopposed 17beta-estradiol reduced carotid IMT progression in postmenopausal women in part by increasing HDL-cholesterol and decreasing LDL-cholesterol. Although women randomized to estradiol showed improvement in all the markers of carbohydrate metabolism, these factors did not play a significant role in carotid IMT progression.     

Effects of estradiol and the angiotensin II receptor blocker irbesartan on vascular function in postmenopausal women

OBJECTIVE: Estradiol and angiotensin receptor blockers have prominent effects on the renin-angiotensin-aldosterone system. The purpose of this study was to determine whether irbesartan, an angiotensin receptor blocker, has a greater effect on vascular function when combined with estradiol, compared with irbesartan alone, in hypertensive postmenopausal women. DESIGN: Fifty-one women were studied while off any antihypertensive medications or hormone therapy at baseline and after randomization to one of four treatment arms for 12 weeks: (1) irbesartan and estradiol, (2) irbesartan and placebo, (3) estradiol and placebo, and (4) placebo/placebo. Estradiol and placebo arms served as control groups. Blood pressure, brachial reactivity, aldosterone, insulin, glucose, 24-hour urinary catecholamines, urinary sodium, and creatinine were measured. Fisher's exact test was used for comparison of differences in blood pressure in the treatment arms. Paired t test and analysis of variance were also performed for within- and between-group analysis. RESULTS: A significantly larger number of women in the irbesartan and estradiol group had a decrease of 5 mm Hg or more in both systolic and diastolic blood pressures (P < 0.05) compared with irbesartan alone group. Forearm vascular reactivity was increased significantly compared with baseline (P < 0.05), and there was a significant decrease in the serum aldosterone level after treatment compared with baseline (P < 0.05) in the irbesartan and estradiol combination group. Fasting glucose and insulin, urinary sodium/creatinine ratio, and catecholamines were similar at each time point. CONCLUSIONS: The results suggest that irbesartan and estradiol, when used in combination, may cause a greater lowering of blood pressure in postmenopausal hypertensive women. This effect may be mediated via increased vasodilation and lower aldosterone levels. These results warrant further testing in larger clinical trials.     

Circulating osteoprotegerin is associated with age and systolic blood pressure, but not with lipid profile or fasting glucose, in postmenopausal women

OBJECTIVE: Osteoprotegerin (OPG), an inhibitor of osteoclastogenesis and osteoclast activation, has been reported to be linked to vascular biology. The aim of this study was to clarify the relationships between circulating OPG and the risk factors for vascular disorders in postmenopausal women. DESIGN: Eighty Japanese postmenopausal women were enrolled in this cross-sectional study. Clinical parameters (age, number of years since menopause, body mass index, systolic and diastolic blood pressure); serum concentrations of OPG, creatinine, calcium, and phosphorus; serum lipid profile; plasma glucose; and bone mineral density of the L2-4 vertebral bodies were determined for each woman. RESULTS: In rank-order correlation analysis, serum OPG concentrations had significant positive correlations with age (r = 0.29, P = 0.03), systolic blood pressure (r = 0.45, P < 0.01), diastolic blood pressure (r = 0.34, P < 0.01), and serum creatinine (r = 0.29, P = 0.04). Serum OPG concentration also had a marginally significant negative correlation with bone mineral density of the L2-4 vertebral bodies (r = -0.25, P = 0.06). However, serum OPG did not correlate with body mass index, serum lipid profile, or plasma glucose. The correlation of serum OPG with systolic blood pressure persisted after adjustment for both age and serum creatinine. CONCLUSIONS: These results suggest that increased circulating OPG in postmenopausal women is closely related to higher systolic blood pressure, which could cause atherosclerosis.     

Dietary calcium intake and blood pressure in normotensive subjects

Epidemiological and prospective studies in man and animals have indicated an inverse relationship between calcium intake and cardiovascular mortality and blood pressure (BP). We have therefore studied the effect of dietary calcium on blood pressure in two groups of women. In a cross-sectional study 103 early postmenopausal women were stratified into three groups according to daily calcium intake calculated from a questionnaire. Both diastolic and systolic blood pressures were identical in the three groups. We thereafter conducted a prospective placebo-controlled trial on the effect of calcium supplementation. Twenty-eight healthy women were randomized to placebo treatment (n = 14) or calcium supplementation 2,000 mg daily (n = 14) for one year. In both groups BP remained at initial levels throughout the study and was identical in the two groups at measurements every three months. We thus conclude that calcium supplementation has no effect on BP in normotensive subjects on a high calcium diet.     

