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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 3 1303-1309
Copyright © 2003 by The Endocrine Society

A Comparison of Low-Dose and Standard-Dose Oral Estrogen on Forearm Endothelial Function in Early Postmenopausal Women

Mitsuhiro Sanada, Yukihito Higashi, Keigo Nakagawa, Mikio Tsuda, Ichiro Kodama, Masashi Kimura, Kazuaki Chayama and Koso Ohama

Department of Obstetrics and Gynecology (M.S., M.T., I.K., K.O.) and First Department of Internal Medicine (Y.H., K.N., M.K., K.C.), Faculty of Medicine, Hiroshima University, Hiroshima 734-8551, Japan

Address all correspondence and requests for reprints to: Mitsuhiro Sanada, M.D., Ph.D., Department of Obstetrics and Gynecology, Faculty of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail: msanada64{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We investigated the effects of low-dose estrogen plus progestin on endothelial function. Postmenopausal women received daily doses of conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) (standard-dose group, n = 18), CEE (0.3 mg) plus MPA (2.5 mg) (low-dose group, n = 18), or no treatment (control group, n = 15) for 3 months. Serum concentrations of lipids and malondialdehyde (MDA)-modified low-density lipoprotein (LDL) were measured. Forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin administration was measured by strain-gauge plethysmography. Decreases in serum concentrations of LDL cholesterol and MDA-modified LDL and increases in high-density lipoprotein cholesterol and nitrite/nitrate were observed in both treatment groups. After 3 months of treatment, similar increases in the maximal FBF response during reactive hyperemia were observed in both treatment groups (standard-dose group, from 35.8 ± 3.0 to 47.5 ± 2.8 ml/min per 100 ml tissue; and low-dose group, from 35.2 ± 2.2 to 46.8 ± 3.4 ml/min per 100 ml tissue, P < 0.01). FBF levels in the control group were unchanged. Treatment did not affect nitroglycerin-induced dilation. The incidences of vaginal bleeding and breast tenderness were lower with the low-dose group than with the standard-dose group. Low-dose CEE plus MPA augments endothelial function in forearm resistance arteries and decreased MDA-modified LDL levels similarly to standard doses of CEE plus MPA, with fewer side effects.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ESTROGEN PLUS PROGESTIN component of the Women’s Health Initiative (WHI) (1), a randomized controlled primary prevention trial (planned duration, 8.5 yr), in which 16,608 postmenopausal women (50–79 yr old, with an intact uterus) participated, was stopped early based on the assessment that the overall health risks exceeded health benefits, after an average follow-up of 5.2 yr. This trial found increases in coronary heart disease (CHD), stroke, and pulmonary embolism in study participants on estrogen plus progestin [0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA) daily], compared with women taking placebo pills. The WHI finding that estrogen plus progestin does not confer benefit for preventing CHD among women concurs with the Heart and Estrogen/Progestin Replacement Study (HERS) trial (2), which found no effect of hormone replacement therapy (HRT) for secondary prevention of CHD. However, the authors said, in the study limitations, that the results of WHI do not necessarily apply to lower dosages of these drugs and to estrogens and progestins administered through the transdermal route. Estrogen exerts many protective effects on the cardiovascular system, including a lipid-lowering effect (3), an antioxidant effect (4), inhibition of fibrosis (5), and a vasodilating effect (6). These observations are mainly based on the use of commercially available estrogen preparations. The paper from the Nurses’ Health Study (7) reported that women using lower doses of estrogen derived the same degree of cardiovascular protection as women using full-strength estrogen. Data on stroke also indicated a reduced risk by lower estrogen dosage. Despite the observational design of this study, the authors may provide another possibility of low-dose HRT, as compared with standard-dose HRT.

Alleviation of vasomotor symptoms and bone preservation has been reported to accrue when the average serum estradiol concentration is less than 110 pM in women receiving low-dose esterified estrogen (8). One recent study (9) has reported that low-dose esterified estrogen improves hemodynamic patterns in postmenopausal women in a manner similar to that of standard doses of CEE. If the physiologic effect of low-dose estrogen on vascular function is comparable with that of standard doses of estrogen, patient compliance may improve, because the incidence of side effects is likely to be lower.

