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(Hypertension. 1999;34:1041-1046.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Effects of Transdermal 17ß-Estradiol on Left Ventricular Anatomy and Performance in Hypertensive Women

Maria Grazia Modena; Nicola Muia, Jr; Pietro Aveta; Rosella Molinari; Rosario Rossi

From the Institute of Cardiology II, Department of Internal Medicine, University of Modena, Italy.

Correspondence to Maria Grazia Modena, MD, FESC, FACC, Institute of Cardiology II, Policlinico Hospital, Via del Pozzo, 71, 41100 Modena, Italy. E-mail modena.m{at}policlinico.mo.it

	Abstract

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Abstract—To reduce cardiovascular complications, antihypertensive therapy should not only normalize blood pressure but also induce a regression of structural abnormalities, which are the expression of end-organ damage. We investigated the effects of transdermal 17ß-estradiol, combined with standard antihypertensive therapy, on the modification of left ventricular anatomy and systolic performance in hypertensive postmenopausal women. In a randomized, double-blind, placebo-controlled study, we enrolled 169 postmenopausal women with mild or moderate hypertension. Eighty-six patients (group 1) received transdermal 17ß-estradiol (50 µg/d) and norethisterone acetate (2.5 mg/d, orally), and 83 patients (group 2) received placebo. At baseline, all women underwent M-mode and 2-D echocardiogram, which was repeated after 6, 12, and 18 months of follow-up. After 18 months of treatment, we observed a significant decrease in left ventricular diastolic septal and posterior wall thickness and mass in both groups. Furthermore, after 18 months, left ventricular mass was significantly less than in the estrogen-treated group. No significant modifications were observed in left ventricular systolic and diastolic dimensions or in systolic performance, as expressed by left ventricular fractional shortening. In conclusion, transdermal 17ß-estradiol, which is associated with antihypertensive therapy, may contribute in the reduction of left ventricular mass in hypertensive postmenopausal women.

Key Words: hypertension, mild • hypertrophy • trials • drugs • estrogen • menopause • echocardiography

	Introduction

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The increase in left ventricular mass (LVM) represents the general structural mechanism of adaptation of the heart in response to a chronic pressure overload of the left ventricle.¹ Epidemiological data indicates that left ventricular hypertrophy (LVH) is the most important independent risk factor for coronary heart disease in women.² No critical value has been detected to distinguish between compensatory and pathological hypertrophy; the risk of cardiovascular sequelae increases progressively with the increase in LVM.³

Serum levels of 17ß-estradiol, which decrease at menopause, can be replaced by therapeutic intervention. The oral administration of estrogen improves the cardiovascular risk profile in postmenopausal women;⁴ observational studies have shown its protective effect on the cardiovascular system,^{5 6 7} and the Heart and Estrogen/progestin Replacement Study (HERS),⁸ which is the only published trial on the secondary prevention of cardiovascular events in postmenopausal high-risk women, did not demonstrate beneficial effects of hormone replacement therapy (HRT). Transdermal application has been proposed as an alternative and effective route of administration,^{9 10 11} with the advantage that natural estrogen is used.

There have been animal studies¹² that demonstrated some estrogen effect on cardiac anatomy, but there are none, to the best of our knowledge, that investigated the effects of estrogen on left ventricular anatomy and function in humans. In this randomized, double-blind, placebo-controlled study, we evaluated, by echocardiography, the modification of left ventricular morphology and systolic performance in hypertensive postmenopausal women treated with standard antihypertensive therapy plus transdermal 17ß-estradiol.

	Methods

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Study Design
From February 1995 to April 1996, one hundred sixty-nine consecutive postmenopausal patients with newly diagnosed mild to moderate hypertension (Stages 1 and 2 according to the Fifth Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, JNC V¹³ ) were enrolled into the study. Menopause was defined by the absence of menstruation for at least 12 months and by follicle-stimulating hormone blood levels >40 IU/L and 17ß-estradiol levels <110 pmol/L.