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.     

Percutaneous 17beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women

OBJECTIVE: To determine the efficacy and tolerability of two strengths of percutaneous 17beta-estradiol in a hydroalcoholic gel and placebo in controlling vasomotor symptoms of menopause. DESIGN: A total of 221 postmenopausal women were assigned randomly to treatment with percutaneous 17beta-estradiol gel 1.25 g (containing 0.75 mg of estradiol) or 2.5 g (containing 1.5 mg of estradiol) or placebo gel applied once daily for 12 weeks. The primary efficacy variable was the mean change from baseline in the frequency of moderate/severe hot flushes. In addition, the mean changes from baseline in the frequency and severity of all hot flushes were assessed. Safety and tolerability were evaluated from endometrial biopsy, adverse events, and laboratory tests. RESULTS: A significant reduction (P < 0.05) in the mean frequency of moderate-to-severe hot flushes and mean frequency and severity of all hot flushes was observed with both 17beta-estradiol gel groups compared with placebo. The mean number of moderate-to-severe hot flushes at the end of the study with 17beta-estradiol gel 2.5 g, 17beta-estradiol gel 1.25 g, and placebo gel was 2.0, 2.8 and 5.2, respectively. The overall incidence of adverse events was not significantly different among groups, though a higher incidence of estrogen-related adverse events was reported with the 17beta-estradiol gel 2.5-g dose. CONCLUSIONS: 17beta-estradiol gel was effective and well tolerated for alleviating moderate-to-severe hot flushes in postmenopausal women. Therapy may be initiated with the 1.25-g dose with an increase to the 2.5-g dose if needed.     

Resistive index of renal artery and blood pressure in postmenopausal women

Causal association between perimenopausal changes and symptoms and disease is commonly accepted even if not definitely explained. Resistive index (RI) of renal artery assessed by Doppler echography is related to renal function and systemic circulatory adaptation in patients with chronic renal failure and hypertension. Echocardiographic measurement of left ventricular myocardial mass (LVMM) is a useful tool for assessing effects of arterial hypertension on heart. Aim of the study was to assess RI in normotensive postmenopausal women and relationship, if any, with blood pressure and LVMM. We studied 28 normotensive, non-obese postmenopausal women, age 52.21 +/- 5.40 years, with normal creatinine clearance. Renal colour-Doppler echography was performed assessing intra-parenchimal renal artery mean velocity (mVRA) and intra-parenchimal RI [(peak systolic velocity - end diastolic velocity)/peak systolic velocity]. Echocardiography was performed as well. RI of intra-parenchimal renal artery is 0.67 +/- 0.05 and it shows correlations vs. diastolic blood pressure (r=0.41; P<0.03) and vs. mean BP (r=0.47; P<0.01). LVMM has correlation (r=0.41; P>0.03) with RI. Age, body weight, body mass index, menarche age, fertility years and postmenopausal years do not show correlation with RI. Heart rate, creatinine clearance, hemoglobin, serum albumin do not show any correlation with RI. Higher RI is associated with alcohol intake, liver steatosis, biliary gallstones and family history of diabetes mellitus, but not with postmenopausal years, unrespective of surgical or non-surgical menopause. Among echocardiographic measurements only LVMM is correlated with RI; mVRA does not show correlation. LVMM and BP do not show other independent correlation except that the one already reported vs. RI. RI, as a pathophysiological measurement whose increase preludes to arterial hypertension, could help to ascertain perimenopausal women at risk for arterial hypertension and left ventricular hypertrophy, but does not seem directly associated with the loss of ovarian function.     

