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Am J Physiol Heart Circ Physiol 276: H1355-H1360, 1999;
0363-6135/99 $5.00
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Vol. 276, Issue 4, H1355-H1360, April 1999

Physiological doses of estradiol decrease nocturnal blood pressure in normotensive postmenopausal women

Angelo Cagnacci1, Lucio Rovati2, Annalisa Zanni1, Stefania Malmusi1, Fabio Facchinetti1, and Annibale Volpe1

1 Institute of Obstetrics and Gynecology, University of Modena, 41100 Modena; and 2 Rotta Research Laboratorium Società per Azioni, 20052 Monza, Italy


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The effect of a 2-mo treatment with transdermal estradiol (50 µg/day) versus placebo on 24 h of blood pressure rhythm was investigated in 18 normotensive healthy postmenopausal women. Whereas daytime blood pressure was not modified, nighttime blood pressure was reduced by estradiol. Estradiol magnified the nocturnal decrement of systolic (14.3 ± 7.2 vs. 9.8 ± 6.7 mmHg, P = 0.0033), diastolic (11.6 ± 5.0 vs. 7.5 ± 7.3 mmHg, P = 0.028), and mean (10.8 ± 5.6 vs. 7.2 ± 4.5 mmHg, P = 0.011) blood pressure. As a consequence, the 24-h rhythm of mean blood pressure was restored in 50% of the subjects (P = 0.045) in whom it was absent and was amplified in the remaining 50% of the subjects. Body mass index was an independent determinant of blood pressure values being directly related to the amplitude of the 24-h mean blood pressure rhythm (r2 = 0.38; P = 0.0067). In normotensive postmenopausal women, physiological doses of estradiol amplify the nocturnal decline of blood pressure.

circadian; menopause; cardiovascular risk; hypertension


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

CARDIOVASCULAR DISEASES represent the primary cause of death in women, and coronary artery disease is the leading cause (32). Mortality for coronary artery disease is shifted toward women of older age (23, 32) and is believed to be reduced, through still uncertain mechanisms (2, 10, 43, 49), by postmenopausal hormone replacement therapy (HRT) (11, 16, 17, 39, 49). Along with smoking, hypercholesterolemia, and diabetes, elevation of blood pressure is one of the leading risk factors for cardiovascular diseases (13, 36). An increase in blood pressure has been documented after menopause, but it is still unclear whether this increase is due to estrogen withdrawal, aging, or variations in body weight and composition (44). However, when corrected for significant covariates, the slope of systolic blood pressure with age is steeper in post- than in premenopausal women (45). Whereas the administration of oral contraceptives increases (even slightly) blood pressure (22, 50), HRT has been reported to either increase (27), decrease (19, 26, 55), or not modify (20, 21, 31, 35, 40, 51, 55) blood pressure of postmenopausal women. The nighttime values of blood pressure, besides the daytime, are important for the definition of a woman's cardiovascular risk (28, 41, 52, 53). Indeed, the risk is lower in dipper individuals, who show a physiological nocturnal blood pressure decline, than in nondippers (28, 41, 52, 53). Accordingly, in the present study we investigated how replacement with physiological doses of estrogens may influence the 24-h control of blood pressure in normotensive postmenopausal women.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Study population. Eighteen healthy postmenopausal women in natural menopause for at least 1 yr were recruited at the Menopause Center of our Institute and voluntarily signed an informed consent to participate in the study, which was previously approved by the local ethical committee. All subjects were free from medications and were not suffering from severe climacteric complaints, as evaluated by an arbitrary 0 to 3 score system (0 = absent, 1 = slight, 2 = moderate, 3 = severe). No subject was taking or had received antihypertensive drugs or HRT in the 3 preceding months. Women with an altered thyroid status as well as women who smoke were excluded from the study. Circulating levels of follicle-stimulating hormone (FSH), estradiol, lipoproteins, apolipoprotein A (ApoA), apolipoprotein B (ApoB), glucose, and insulin were determined at baseline. Available radioimmunological kits were used for the analysis of FSH (Sorin Biomedica, Saluggia, Vercelli, Italy), estradiol (Medical System, Genova, Italy), and insulin (Biodata, Guidonia Montecelio, Roma, Italy; range for fasting levels 5-25 mU/ml)(7). Plasma total cholesterol and triglycerides were measured by enzymatic methods (Olympus), whereas high-density lipoprotein (HDL) cholesterol was determined after precipitation with PEG 6000. Low-density lipoprotein (LDL) cholesterol levels were calculated by the formula of Friedewald et al. (14). ApoA (normal range 102-205 mg/dl) and ApoB (normal range 59-155 mg/dl) were determined by immunonephelometry on a Behring Nephelometer Analyzer (Behringwerke Marburg). Glucose levels were measured by the glucose oxidase method. Values of FSH >40 IU/l and of estradiol <25 pg/ml confirmed the postmenopausal status. Women with glucose intolerance (fasting glucose >110 mg/dl) or marked alterations in lipid metabolism (LDL cholesterol or triglycerides values >200 mg/dl) were excluded. Normotension was initially diagnosed by office blood pressure measurement, using a mercury sphygmomanometer according to the recommendations of the American Society of Hypertension (1). Three blood pressure readings measured with the woman sitting quietly for 5 min were averaged to determine conventional blood pressure. Women with blood pressure >140/90 mmHg were excluded from the study.