Hypertension was diagnosed by 2 consecutive measurements at an interval of 1 week after an initial high reading and blood pressure measurements were performed, which was in accordance with the American Society of Hypertension recommendations.¹⁴ Patient history, physical examination, 12-lead ECG, and echocardiogram were used to exclude past or present heart disease. All hypertensive women were advised to modify their lifestyle habits according to the recommendation of the JNC V.¹³ If these measures were unable to reduce blood pressure values, pharmacological therapy was initiated. Therapies were assigned to maintain systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg. This phase of antihypertensive therapy adjustment lasted 6 months; during this period, study subjects were controlled every 4 weeks. The choice of the antihypertensive drug therapy was at the discretion of the study investigators and was done by a "step-by-step" approach when blood pressure values were unsatisfactory (>140/90 mm Hg). All the blood pressure measurements followed the same procedure.

When blood pressure values were <140/90 mm Hg for 3 consecutive measurements, ie, at least 3 months of controlled blood pressure, patients were randomly assigned, in a double-blind fashion, to receive 17ß-estradiol or placebo. Women were excluded from the study for the following reasons: hypertension >stage 2¹³ at admission; failure to achieve blood pressure values <140/90 mm Hg after 6 months, despite antihypertensive therapy; past, present, or suspected neoplastic pathology; unexplained uterine bleeding within the 6 months before randomization; surgical hysterectomy; past or present use of any estrogen or progestin-containing compounds or other hormonal agents, such as tibolone or selective estrogen receptor modulators, such as tamoxifen; cardiomyopathies; history of deep vein thrombosis or pulmonary embolism; history of gallbladder disease; hepatic failure (serum bilirubin >2 times upper normal limit); renal failure (serum creatinine >2.0 mg/dL); alcoholism or other drug abuse; uncontrolled diabetes (fasting blood glucose levels >300 mg/dL); serum triglyceride levels >300 mg/dL; unlikely to remain geographically accessible for study visits for at least 2 years; disease judged likely to be fatal within 2 years; and current participation in ongoing clinical trials.

17ß-estradiol was administered in the form of self-adhesive cutaneous patches, which provided a cutaneous absorption rate of 50 µg/24 h. The placebo patches were identical in appearance; all patches were changed twice weekly. Patients treated with estrogen received norethisterone acetate (2.5 mg/d, orally), whereas patients not treated with estrogen received placebo. In case of untoward effects, the dose of estrogen was reduced (from 50 to 25 µg/d), and if the effects persisted, the patients were dropped from the study.

At baseline, all women underwent an M-mode and 2-D echocardiogram. After 6, 12, and 18 months of HRT, blood pressure measurement and an echocardiogram were repeated. Telephone contact was used after 3, 9, and 15 months to increase compliance and reduce drop out rate. All enrolled subjects gave written informed consent, and the Ethics Committee of the University of Modena approved the study protocol.

Echocardiographic Examination
Echocardiographic examination was performed with a 7-MHz transducer (Acuson 128 XP/10c, Acuson Inc) with a 2.5-Mhz transducer frequency. Left ventricular end-diastolic (LVEDD, mm) and end-systolic diameter (LVESD, mm) and left ventricular diastolic septal (LVDSWT, mm) and posterior wall thickness (LVDPWT, mm) were measured by M-mode with 2-D guidance at conventional levels, according to the American Society of Echocardiography (ASE) recommendations. All echocardiographic measurements were made over 3 consecutive cardiac cycles, and the mean value was used for statistical analysis. Left ventricular systolic fractional shortening (LVFS, %) was calculated with the following formula: 100x(LVEDD-LVESD)/LVEDD. Left ventricular mass (g) was calculated with the ASE formula modified by Devereux¹⁵ and was indexed by height^2.7 (LVMI, g/m^2.7), a method that is unaffected by within-group distribution of body mass index.¹⁶ To assess the geometric pattern of the left ventricle, relative wall thickness (RWT), according to Ganau et al, ¹⁷ was measured at end diastole as the ratio of 2x(LVDPWT/LVEDD). With the same M-mode and 2-D echocardiographic method, we evaluated 45 healthy postmenopausal women who were never treated with HRT (mean age: 56±6 years). LVMI was 39.8±10.5 g/m^2.7 and the RWT was 0.37±0.06; we considered LVH when LVMI exceeded the mean value plus 2 SD, ie, 60.1 g/m^2.7.