Elevated arterial stiffness in postmenopausal women with osteoporosis

OBJECTIVES: Osteoporosis and increased pulse wave velocity (PWV) are cardiovascular risk factors. We investigated the relationship between PWV and bone mass in the lumbar spine in postmenopausal women. METHODS: We studied the PWV in 95 women; 38 postmenopausal women with normal spinal bone mineral density (BMD), 32 osteopenic postmenopausal women, and 25 osteoporotic postmenopausal women. The brachial-ankle PWV (baPWV) was measured using an automated device. The BMD of the lumbar spine (L2-L4) was measured using dual-energy X-ray absorptiometry. RESULTS: After adjusting for age and years since menopause, women with osteoporosis had a significantly higher baPWV than those with normal BMD (1500 +/- 220 cm/s versus 1340 +/- 215 cm/s; P < 0.05), but no significant differences in baPWV were seen between the osteoporotic and osteopenic groups or between the osteopenic and normal BMD groups. In univariate regression analysis, the baPWV was significantly negatively correlated with BMD (r = -0.450, P < 0.01), and significantly positively correlated with age (r = 0.601, P < 0.01), years since menopause (r = 0.577, P < 0.01), systolic blood pressure (r = 0.295, P < 0.01), and diastolic blood pressure (r = 0.264, P < 0.05), but was not with other variables. In multivariate regression analysis, the baPWV was significantly correlated with BMD (P < 0.05), but not with other variables. CONCLUSIONS: Postmenopausal women with osteoporosis may have elevated arterial stiffness, suggesting that osteoporotic postmenopausal women may have a higher risk of cardiovascular disease.     

Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women

BACKGROUND: Catechol-O-methyltransferase (COMT) is the principal enzyme in the conjugation pathway for hydroxylated estrogens. We hypothesize that blood 17beta-estradiol (E(2)) and estrone (E(1)) levels in postmenopausal women receiving an oral E(2) preparation are dependent on the enzyme activity of COMT. METHODS: To determine the influence of this enzyme on E(2) serum levels three groups of 12 selected from 159 healthy normotensive postmenopausal women were selected according to their codon 158 COMT genotype (COMT(HH), COMT(HL), COMT(LL)) which is known to be associated with enzyme activity. All selected women received one 2 mg tablet estradiol valerate and blood samples were taken before treatment and after 1, 3 and 48 h. RESULTS: After 3 h the serum levels of E(2) were significantly higher in women with the COMT(LL) genotype (median 69 pg/ml, range 58-91) and the COMT(HL) genotype (median 69 pg/ml, range 43-84) compared with women with the COMT(HH) genotype (median 45 pg/ml, range 15-68, P < 0.005). In a univariate analysis of variance, considering age, body weight, and COMT genotype, body weight (P = 0.034) and COMT genotype (P < 0.001) were independently related to the increase of serum E(2) levels, whereas age was not. CONCLUSIONS: Our data demonstrate that serum E(2) levels significantly correlate with the COMT genotype. Differences in COMT genotype might be involved in causing variable effects of estrogens on diseases such as hormone-dependent cancers, coronary heart disease and on efficacy of hormone replacement therapy.     

Esterified estrogens combined with methyltestosterone improve emotional well-being in postmenopausal women with chest pain and normal coronary angiograms.

OBJECTIVE: The cardiac syndrome X is described as the triad of angina pectoris, a positive exercise test for myocardial ischemia, and angiographically smooth coronary arteries. Although syndrome X does not result in an increased risk of cardiovascular mortality, the symptoms are often troublesome and unresponsive to conventional antianginal therapy. The majority of patients are postmenopausal, and estrogen therapy can alleviate anginal symptoms. We investigated the effect of esterified estrogens combined with methyltestosterone (Estratest) on quality of life in postmenopausal women with syndrome X. DESIGN: Patients were withdrawn from antianginal therapy. Sublingual nitrates were allowed for treatment of anginal episodes. Patients underwent treadmill testing, and quality of life was assessed by using the Short Form-36 and Cardiac Health Profile questionnaires after the women had received 8 weeks of Estratest or identical placebo in a randomized, double-blind, cross-over study. RESULTS: Nineteen patients were randomized, and 16 patients completed the protocol. Plasma 17beta-estradiol concentrations were significantly increased by Estratest; however, total testosterone levels were not. The "emotional" score of the Cardiac Health Profile questionnaire was significantly improved after Estratest use compared with placebo (p = 0.03); however, there was no significant change in the Short Form-36 questionnaire for any variable. Estratest significantly increased systolic blood pressure and rate pressure product at rest but had no effect on exercise parameters. Time to onset of chest pain during exercise was also unaffected. CONCLUSIONS: We have demonstrated a beneficial effect of Estratest on emotional well-being in postmenopausal women with cardiological syndrome X. There was no significant treatment effect on exercise parameters, including time to onset of chest pain.     