Ambulatory monitoring. Blood pressure was measured by a 24-h oscillometric blood pressure monitoring device (ABP Monitor, Spacelabs Medical, Redmond, WA). Calibration of the system was checked for each single 24-h recording by a full-size mercury sphygmomanometer, with monitor readings maintained within 3 mmHg of the manometer readings. Blood pressure was sampled every 30 min. When unsuccessful at the first try, blood pressure was checked again. Unsuccessful readings were recorded as event codes (subjects movements, heart arrhythmias, unreasonable blood pressure, etc.). Twenty-four-hour reports were considered appropriate when successful readings exceeded 90%. Readings used for analysis were those collected between 8:00 PM and 8:00 PM of the next day, when subjects were discharged. Raw blood pressure and pulse rate readings were then transferred to a computer and elaborated.

Study design. After a preliminary 24-h blood pressure-monitoring period utilized to accommodate the subjects to the procedure, each woman was randomized to receive a treatment in a double-blind fashion for 2 mo with patches calibrated to deliver either 50 µg/day of 17beta -estradiol (Dermestril 50; Rotta Research Laboratorium SpA)(n = 9) or placebo (n = 9). At the end of the 2 mo each subject was switched to the alternate treatment for another 2 mo. Subjects were requested to maintain their lifestyle and physical activity as constant as possible during the two treatment periods. Blood pressure was monitored for 24 h at the end of each 2-mo treatment period. During the 24-h blood pressure-monitoring period, subjects were requested to maintain the arm motionless and parallel to the trunk when the cuff was inflated. Subjects were admitted to the hospital between 3:00 PM and 4:00 PM. During the daytime, subjects were free to walk inside the hospital and to eat at scheduled times. Caloric intake was 25-30 calories · kg · day and salt intake was 50-60 meq · m2 · day. Food was divided into three meals containing 20% of the calories at breakfast (7:30-8:00 AM), 40% of the calories at lunch (12:30-1:00 PM), and 30% of the calories at dinner (7:30-8:00 PM). Napping was not allowed during the daytime, although subjects were asked to sleep from 11:00 PM to 7:00 AM in complete darkness. A morning blood sample was also collected for the analysis of FSH, estradiol, and insulin levels. Blood pressure values were analyzed as the 24-h mean, the daytime mean (7:00 AM-11:00 PM), and the nighttime mean (11:00 PM-7:00 AM). Pulse pressure was also analyzed. The vascular overload index, which defines the variation from an ideal blood pressure of 120/80 mmHg, was calculated as the sum of the variation of mean blood pressure on an ideal value of 93.3 mmHg plus the variation of pulse pressure on an ideal value of 40 mmHg (13).