Our purpose was to determine whether the beneficial effects on endothelial function of the most commonly prescribed doses of CEE combined with MPA would be comparable with those in women receiving lower doses of CEE plus MPA. We measured forearm blood flow (FBF) both during reactive hyperemia (an index of endothelium-dependent vasodilation) and in response to nitroglycerin (NTG) (an index of endothelium-independent vasodilation). In addition, we evaluated the effects of HRT on malondialdehyde (MDA)-modified low-density lipoprotein (LDL), which may reflect endothelial injury or plaque instability (10).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We studied 51 naturally postmenopausal Japanese women with the following characteristics: mean age, 54 yr (range, 47–57 yr); mean body mass index, 22.3 kg/m2 (range, 17.1–25.2 kg/m2); and mean menopausal interval, 6 yr (range, 1–12 yr). No subject had undergone ovariectomy, and none had menstruated for at least 1 yr. Menopausal status was confirmed by a serum FSH concentration more than 40 IU/liter, and a serum estradiol concentration less than 73.4 pM. Excluded from the study were cigarette smokers and women with hypertension, diabetes mellitus, clinical manifestations of arteriosclerosis (CHD, peripheral artery disease, or cerebrovascular disease), venous thromboembolic disease, liver disorders, unexplained vaginal bleeding, and a personal or family history of breast cancer. Before enrollment in the study, each subject underwent a physical examination, including gynecologic evaluation and mammography. None of the subjects had received HRT, other steroid hormones, or any medication known to affect lipoprotein metabolism or blood pressure. No women underwent exercise or dietary therapy before or during the study. The Ethics Committee of the Department of Obstetrics and Gynecology, Hiroshima University, approved the study protocol. Written, informed consent for participation was obtained from each subject before enrollment.

Fifty-five patients were randomly assigned in open, parallel-group fashion, to one of three groups. Sealed envelopes that contained group assignment, as determined by a random number generator, were opened. Neither the subject, nor the physician, nor the investigator knew the subject’s group assignment in advance. For 3 months, subjects in the standard-dose group received 0.625 mg CEE (Premarin; Wyeth-Ayerst Laboratories, Inc., Philadelphia, PA) plus 2.5 mg MPA (Provera; Pharmacia \|[amp ]\| Upjohn, Inc., Peapack, NJ) daily (n = 18); those in the low-dose group received 0.3 mg CEE plus 2.5 mg MPA daily (n = 18); and those in the control group did not receive HRT (n = 15). Medication was taken every morning for 3 months, and all participants were followed for 3 months. Each subject was asked to avoid making any changes in lifestyle or dietary habits during the study. A second physical examination, including gynecologic evaluation and mammography, was performed 3 months later. The presence or absence of vaginal bleeding and breast tenderness in each woman at the end of the study was recorded.

Analytical methods

Samples of venous blood were placed in polystyrene tubes containing sodium EDTA (1 mg/ml) and immediately chilled in an ice bath. Plasma was separated by centrifugation at 3100 rpm at 4 C for 10 min. Serum was separated at 1000 rpm at room temperature for 10 min. Samples were stored at -80 C until assayed. Routine chemical methods were used to determine the serum concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), creatinine, glucose, and electrolytes. The serum concentration of LDL cholesterol was determined by Freidewald’s method (11). Serum concentrations of estradiol were measured by an RIA. Nitrite/nitrate concentrations were measured with an autoanalyzer (flow injection analyzer, TCI-NOX1000; Tokyo Kasei Kogyo, Tokyo, Japan), which uses a protocol based on the Griess reaction (12). Serum angiotensin-converting enzyme (ACE) activity (in international units per liter at 37 C) was measured with ACE Color (Fuji Rebio Co., Ltd., Tokyo, Japan). Plasma renin activity (PRA) was determined by RIA. A monoclonal antibody 1H11-based competition ELISA was used for the quantification of MDA-modified LDL in serum (13).

