Premenopausal women have a lower cardiovascular

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1 AJH 1998;11: Ambulatory Not Office Blood Pressures Decline During Hormone Replacement Therapy in Healthy Postmenopausal Women Frans J. van Ittersum, W. Marchien van Baal, Peter Kenemans, Velja Mijatovic, Ab J.M. Donker, Marius J. van der Mooren, and Coen D.A. Stehouwer Hormone replacement therapy (HRT, estrogen plus progestagen) in postmenopausal women has beneficial effects on the cardiovascular system. However, effects on blood pressure, determined with office measurements, remain controversial. We studied the effects of HRT in 29 healthy normotensive postmenopausal women (mean age 52.3 [3.8] years, median duration of amenorrhea 34.5 months), using ambulatory blood pressure monitoring at baseline and at 3 and 12 months of follow-up. Women were randomized to two groups: an HRT group (N 14), treated with 1 mg 17 -estradiol once daily and 5 or 10 mg dydrogesterone once daily during the third and fourth week of every 4 weeks; and a control group (C-group, N 15), which did not receive therapy. Blood pressures did not differ between the groups at baseline (HRT group (9.2)/74.4 (6.6) mm Hg, C-group (11.2)/71.3 (7.4) mm Hg). During the follow-up period, changes from baseline of Premenopausal women have a lower cardiovascular risk than age-matched men. 1 Menopause is believed to greatly increase the risk for cardiovascular diseases and to remove the advantage over men, as demonstrated in the Framingham Study. 1 A hypothetical explanation of this phenomenon is a postmenopausal lack of estrogen. office blood pressures did not differ significantly between the groups. However, changes (95% CI) of mean 24-h blood pressures differed significantly between the two groups after 1 year of follow-up: a decrease of blood pressures was observed in the HRT group ( systolic/ diastolic 5.54 [ 8.86 to 2.21]/ 4.23 [ 6.66 to 1.80] mm Hg), whereas an increase was found in the C-group ( 3.33 [ 0.69 to 7.35]/ [ 1.75 to 5.09] mm Hg; P [HRT v control group].001/.005). We conclude that HRT may have blood pressure lowering properties in healthy, normotensive postmenopausal women. Am J Hypertens 1998;11: American Journal of Hypertension, Ltd. KEY WORDS: Twenty-four-hour ambulatory blood pressure monitoring, office blood pressures, hormone replacement therapy, postmenopausal women. Metaanalyses of observational studies suggest a 50% reduction in heart disease risk in postmenopausal women taking estrogen replacement therapy (ERT). 2,3 Not only does administration of estradiol in postmenopausal women lead to an increase in HDL-cholesterol and a decrease in LDL-cholesterol, but it also leads to systemic vasodilation, an increase in cardiac Received July 31, Accepted May 19, From the Institute for Cardiovascular Research Vrije Universiteit Amsterdam, Department of Medicine (FJvI, AJMD, CDAS), and Department of Obstetrics and Gynecology, (WMvB, PK, VM, MJvdM) Academisch Ziekenhuis Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. Address correspondence and reprint requests to F.J. van Ittersum, MD, Department of Medicine, afdeling 0-Noord, Academisch Ziekenhuis Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; fj.vanittersum@azvu.nl 1998 by the American Journal of Hypertension, Ltd /98/$19.00 Published by Elsevier Science, Inc. PII S (98)

2 1148 VAN ITTERSUM ET AL AJH OCTOBER 1998 VOL. 11, NO. 10, PART 1 output and reversal of the decreased arterial compliance, 4 6 as well as to an enhancement of systemic fibrinolysis. 7 Observational studies indicate that hormone replacement therapy (estrogen plus progestagen, HRT) may be as effective as ERT in decreasing the cardiovascular risk in postmenopausal women. 8 The beneficial effects of HRT on the cardiovascular system cannot be fully explained by the effects on the lipid profile. 9,10 Therefore, other factors may play a role. Because menopause is associated with an increase in both office and 24-h ambulatory blood pressures, 11 blood pressure elevation may be also a factor contributing to the elevated cardiovascular risk in postmenopausal women, and the beneficial effects of HRT on the cardiovascular risk may be related, in part, to blood pressure lowering. Previous prospective studies in normotensive and hypertensive postmenopausal women 12,13 have not shown any effects of HRT on blood pressure. However, these studies used office blood pressure measurements, which are not very accurate. A more accurate technique for blood pressure determination, 24-h ambulatory blood pressure monitoring (ABPM), did not show blood pressure changes during oral treatment with conjugated estrogens and dydrogesterone in a nonrandomized study of otherwise healthy postmenopausal women or in postmenopausal women with established cardiovascular disease. 