Statistical analysis. Twenty-four-hour mean blood pressure values were analyzed by cosinor analysis. Cosinor analysis represents a rhythmometric method in which the entire time series of data are fitted by a least-squares cosine function. To minimize type I errors, rejection of the null hypothesis was set at a significance level of 0.05. Rejection of the null hypothesis signifies that the fitted curve approximates the data more closely than does a straight line with zero slope (implying consistency) (33). When cosinor analysis was significant, we calculated and recorded the mesor (mean cosine value), which is the mean 24-h blood pressure value, the acrophase (time of maximal cosine function), which is the time in the 24-h period when blood pressure values are maximal, and the amplitude (maximal difference of the cosine function from the mesor), which is one-half of the blood pressure excursion in the 24-h period (5). After the assessment of the normal distribution of the differences via the coincidence of the arithmetic mean with the median, we used the paired t-test to evaluate whether the dependent variables, i.e., 24-h, daytime, or nighttime circulatory parameters (systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate, pulse pressure, or vascular overload index) were different during the administration of placebo or estradiol (independent variables). The null hypothesis of no difference between the two administrations was rejected at a level of significance for a two-tailed test of 0.05. Two-factor ANOVA for repeated measures was used on data that were independently sampled from multivariate distinct populations with the same variance structure for each group. Differences in factor 1 and factor 2 and interference between factor 1 and factor 2 were considered significant at a P value of 0.05. ANOVA was used to investigate whether treatments (placebo or estradiol; factor 1) were capable of influencing the daytime to nighttime (factor 2) variation of blood pressure in the investigated subjects (replicates). Similarly, ANOVA was used to test whether, in the investigated subjects (replicates), treatments (placebo or estradiol; factor 1) had a different influence in the daytime-nighttime difference of systolic or diastolic pressure (factor 2). The number of women in whom 24-h mean blood pressure values were fitted by a cosine function during placebo was compared with that observed during transdermal estradiol by the chi-square test. A P value of 0.05 was used to reject the null hypothesis of a similar percentage during the two treatments. To determine whether blood pressure parameters were influenced by endocrine and clinical parameters, values of either daytime, nighttime, or 24-h systolic, diastolic, or mean blood pressures were separately regressed (dependent variable) by multiple regression analysis on age and months since menopause, body mass index (BMI), insulin, and estradiol. Analyses were performed after the assumptions of normality of residuals and homogeneity of variance were satisfied. The null hypothesis of no relationship between blood pressure and the included parameters was rejected at a P value of 0.05. A separate analysis on data obtained only during transdermal estradiol administration was also performed.

All the results are expressed as means ± SD.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Baseline characteristics of enrolled subjects are reported on Table 1.

                              
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  		Table 1.   Biophysical and biochemical parameters at baseline

No effect of the sequence of the treatment was observed, and all the placebo data were compared with all the estradiol data. Estradiol levels were lower during the placebo treatment than during the estradiol treatment (16.31 ± 6.12 vs. 38.1 ± 19.1 pg/ml; P = 0.0001), whereas FSH levels were higher in the placebo treatment than the estradiol treatment (79.9 ± 36.2 vs. 51.2 ± 28.2 IU/l; P = 0.0001). During placebo or estradiol administration, similar mean scores were found for hot flushes (0.92 ± 1.06 vs. 0.58 ± 0.15) or insomnia (0.71 ± 0.88 vs. 0.38 ± 0.77). Similarly, no difference was found between the two treatments in terms of side effects related to estrogen administration as breast tenderness, weight gain, and vaginal bleeding or spotting. A tendency toward lower levels was observed during transdermal estradiol for 24-h systolic, diastolic, and mean blood pressures (Fig. 1), whereas heart rate tended to be higher (Table 2). Pulse pressure was similar in the two conditions, whereas the vascular overload index tended to be lower during 17beta -estradiol (Table 2). The same trend was observed for daytime parameters (7:00 AM-11:00 PM) of blood pressure, which were not significantly modified by estradiol (Fig. 1; Table 2). During transdermal estradiol, lower values of systolic, diastolic, and mean blood pressures and vascular overload index were observed at night (Fig. 1; Table 2). ANOVA showed that the nighttime decline (P = 0.0001) of circulatory parameters was different between the placebo and estradiol administration for systolic (P = 0.021), diastolic (P = 0.031), and mean blood pressure (P = 0.029) and vascular overload index (P = 0.049) but not for heart rate. Accordingly, the daytime-nighttime difference in systolic, diastolic, and mean blood pressure was greater during estradiol treatment than during placebo treatment (Table 3). The influence of estradiol was similar on systolic and diastolic blood pressures (ANOVA).