Measurement of FBF

The vasodilator responses to reactive hyperemia and sublingual NTG in each subject were measured at baseline and 3 months later. This evaluation began at 0830 h. Each subject had fasted for at least 14 h, and then rested supine in a quiet, air-conditioned room (constant temperature, 22–25 C). After 30 min of rest, the basal FBF was measured as described below. Next, the effects of reactive hyperemia and of sublingual NTG administration on FBF were evaluated by inflating a cuff over the left upper arm to 280 mm Hg for 5 min. After the cuff occlusion was released, the FBF was measured for 3 min. Next, a NTG tablet (0.3 mg) (Nihonkayaku Co., Tokyo, Japan) was administered sublingually, and the FBF was again measured for 3 min. These studies were carried out in a randomized fashion. Each study proceeded after FBF had returned to baseline. In a preliminary study, we confirmed the reproducibility of the FBF response to reactive hyperemia and sublingual NTG on 2 separate occasions in 28 healthy male subjects (mean age, 27 ± 5 yr). The coefficients of variation were 4.3% and 2.8%, respectively.

The FBF was measured with a mercury-filled SILASTIC strain-gauge plethysmograph (EC-5R; D. E. Hokanson, Inc., Issaquah, WA), as previously described (14, 15). Briefly, the strain gauge was attached to the left upper arm, supported above the right atrium, and connected to the plethysmography device. A wrist cuff was inflated to 50 mm Hg above the systolic blood pressure, to exclude hand circulation from the measurements, beginning 1 min before each measurement, and was continued throughout the determination of FBF. The upper arm cuff was inflated to 40 mm Hg for 7 sec in each 15-sec cycle to occlude venous outflow from the arm, using a rapid cuff inflator (EC-20; D. E. Hokanson, Inc.). The FBF output signal was transmitted to a recorder (U-228; Advance Co., Nagoya, Japan). The FBF was expressed as milliliters per minute per 100 ml forearm tissue volume. The FBF was calculated by two independent observers, who had no knowledge of the subject’s profile, based on linear portions of the plethysmographic recordings. The intraobserver coefficient of variation was 3.0 ± 1.6%. Four plethysmographic measurements were averaged to obtain the FBF at baseline, during reactive hyperemia, and after the administration of sublingual NTG.

Statistical analysis

Results are presented as the mean ± SD. One-way ANOVA was used to compare the baseline clinical characteristics, lipids, hormones, hemodynamic parameters, and MDA-modified LDL levels between the three groups. Comparison of changes in the controls and changes in the active-treatment women, including maximal FBF during reactive hyperemia and maximal FBF response to NTG, were also carried out by one-way ANOVA, followed by the Bonferroni correction. One-way ANOVA was used to compare the {delta}-differences in the serum concentrations of MDA-modified LDL and the maximal FBF during reactive hyperemia. If ANOVA indicated that a significant difference existed, Scheffé’s multiple-comparison procedure was used to determine which groups were different. Student’s paired t test was used to analyze the differences between values recorded at baseline and after each treatment. The correlations between variables were determined by linear regression analysis. The intergroup differences in the incidence of vaginal bleeding and breast tenderness were compared by the {chi}2 test. A level of P < 0.05 was accepted as statistically significant. Data were processed using the software package Statview IV (Brain Power, Inc., Berkeley, CA) or Super ANOVA (Abacus Concepts, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline clinical characteristics

There were no differences in baseline clinical characteristics in the standard-dose group, the low-dose group, and the untreated control group (Table 1Go). Abnormal endometrial histology, including hyperplasia and carcinoma, was not detected in any woman. No woman was diagnosed with breast cancer during the study. No patients dropped out of the study.


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  		Table 1. Comparison of demographics and clinical characteristic of postmenopausal women receiving no treatment, standard-dose, or low-dose HRT for 3 months