Images were stored on Super VHS videotape with a videocassette recorder for possible later evaluation. All examinations were performed by the same sonographer, who was unaware of the study protocol and of the assumed therapy. To evaluate the reproducibility of the echocardiographic measurements, 50 echocardiograms were re-examined by 2 different expert cardiologists (M.G.M. and R.R.). These echocardiograms were selected at random without knowledge of the patient’s identity or previous evaluation results. The interobserver coefficient of variation resulted in 7.2% for LVDSWT, 2.5% for LVEDD, 7.5% for LVDPWT, and 9.7% for LVM.

Statistical Analysis
The continuous variables were expressed as mean±1 SD, and the categorical variables were expressed as percentages. The 2 groups were compared by the Student t test for unpaired data and the ² test with the Yates correction for continuity, when appropriate. Baseline values and those recorded after 6, 12, and 18 months were compared by repeated measures of variance. When significant differences were seen between time points, the paired t test with the Bonferroni correction were applied to obtain pairwise comparisons. All probability values are 2-tailed. A P<0.05 was taken as significant. Data were collected in a Windows-based relational database (Microsoft Access 3.11) and analyzed with the SPSS (Statistical Package for the Social Science, version 7.0) for Windows 95 (Microsoft Corp).

	Results

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Among 169 postmenopausal women with primary mild to moderate hypertension, 86 (50.9%) (group 1) were randomly assigned to the treatment with transdermal 17ß-estradiol plus norethisterone acetate and 83 (49.1%) (group 2) were randomly assigned to placebo. Baseline demographic, clinical, and echocardiographic parameters were compared between the groups, and no significant differences were found (Table 1). After 18 months of treatment, 17ß-estradiol plasma levels increased from 54±32 pmol/L to 392±63 pmol/L in group 1 (P<0.0001), whereas in the placebo group, it did not vary significantly (from 60±25 pmol/L to 58±30 pmol/L; P=ns). None of the patients had to suspend hormonal therapy for untoward effects; in 8 of 86 treated patients (0.9%), we had to reduce the dosage of 17ß-estradiol to 25 µg/d because of vaginal bleeding (2 cases) or breast tenderness (6 cases). The antihypertensive regimens and the proportions of subjects who received lifestyle measures only, angiotensin-converting enzyme inhibitors, calcium channel blockers, ß-blockers, and thiazide diuretics, alone or combined, or other drugs are shown in Table 2. The distribution of antihypertensive treatments did not differ among the 2 groups. There was also no difference in the drop out rate: 6 patients in group 1 (6.9%) and 4 patients in group 2 (4.8%) (P=ns). During the follow-up, no acute cardiovascular and cerebrovascular events or deaths were recorded.

View this table: [in this window] [in a new window]   Table 1. Main Demographic, Clinical, and Echocardiographic Characteristics of the Participants at Baseline: Comparison Between Groups

View this table: [in this window] [in a new window]   Table 2. Antihypertensive Treatment: Comparison Between Groups

Effects of Treatment on Echocardiographic Parameters
The intragroup comparison revealed that after 18 months of therapy, we observed a significant decrease in LVDSWT, LVDPWT, LVM, and LVMI. Compared with baseline, these indexes showed a significant decrease in both groups, as well as the prevalence of LVH (Table 3). The intergroup comparison highlighted that after 18 months of treatment, LVDSWT, LVDPWT, LVM, LVMI, and the prevalence of LVH occurred significantly less often in the estrogen-treated group compared with the placebo-treated group (Table 3). The reduction of LVM was not accompanied by a significant modification of RWT, reflecting an inconsistent change in left ventricular geometric pattern in both groups. Furthermore, no significant modifications were observed in left ventricular systolic and diastolic dimensions or in systolic performance expressed by LVFS (Table 3).