Effect of postmenopausal hormone replacement on atherosclerosis in femoral arteries.

OBJECTIVES: On the basis of epidemiological and experimental data, it has been supposed that hormone replacement therapy (HRT) inhibits atherosclerosis in postmenopausal women. This randomized controlled trial examined whether 1 mg 17beta-estradiol daily, combined cyclically with 0.025 mg gestodene in every month (HRT 1), or in every third month (HRT 2) slows the increase of intima-media thickness in femoral arteries compared with no HRT. METHODS: Healthy postmenopausal women (n=321) with an increased risk for future vascular disease as indicated by >1 mm of intima-media thickness in the carotid arteries were equally randomized to one of the three groups for 48 weeks. Ultrasound scans of femoral arteries were recorded at study start and study end, together with a thorough clinical examination and laboratory work-up. RESULTS: Complete scans were obtained in 260 of the 264 subjects who participated until study end. Mean maximum intima-media thickness of four femoral artery segments (common and superficial, both sides) was 0.93+/-0.37 mm (mean+/-S.D.) at study start. It increased by 0.02+/-0.05, 0.02+/-0.05, and 0.03+/-0.05 mm in the HRT 1, HRT 2 and no HRT groups, respectively (HRT 1 versus no HRT, HRT 2 versus no HRT; both P>0.2). Compared with no HRT, HRT significantly lowered follicle stimulating hormone, low-density lipoprotein cholesterol, and fibrinogen. CONCLUSIONS: In this 1-year trial, irrespective of the progestogen dose used, HRT with 1 mg 17 beta-estradiol did not inhibit progression of femoral artery atheroslerosis in postmenopausal women with subclinical vascular disease.     

Use of vascular Doppler ultrasound to detect acute estradiol vascular effect in postmenopausal women

OBJECTIVES: To report on a simple practical test for assessing acute estradiol vascular effects on healthy and unhealthy postmenopausal women. INTRODUCTION: Estradiol acts in the endothelium to promote vasodilatation through genomic and non-genomic mechanisms, but its vascular action may be impaired in diabetes mellitus, hypertension, smoking and obesity. METHODS: Nineteen postmenopausal women (nine healthy and 10 with two or more of the above factors) of similar age and time since menopause were examined with vascular Doppler ultrasound. Resistance indexes and systolic and diastolic flow velocities were determined for the brachial and internal carotid arteries at baseline and 20 minutes after administration of a nasal estradiol formulation, available on the market, which reaches 1,200-1,500 pg/ml in the serum in 10-30 minutes. Estradiol blood levels were measured at 30 minutes. RESULTS: The carotid resistance index increased 14.2% (vasoconstriction) in the unhealthy group after estradiol, from a mean +/- S.E. of 0.56 +/- 0.016 at baseline to 0.64 +/- 0.05 (p=0.033), and remained unchanged in healthy women. Brachial diastolic flow velocity increased 19.7% (vasodilatation) in healthy women, from 16.2 +/- 1.93 to 19.4 +/- 0.64 cm/s (p=0.046), and did not change in the unhealthy subjects. Estradiol levels were similar in both groups. DISCUSSION: Healthy postmenopausal women showed brachial vasodilatation while unhealthy postmenopausal women displayed vasoconstriction at the carotid artery. Vascular responses to estradiol were divergent between the groups. CONCLUSIONS: The acute estradiol test, coupled with Doppler ultrasound, seemed to be able to differentiate women with normal and abnormal endothelial function in a simple, non-invasive manner.     