 
Effects of HRT on lipids, hormones, nitrite/nitrate, and MDA-modified LDL

Significant reductions in the serum total and LDL cholesterol concentrations, as well as significant increases in the serum HDL cholesterol concentrations, occurred in both treatment groups. The serum TG concentration increased in the standard-dose group but decreased in the low-dose group. The baseline serum estradiol concentrations remained within the menopausal range in all three groups. Although both treated groups showed an increase in the estradiol concentration at 3 months, the serum estradiol concentration was lower in the low-dose group than in the standard-dose group (74.5 ± 21.6 pM vs. 161.5 ± 27.1 pM, P < 0.01). Decreases in the serum FSH were similar in the two treatment groups (P < 0.01). Increases in PRA and decreases in ACE activity occurred in both treatment groups (P < 0.05). Similar increases in the serum nitrite/nitrate concentration occurred in both treatment groups (standard-dose group, from 23.4 ± 9.8 to 41.9 ± 17.2 µM; and low-dose group, from 28.7 ± 11.5 to 40.4 ± 19.8 µM; P < 0.05) (Table 1Go). The serum concentrations of MDA-modified LDL decreased similarly in the two treatment groups (P < 0.01) (Fig. 1Go, A and B). No such changes occurred in the control group.



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  		Figure 1. Comparison of changes in the serum concentrations of MDA-modified LDL in the control group (no treatment, n = 15), standard-dose group [CEE (0.625 mg) plus MPA (2.5 mg), n = 18], and low-dose group [CEE (0.3 mg) plus MPA (2.5 mg), n = 18] before and after 3 months (A). Serum concentrations of MDA-modified LDL from baseline decreased similarly in both active-treatment groups (B). The results are presented as the mean value ± SD. *, P < 0.01 by ANOVA.

 
Effects of HRT on hemodynamic parameters and endothelial function in forearm resistance arteries

Systolic and diastolic blood pressure, heart rate, and basal FBF did not change in any of the three groups during the study (Table 1Go), and the FBF response to reactive hyperemia was similar in the three groups at baseline. After 3 months, similar increases in the maximal FBF response to reactive hyperemia were observed in the two treatment groups (P < 0.01, respectively) (Fig. 2Go, A and B), whereas no change was observed in the control group. The changes in FBF after sublingual administration of NTG were similar in all three groups at baseline and after the 3-month study period (N S). The increase in the maximal FBF response to reactive hyperemia correlated with the change in MDA-modified LDL after 3 months, in both treatment groups (standard-dose group, r = -0.46; and low-dose group, r = -0.49; P < 0.05, respectively) (Fig. 3Go).



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  		Figure 2. Comparison of changes in the maximal FBF response to reactive hyperemia in the control group (no treatment, n = 15), standard-dose group [CEE (0.625 mg) plus MPA (2.5 mg), n = 18], and low-dose group [CEE (0.3 mg) plus MPA (2.5 mg), n = 18] before and after 3 months (A). Similar increases in the maximal FBF response to reactive hyperemia were observed in both treatment groups (B). The results are presented as the mean value ± SD. *, P < 0.01 by ANOVA.

 


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  		Figure 3. Relationship between the changes in maximal FBF and the changes in MDA-modified LDL in the standard-dose group [CEE (0.625 mg) plus MPA (2.5 mg), n = 18], and low-dose group [CEE (0.3 mg) plus MPA (2.5 mg), n = 18] after 3 months.

 
The incidence of vaginal bleeding and breast tenderness

Eight women in the standard-dose group (44%) and two women in the low-dose group (11%) experienced vaginal bleeding or spotting; seven women in the standard-dose group (39%) and one woman in the low-dose group (5.6%) experienced breast tenderness. The differences in both the incidence of bleeding and breast tenderness were higher in the standard-dose than low-dose treatment group (P < 0.01) (Table 2Go).


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  		Table 2. Comparison of the incidence of vaginal bleeding and breast tenderness in postmenopausal women receiving no treatment, standard-dose, or low-dose HRT

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The WHI provides evidence from a large randomized trial that addresses the important issue of whether most women with an intact uterus, in the decades of life following menopause, should consider hormone therapy to prevent chronic disease. The results of the WHI, which found no effect of standard-dose HRT for primary prevention of CHD, raised questions about the safety and efficacy of this regimen for cardiovascular disease prevention. Our findings suggest that low-dose CEE plus MPA augments endothelial function in forearm resistance arteries and decreases MDA-modified LDL levels similarly to standard doses of CEE plus MPA, with fewer side effects.