14,15 Therefore, we performed a prospective, randomized, open study of the effect of 17 estradiol in combination with dydrogesterone on blood pressures determined with ABPM in healthy, normotensive postmenopausal women. METHODS Postmenopausal, nonhysterectomized women without a history of cardiovascular disease were asked to participate in the study through an advertisement in a newspaper. The first 30 consecutive, healthy postmenopausal women (absence of menstrual blood loss during 6 months and a plasma level of follicle stimulating hormone (FSH) above 21 U/L) without a history of hypertension and with an office blood pressure 170/105 mm Hg were entered into the study within 3 months. Prior use of estrogens, progestagens, or androgens was not allowed. Further exclusion criteria were presence of acute or chronic liver disease, active deep venous thrombosis or cerebral vascular accident, cardiac failure or manifest coronary heart disease, presence of premalignant or malignant disease, abnormal mammogram at screening, abnormal serum thyroid stimulating hormone level, and known diabetes mellitus. Women were randomized to two groups: 15 women were included in the treatment group (HRT group) and 15 women in the control group. During the study three women withdrew: two from the control group because of estrogen use for climacterial complaints (N 1, at 11 months of follow-up) and lack of motivation to participate (N 1, at 10 months of follow-up), and one from the HRT group (lack of compliance at 6 weeks after the start of treatment period). As this last woman did not continue the HRT schedule, she was removed from the analysis. Thus, data for 29 women (14 in HRT group, 15 in the control group) were analyzed. All women in the HRT group took part in a double-blind, randomized multicenter trial to investigate the efficacy and safety of dydrogesterone in endometrial protection during continuous 17 -estradiol replacement, and were randomized to treatment with either 5 or 10 mg dydrogesterone. Thus, this treatment group received therapy consisting of 28-day cycles: 1 mg of micronized 17 -estradiol (Zumenon, Solvay Duphar B.V., Weesp, The Netherlands) in an open fashion once daily, and 5 or 10 mg (N 7 each) dydrogesterone (Duphaston, Solvay Duphar B.V.) once daily during the last 14 days of each 28-day treatment cycle in a blinded fashion. Women in the control group did not receive any treatment. Follow-up was 1 year. The protocol was approved by the Institutional Review Board and all women gave written informed consent. Ambulatory Blood Pressure Monitoring ABPM was performed with a SpaceLabs monitor (SpaceLabs Inc., Redmond, WA) in 30 women at baseline, in 29 women at 3 months, and in 27 women at 12 months of follow-up between the eighth and twelfth day of the 28-day treatment cycle. At the start of each ABPM registration three measurements were taken with the SpaceLabs monitor in the outpatient clinic. Means of these three blood pressure readings were considered as office blood pressures. Thereafter, blood pressure readings were taken at 15-min intervals from 7:00 am to 10:00 pm and at 20-min intervals from 10:00 pm to 7:00 am. Results of blood pressure measurements were not displayed by the monitor. Mean systolic and diastolic blood pressure values of the waking and sleeping periods were calculated as means of hourly averages. The waking and the sleeping periods were taken from the patients diaries. Other Data Hemoglobin and creatinine were determined with routine laboratory methods; FSH with a chemiluminescence-enhanced immunoassay (Amerlite Technique, Amersham Amerlite Analyser, Amersham Radiochemical, Amersham, Buckinghamshire, England). Body mass index (BMI) was calculated as body weight (kg) divided by height squared (m 2 ). Statistics Comparisons of means of the two groups were performed with nonpaired Student t tests; comparison of duration of amenorrhea was made with a Wilcoxon test. Effects of therapy over time were studied with analysis of variance (ANOVA) for repeated