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  		Fig. 1.   Values are means ± SD of 24 h mean (A), systolic (B), and diastolic (C) blood pressure measured in postmenopausal women during 2-mo administration of placebo or a transdermal patch rated to deliver 50 µg/day of estradiol. Gray areas indicate nighttime period.

                              
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  		Table 2.   Cardiovascular parameters


                              
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  		Table 3.   Daytime-nighttime differences in cardiovascular parameters

A cosine function was fitted to the 24-h mean blood pressure of nine women (50%) during placebo treatment and of all women (100%) during estradiol treatment (P = 0.045 by the chi-square test). In the nine women in whom mean blood pressure was fitted during placebo (Fig. 1), the cosinor function revealed that during estradiol the mesor was reduced (from 89.56 ± 7.2 to 86.22 ± 6.74 mmHg; P = 0.015), the amplitude was increased (from 7.35 ± 1.84 to 9.6 ± 3.32 mmHg; P = 0.042), and the acrophase was not modified (from 14.52 h ± 121 min to 14.36 h ± 180 min).

By multiple regression analysis, BMI and estradiol were the only two parameters related to blood pressure values. After exclusion of estradiol, BMI was the only index related to blood pressure. BMI was directly related to 24-h systolic (r2 = 0.12, P = 0.045), diastolic (r2 = 0.14, P = 0.031), and mean (r2 = 0.13, P = 0.04) blood pressure and to daytime diastolic (r2 = 0.12, P = 0.049) and mean (r2 = 0.13, P = 0.034) blood pressure. The relation of BMI with daytime systolic blood pressure was close to the arbitrarily defined cutoff for statistical significance (r2 = 0.1; P = 0.062). BMI was not related to any parameter of nighttime blood pressure. In the analysis restricted to the estradiol treatment, BMI was related directly (r2 = 0.38; P = 0.0067) to the amplitude of the 24-h mean blood pressure rhythms and to daytime (r2 = 0.34; P = 0.014) but not to nighttime mean blood pressure values (Fig. 2).


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  		Fig. 2.   Regression between body mass index and amplitude of 24-h mean blood pressure rhythm (A), mean daytime (7:00 AM-11:00 PM) values (B), and mean nighttime (11:00 PM-7:00 AM) values (C) in 18 normotensive postmenopausal women during 17beta -estradiol administration.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

To our knowledge this is the first placebo-controlled study documenting the 24-h blood pressure variation in normotensive postmenopausal women during the prolonged replacement with physiological doses of estradiol. As previously reported (6, 7, 9), the dose of transdermal estradiol used is capable of inducing circulating levels of the hormone in the range of the early follicular menstrual phase. For periods shorter than 3 mo, doses of transdermal estradiol similar to those used in the present study are believed not to induce relevant modifications of lipid or glucose levels and slightly to reduce fasting insulin levels (6, 7, 9, 54). The effect of estrogens on blood pressure has not been consistently determined, and increases (27), no modifications (20, 21, 31, 35, 40, 51, 55), or decreases (19, 26, 55) of blood pressure have all been documented. Transdermal estradiol does not influence the liver synthesis of the renin substrate, and its administration in doses capable of reproducing early follicular phase values (6, 9) is ideal for studying the physiological effect of ovarian estrogens on the control of blood pressure.