Endothelial function

Direct intraarterial infusion of a vasoactive agent into the forearm is the best way to assess the endothelial function. Recently, Celermajer et al. (16) developed a noninvasive method for producing reactive hyperemia as an index of endothelial function. The present study used strain-gauge plethysmography to measure the FBF response to reactive hyperemia. This technique is useful for assessing forearm arterial resistance and endothelial function. This technique is simple and reproducible and causes no adverse effects.

Previous studies have shown that estrogen replacement, with or without progestins, improves forearm endothelial function in postmenopausal women (17, 18, 19). Hashimoto et al. (20) have reported that even at half the usual dose of estrogen, HRT may improve endothelial function and the progression of carotid intima-media thickening in postmenopausal women. The present study showed that the increases in the FBF response to reactive hyperemia are similar in low-dose and standard-dose HRT, whereas no change in the FBF is seen after sublingual NTG administration. These results support the findings of others and suggest that the beneficial effects of low-dose estrogen, as well as of standard dosages, is derived mainly from changes in the vascular endothelium, as opposed to vascular smooth muscle.

Reactive hyperemia in the peripheral arteries is mediated mainly by the release of nitric oxide (NO), an endothelium-derived relaxant factor (21). Some studies (22) have suggested that estrogen affects the release of NO from the vascular endothelium. Estrogens increase NO activity, both by enhancing NO production secondary to the induction of constitutive NO synthase and by inhibiting superoxide anion production, thus reducing NO degradation. Estrogen may directly up-regulate endothelial NO synthase gene expression through its {alpha}-type receptor (23). The present study shows that although the serum concentrations of estradiol are lower with low-dose than standard-dose HRT, the increase in serum concentrations of nitrite/nitrate, metabolites of NO, are similar. These findings suggest that the enhanced NO release in healthy postmenopausal women occurs with both low-dose CEE plus MPA and standard-dosage groups. Another possible mechanism of enhancement is based on the observation that ACE inhibition resulting from HRT may improve overall endothelial function. We recently reported that inhibition of ACE activity by estrogen therapy might be one basis for an endothelial benefit from estrogen (24, 25). In the present study, similar decreases in serum ACE activity and increases in PRA were found in the two treatment groups. These results are consistent with previous reports (26). The increase in PRA presumably occurs in response to a decrease in angiotensin II, the product of ACE activity. Angiotensin II increases vascular superoxide production through the activation of membrane-associated nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate oxidase, resulting in NO inactivation and toxic peroxynitrite production (27). Accordingly, ACE inhibition by HRT may increase NO by inhibiting angiotensin II production. Inhibition of ACE also delays degradation of bradykinin, a substance that increases NO release and increases production of prostacyclin and endothelium-derived hyperpolarizing factor (28).

MPA is commonly used as a progestin in combination with estrogen therapy, as was done in the HERS. Data suggest that synthetic (but not natural) progestin may negate the beneficial effects of estrogen, possibly because of MPA’s androgenic properties (29). Similar doses of MPA were combined with estrogen in both active-treatment groups. Therefore, we were unable to isolate the effects of MPA on endothelial function in the present study. Thus, further studies are needed to fully evaluate the relationship between the effect of progestin and endothelial function in postmenopausal women receiving low-dose ERT.

Lipid and MDA-modified LDL

In the present study, similar reductions in the serum concentrations of total and LDL cholesterol and increases in the serum concentrations of HDL cholesterol were observed in the two treatment groups. These results are generally consistent with the findings of the Women’s Health Osteoporosis, Progestin, Estrogen Study (30). However, the changes in TG were different in the two treatment groups. The serum TG concentration in the standard-dose group rose, whereas the concentration in the low-dose group fell. Schnell et al. (31) have reported that modest elevations in the TG concentration are not associated with impaired endothelial function in the brachial artery. Although the increase in the standard-dose group and the decreases in the low-dose group were significant, the absolute values remained within the normal range throughout the study. Therefore, these findings suggest that modest changes in the serum TG concentration induced by HRT may have only a small effect on the forearm endothelial function in postmenopausal women free from other risk factors for CHD.