Estrogen therapy selectively enhances prefrontal cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women

OBJECTIVE: Estrogen therapy (ET) seems to differentially effect cognitive processes in younger versus older postmenopausal women, suggesting a window of opportunity when ET is most beneficial. Cognitive improvement in younger postmenopausal women has been attributed to ET's influence on hot flushes and sleep, but empiric examination of the mediating role of menopause symptoms versus direct effects of ET on the brain is limited. DESIGN: In a double-blind trial, 52 women were randomly assigned to estradiol 0.05 mg/day (n = 26) or placebo transdermal patches (n = 26) for 12 weeks. Women completed tests of memory, learning, and executive functioning, and hot flush and sleep assessments at baseline and study end. A subset of women (five ET treated, six placebo treated) also underwent blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. RESULTS: Nondepressed perimenopausal and postmenopausal women were studied. The majority had hot flushes and sleep impairment. Compared with placebo, ET selectively reduced errors of perseveration during verbal recall (P = 0.03), a frontal system-mediated function, but did not influence other cognitive processes. Women with baseline hot flushes had greater cognitive benefit with ET (P < 0.05). Cognitive benefit was not associated with sleep problems or its improvement. Measures of fMRI BOLD activation during tests of verbal and spatial working memory showed significant increases in frontal system activity with ET (P < 0.001). CONCLUSIONS: Estrogen therapy selectively improves executive functioning as demonstrated by reduced perseverative errors and prefrontal cortex activation during verbal recall tasks. Cognitive improvement with ET is associated with hot flushes, but not with sleep, suggesting that ET has a direct central nervous system effect, rather than an indirect effect mediated through improvement of sleep.     

Aerobic training abolishes ambulatory blood pressure increase induced by estrogen therapy: a double blind randomized clinical trial

Emerging data reveal that oral estrogen therapy can increase clinic blood pressure (BP) in post-menopausal women; however, it is important to establish its effects on ambulatory BP, which is a better predictor for target-organ damage. Besides estrogen therapy, aerobic training is widely recommended for post-menopausal women, and it can decrease ambulatory BP levels. This study was designed to evaluate the effect of aerobic training and estrogen therapy on the ambulatory BP of post-menopausal women. Forty seven healthy hysterectomized women were randomly divided (in a double-blind manner) into 4 groups: placebo-control (PLA-CO=12), estrogen therapy-control (ET-CO=14), placebo-aerobic training (PLA-AT=12), and estrogen therapy-aerobic training (ET-AT=09). The ET groups received estradiol valerate (1 mg/day) and the AT groups performed cycle ergometer, 3×/week at moderate intensity. Hormonal status (blood analysis), maximal cardiopulmonary exercise test (VO(2) peak) and ambulatory BP (24-h, daytime and nighttime) was evaluated before and 6 months after interventions. A significant increase in VO(2) peak was observed only in women who participated in aerobic training groups (+4.6±1.0 ml kg(-1) min(-1), P=0.00). Follicle-stimulating hormone was a significant decreased in the ET groups (-18.65±5.19 pg/ml, P=0.00), and it was accompanied by an increase in circulating estrogen (56.1±6.6 pg/ml). A significant increase was observed in the ET groups for daytime (P=0.01) and nighttime systolic BP (P=0.01), as well as nighttime diastolic BP (P=0.02). However, daytime diastolic BP was increased only in the ET-CO group (+3.4±1.2 mmHg, P=0.04), and did not change in any other groups. No significant effect was found in ambulatory heart rate. In conclusion, aerobic training abolished the increase of daytime ambulatory BP induced by estrogen therapy in hysterectomized, healthy, normotensive and postmenopausal women.     