The effect of transdermal estradiol on blood pressure, similar among normolipemic and slightly hyperlipemic subjects, was less evident during the day than at night. Either the effect of estradiol is counteracted during the day or it is enhanced at night. The nocturnal decline in noradrenergic activity can be enhanced by estrogens (29, 48), and estradiol may restore an endogenous opiodergic tone (6), which has been reported to be critical for the nocturnal blood pressure decline (37). Estradiol may also potentiate the cardiovascular effect exerted by substances selectively produced at night, one of which is melatonin (4, 5). The nocturnal blood pressure decline is strictly linked to modifications of body temperature regulation (42), most of which are mediated by the nocturnal surge of melatonin (5). Melatonin has recently been reported to decrease blood pressure and catecholamine levels in women (4), and in contrast to its levels, its action on some endocrine functions such as cortisol regulation is modulated by gonadal steroids (8). A reduction in climacteric symptoms and insomnia can also be involved in the observed modifications of blood pressure induced by estradiol (24, 25, 34, 46), but although monitored only by an arbitrary score, subjective hot flushes and insomnia were very mild and not significantly different between the estradiol and placebo administration.

By the amplification of the nighttime decline of blood pressure, estradiol restores and amplifies the 24-h blood pressure rhythm, as evidenced by cosinor analysis. In some cases cosinor analysis may be incorrect in determining the 24-h rhythm of blood pressure (47), but the observed amplification of the rhythm amplitude was confirmed by an enhancement in the daytime-nighttime difference of blood pressure induced by estradiol. Independently of estradiol, the rhythm amplitude was directly related to BMI. BMI was related to daytime but not nighttime values of blood pressure. Accordingly, whereas estradiol enhances the nighttime decline, BMI enhances the daytime increase of blood pressure and contributes to the determination of hypertension (15, 18, 38).

The data of the present 24-h investigation in normotensive postmenopausal women treated with transdermal estradiol at the dose of 50 µg/day are at variance with two studies in which the 24-h blood pressure investigations were evaluated in hypertensive postmenopausal women. In one study a dose of estradiol, twice the dose used in the present study, administered 12 h before testing, was reported to reduce daytime but not nighttime blood pressure (30), and in the other study the prolonged administration of oral estrogens did not modify 24-h blood pressure values (40). Eventual differences in the blood pressure response to estradiol between hypertensive and normotensive women need to be investigated with the prolonged administration of physiological levels of estradiol.

Not only systolic but also nighttime mean blood pressure and the vascular overload index were significantly reduced by estradiol. Systolic blood pressure is directly related to an increase in cardiovascular risk, particularly heart disease and stroke (13), but this relation is stronger when the vascular overload index is considered (13). Indeed, the vascular overload index takes into account variations from an ideal condition of two critical variables for the cardiovascular risk as systemic static resistance, indicated by mean blood pressure variation, and dynamic resistance, indicated by pulse pressure variation (3, 12). In the present study a significant decline of mainly mean blood pressure, an index of static systemic resistance, was observed during estradiol administration.

In perspective, in hypertensive old subjects, a decrease of 9 mmHg in systolic blood pressure is capable of significantly reducing the risk of stroke, transient ischemic attack, myocardial infarction, and left ventricular failure (12). Similarly, a reduction of 6 mmHg in diastolic blood pressure in mild to moderate hypertensive individuals has been reported to reduce overall mortality from vascular disease by 21% (36). In the present study, mean nighttime values of systolic and diastolic blood pressure were lower of about 6 and 3 mmHg, respectively, during estradiol than placebo administration. At the present time, it is not known whether the effect observed after 2 mo of treatment can be maintained in the long term. Similarly, it is presently unclear whether a similar reduction in blood pressure limited to the night and in normotensive women may really reduce the risk for cardiovascular diseases, but this possibility cannot be disregarded.


    ACKNOWLEDGEMENTS

This study was supported by a grant from Rotta Research Laboratorium, Società per Azioni.


    FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: A. Cagnacci, Istituto di Clinica Ostetrica e Gincecologica, via del Pozzo 71, 41100 Modena, Italy (E-mail: cagnacci{at}unimo.it).

Received 26 August 1998; accepted in final form 16 December 1998.


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ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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Am J Physiol Heart Circ Physiol 276(4):H1355-H1360
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