We also evaluated the effects of HRT on MDA-modified LDL, which may reflect endothelial injury or plaque instability, in postmenopausal women. Ischemic injury of the endothelium is associated with prostaglandin synthesis and platelet adhesion and aggregation, which, in turn, releases aldehydes that substitute the lysis residues in the apolipoprotein B-100 moiety of LDL in the absence of lipid peroxidation (32, 33). This type of oxidatively modified LDL is referred to as MDA-modified LDL. Holvoet et al. (34) have reported that plasma levels of MDA-modified LDL are increased in patients with acute coronary syndromes, i.e. unstable angina or acute myocardial infarction. These data suggest that the generation of MDA-modified LDL may be a marker of ischemic injury or plaque instability. Further, a balance between the levels of super oxide and NO plays an important role in maintaining normal endothelial function. Serum MDA-modified LDL levels has been used as indices of oxidative stress. The measurement of MDA-modified LDL has been proposed as the biologic signature of clinical in vivo LDL oxidation (35). In the present study, both standard-dose and low-dose HRT similarly decreased the serum concentrations of MDA-modified LDL. One possible mechanism by which HRT improves the FBF response to reactive hyperemia is decreasing oxidative stress, which may directly cause endothelial dysfunction.

Unacceptable side effects

Lack of compliance with HRT in postmenopausal women is often attributable to fears of breast cancer, unwanted symptoms resulting from the concomitant use of progestins, and irregular vaginal bleeding. Low-dose estrogen can alleviate vasomotor symptoms, and progestins may not be requisite. The incidence of vaginal bleeding and breast tenderness induced by HRT was lower with the low-dose group than the standard-dose HRT group. Therefore, the use of low-dose HRT may improve patient compliance. However, these results must be validated by long-term study.

Study limitations

Reactive hyperemia is mediated by a number of factors, including NO, prostaglandin, endothelium-derived hyperpolarizing factor, and ischemia-induced adenosine release. In our previous study (36), the NO synthase inhibitor NG-monomethyl-L-arginine reduced reactive hyperemia by approximately 50% in Japanese patients. These findings suggest that NO may be responsible for about half of the FBF response to reactive hyperemia. Therefore, we believe that the improvement in the FBF response to reactive hyperemia with HRT is attributable to increased NO production. However, we cannot exclude the possibility that other vasodilators contribute as well.

The present study was done as postmarketing surveillance, and we did not use a masked study design. Whether the beneficial effects of low-dose estrogen, with or without progestins, can reduce the incidence of cardiovascular events long-term can only be established in long-term prospective trials.

Conclusions

The Nurses’ Health Study demonstrated that low-dose HRT reduces the risk of CHD without increasing the risk of stroke in healthy women. These data suggest that prothrombotic effects may be diminished by the use of low-dose HRT. Also, C-reactive protein, as an independent predictor of CHD that shows a rapid increase after initial HRT in conventional dosages, does not show an increase during low-dose HRT (37). We found that the improvement in the lipid profile, MDA-modified LDL levels, and forearm endothelial function with low-dose CEE and MPA was similar to that with standard doses of CEE plus MPA, yet the incidence of vaginal bleeding and breast tenderness was lower. Lower estrogen dosages might provide another cardiovascular risk, as compared with conventional dosages.


   Acknowledgments
 
We thank Hitoshi Nakagawa, M.D., for technical support and Hiromi Muraoka for secretarial assistance.


   Footnotes
 
This study was supported in part by the Tsuchiya Memorial Foundation.

Abbreviations: ACE, Angiotensin-converting enzyme; CEE, conjugated equine estrogen; CHD, coronary heart disease; FBF, forearm blood flow; HDL, high-density lipoprotein; HERS, Heart and Estrogen/Progestin Replacement Study; HRT, hormone replacement therapy; LDL, low-density lipoprotein; MDA, malondialdehyde; MPA, medroxyprogesterone acetate; NO, nitric oxide; NTG, nitroglycerin; PRA, plasma renin activity; TG, triglycerides; WHI, Women’s Health Initiative.

Received July 24, 2002.

Accepted November 25, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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X. Guo, M. Razandi, A. Pedram, G. Kassab, and E. R. Levin
Estrogen Induces Vascular Wall Dilation: MEDIATION THROUGH KINASE SIGNALING TO NITRIC OXIDE AND ESTROGEN RECEPTORS {alpha} AND {beta}
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