Influence of raloxifene on the efficacy of an estradiol-releasing ring for treating vaginal atrophy in postmenopausal women

OBJECTIVE: To determine the potential interaction of oral raloxifene 60 mg/day on the efficacy of a low-dose, estradiol-releasing vaginal ring used to treat signs and symptoms of vaginal atrophy in postmenopausal women. DESIGN: Randomized, double-blind, placebo-controlled, parallel treatment trial of raloxifene and placebo with open-label 17beta-estradiol ring. At 10 sites in the United States, 91 postmenopausal women with at least two signs of vaginal atrophy were treated with a 17beta-estradiol ring and randomized to receive concomitant raloxifene 60 mg/day or placebo for 6 months. Efficacy of treatments was evaluated by comparing investigator assessments of genitourinary atrophic signs, vaginal maturation value, and participant assessments of vaginal symptoms at 6 months. Other measures included rate and severity of hot flashes and assessment of sexual function. Uterine safety was assessed by endometrial biopsy and transvaginal ultrasound. RESULTS: In women treated with a 17beta-estradiol ring, both the raloxifene and placebo treatment groups showed improvements in signs and symptoms of vaginal atrophy at 6 months, with no significant differences in degree of improvement between groups. There were no signs of endometrial proliferation in either group.CONCLUSIONS: Concomitant administration of raloxifene does not alter the effects of the 17beta-estradiol ring on alleviating signs and symptoms of genitourinary atrophy in postmenopausal women.     

Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years

OBJECTIVE: To investigate the effect of ultralow-dose transdermal estradiol on postmenopausal symptoms and side effects in a cohort of largely asymptomatic postmenopausal women aged 60 to 80 years. DESIGN: This secondary analysis used data from the UltraLow-dose Transdermal estRogen Assessment trial, a randomized, placebo-controlled, double-blind trial in postmenopausal women to determine the skeletal effects and safety of ultralow-dose transdermal estradiol. Four hundred seventeen postmenopausal women, aged 60 to 80 years, were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). Participants were queried at each clinic visit about postmenopausal symptoms and side effects purported to be associated with estrogen therapy using a standardized questionnaire. RESULTS: At baseline, 16% of women reported hot flashes, 32% reported vaginal dryness, and 35% reported trouble sleeping. Women who received ultralow-dose estradiol were no more likely to report improvement of hot flashes, vaginal dryness, or sleep difficulties than those who received placebo. Treatment with ultralow-dose estradiol did not cause breast tenderness, uterine bleeding, or other symptoms often attributed to estrogen, but vaginal discharge was more common in women who received estradiol compared with those who received placebo. CONCLUSION: In this population of older, largely asymptomatic women, ultralow-dose transdermal estradiol did not improve postmenopausal symptoms and did not cause side effects other than vaginal discharge. Further study is needed to determine whether this dose of transdermal estradiol is effective in treating symptoms of postmenopause in younger, more symptomatic women.     

Relation of high cytomegalovirus antibody titres to blood pressure and brachial artery flow-mediated dilation in young men: the Cardiovascular Risk in Young Finns Study

Human cytomegalovirus (CMV) infection is associated with a higher risk of cardiovascular disease in immunocompromised organ transplant patients. It has been linked with the pathogenesis of elevated arterial blood pressure. However, controversy exists as to whether CMV infection is associated with endothelial function, and little is known about its role as a potential risk factor for early atherosclerosis development at a young age. We aimed to discover if CMV antibody titres are associated with early vascular changes (carotid intima-media thickness, carotid artery distensibility and brachial artery flow-mediated dilation), blood pressure elevation or other traditional cardiovascular risk factors. CMV antibody titres were measured in 1074 women and 857 men (aged 24-39 years) taking part in the Cardiovascular Risk in Young Finns study. CMV antibody titres were significantly higher in women compared to men. In men, high CMV antibody titres were associated directly with age (P < 0·001) and systolic (P = 0·053) and diastolic (P = 0·002) blood pressure elevation, and associated inversely with flow-mediated dilation (P = 0·014). In women, CMV antibody titres did not associate with any of the analysed parameters. In a multivariate regression model, which included traditional atherosclerotic risk factors, CMV antibody titres were independent determinants for systolic (P = 0·029) and diastolic (P = 0·004) blood pressure elevation and flow-mediated dilation (P = 0·014) in men. High CMV antibody titres are associated independently with blood pressure and brachial artery flow-mediated dilation in young men. This association supports the hypothesis that common CMV infection and/or an immune response to CMV may lead to impaired vascular function at a young age.