View this table: [in this window] [in a new window]   Table 3. Serial Changes in Clinical and Echocardiographic Parameters: Intergroup and Intragroup Comparisons

	Discussion

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To reduce cardiovascular complications, antihypertensive therapy should not only normalize blood pressure values but also induce a regression of structural abnormalities that are the expression of end-organ damage.¹⁸ Echocardiographic investigations indicate that antihypertensive therapy can reduce LVM in hypertensive patients.^{19 20} LVM reduction leads to an improvement in left ventricular systolic and diastolic function,²¹ an increase in coronary blood flow reserve,²² a normalization of cardiopulmonary reflexes,²³ a restoration of reduced response to ß-adrenergic stimulation,²⁴ and a reduction in arrhythmic episodes.²⁵ Data from the Framingham population demonstrated that LVM normalization, detected by ECG, was associated with a reduction in cardiovascular events;²⁶ other studies found a link between reduction of echocardiographically determined LVMI and cardiovascular disease in essential hypertension.^{27 28 29} Muiesan et al²⁷ showed that patients in whom LVH persisted or developed despite antihypertensive therapy were at higher risk to suffer cardiovascular complications than those in whom hypertrophy regressed or was never present. This and other studies suggest that a therapy that reduces LVM improves the outcome in hypertensive patients.^{28 29}

Left ventricular performance is normal or supernormal in patients with hypertension and LVH, and this persists after the regression of LVH.³⁰ Even in our study population, systolic function, evaluated by LVFS, was normal at baseline and after 18 months. Some authors³¹ have demonstrated an improvement in left ventricular systolic function after LVM reduction. In our study, although statistically significant increases of LVFS over time were not recorded, we noticed that LVFS improved in both groups compared with baseline. It is possible that LVFS is not the ideal parameter to study left ventricular performance in hypertensive patients, especially in those with concentric remodeling or hypertrophy. It has been suggested that the midwall fractional shortening end-systolic stress relation represents a more appropriate index of performance because it considers different myocardial fiber displacements in the hypertrophic left ventricular wall; this index was lower even in asymptomatic hypertensive patients at rest.³²

The results of our study clearly indicate that HRT may contribute to the reduction of LVM. To explain this finding, we can hypothesize several mechanisms. It is known that 17ß-estradiol has a powerful calcium antagonist effect on both vascular smooth muscle cells and cardiac fibers.^{33 34} Substantial evidence suggests that 17ß-estradiol has a significant impact on the renin-angiotensin system; Schunkert et al³⁵ demonstrated that both oral and transdermal HRT is related to a substantial suppression of serum renin levels; on the other hand, an increase in angiotensinogen has been described only in women taking oral estrogen. Proudler et al³⁶ highlighted a 20% reduction in the plasma concentration of ACE after 6 months of treatment with transdermal 17ß-estradiol; furthermore, the natural hormone inhibits in vitro the vasoconstriction effect of angiotensin II and therefore is involved in the peripheral sympathetic tone modulation.³⁷ This finding has been demonstrated in humans by Mercuro et al;³⁸ in this study, the acute administration of transdermal 17ß-estradiol was associated with a significant reduction of norepinephrine plasma levels in a population of postmenopausal women. In conclusion, transdermal 17ß-estradiol, associated with antihypertensive therapy, may contribute to the reduction of LVM in hypertensive postmenopausal women; the mechanisms by which this event occurs is little known and may be multifactorial.

	Acknowledgments

 
This study was partially supported by a grant of the Italian MURST (Ministero dell’Università e della Ricerca Scientifica e Tecnologica) and was sponsored by WOCDA (WOmen Cardiovascular Disease Association). Giorgia Origliani provided the technical assistance that made this study possible.

Received March 8, 1999; first decision April 6, 1999; accepted June 30, 1999.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Modena, M. G. Articles by Rossi, R. Search for Related Content PubMed PubMed Citation Articles by Modena, M. G. Articles by Rossi, R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ESTRADIOL Medline Plus Health Information High Blood Pressure Related Collections Other hypertension Hypertrophy Cardiovascular Pharmacology Echocardiography