3 AJH OCTOBER 1998 VOL. 11, NO. 10, PART 1 ABPM DECLINES DURING POSTMENOPAUSAL HRT 1149 TABLE 1. BASELINE CHARACTERISTICS OF THE CONTROL GROUP AND THE STUDY GROUP Control Group Study Group Number Age (years) 53.1 (3.4) 51.4 (4.0).2 Body mass index (kg/m 2 ) 25.6 (4.2) 25.1 (3.7).8 Hemoglobin (mmol/l) 8.2 (0.5) 8.0 (0.5).2 Serum creatinine ( mol/l) 81.7 (9.7) 81.2 (7.8).9 Duration of amenorrhea (months): median range RRsys office (mm Hg) (13.0) (9.0).2 RRdia office (mm Hg) 77.0 (10.2) 80.2 (8.4).4 RRsys 24-h (mm Hg) (11.2) (9.2).4 RRdia 24-h (mm Hg) 71.3 (7.4) 74.4 (6.6).3 Means (SD) unless otherwise indicated. Results of baseline ambulatory blood pressures were obtained in 13 women from the control group and in 14 women from the study group. RRsys, blood pressure systolic; RRdia, blood pressure diastolic; office, office measurement; 24 h, mean 24-h ambulatory blood pressure measurement value. P measurements. In the event of incomplete blood pressure data sets, ANOVA was performed both without the cases with incomplete data sets and with all cases replacing the missing value by its previous one. Linear regression analysis was performed to evaluate the effect of the body mass index (BMI) on the change of the blood pressures in the control group, using the change in systolic or diastolic 24-h ABPM value as the dependent, and the change in BMI as the independent variable. All testing was two-sided; P.05 was considered statistically significant. All tests were performed with the Statistical Package of Social Sciences (SPSS) software package. RESULTS The groups were well matched (Table 1). Successful 24-h ambulatory blood pressure measurements could be obtained in 13 women from the control group and 14 women from the study group at baseline. Baseline characteristics were not different between the two dydrogesterone subgroups (data not shown). Body mass index did not change during the study period in the HRT group (from 25.0 [3.8] to 25.3 [4.2] kg/m 2 at 12 months, P.2), whereas there was a small but significant increase in the control group (from 25.3 [4.7] to 25.8 [4.7] kg/m 2 at 12 months, P.001). Hemoglobin concentrations did not change in either group. Both office and 24-h ambulatory blood pressures were not significantly different between the control group and the HRT group at baseline (Table 1), or at 3 or 12 months of follow-up. Consistent changes of office blood pressures during the study period were not observed and these changes did not differ significantly between the groups (Table 2, Figure 1). Ambulatory pressures, however, increased significantly in the control group at 3 months of follow-up and showed a consistent and significant decline in the HRT group at 12 months (Table 2, Figure 2). ANOVA for repeated measurements (performed in 13 women from the HRT group and 11 from the control group because of four incomplete blood pressure data sets) did not reveal significant changes of office blood pressure over time or differences between the groups. Analysis of blood pressures obtained with ABPM indicated that both systolic and diastolic blood pressures declined significantly in the HRT group (from [9.2]/74.4 (6.6) mm Hg to [7.9]/70.5 TABLE 2. CHANGES FROM BASELINE OF OFFICE BLOOD PRESSURES AND 24-h AMBULATORY BLOOD PRESSURES IN THE HRT AND CONTROL GROUPS AT 3 AND 12 MONTHS OF FOLLOW-UP Control Group Study Group Three months RRsys office (mm Hg) 1.0 ( 7.3 to 5.3) 5.2 ( 10.1 to 0.2)* RRdia office (mm Hg) 2.5 ( 7.8 to 2.8) 1.9 ( 5.0 to 1.1) RRsys 24-h (mm Hg) 4.5 (0.9 to 8.0)* 2.8 ( 5.8 to 0.2) RRdia 24-h (mm Hg) 4.1 (1.6 to 3.6)* 2.3 ( 4.3 to 0.4)* Twelve months RRsys office (mm Hg) 4.5 (0.6 to 8.4)* 2.4 ( 10.7 to 5.9) RRdia office (mm Hg) 0.2 ( 5.5 to 5.2) 3.3 ( 8.3 to 1.7) RRsys 24-h (mm Hg) 3.3 ( 0.9 to 7.4) 5.5 ( 2.2 to 0.9)* RRdia 24-h (mm Hg) 1.7 ( 1.8 to 5.1) 4.2 ( 6.7 to 1.8)* Means (95% CI). * P.05 versus baseline. RRsys, change in systolic blood pressure; RRdia, change in diastolic blood pressure; 95% CI, 95% confidence interval; 24 h, mean 24-h ambulatory blood pressure measurement value.

4 1150 VAN ITTERSUM ET AL AJH OCTOBER 1998 VOL. 11, NO. 10, PART 1 FIGURE 1. Changes in systolic and diastolic office blood pressures from baseline after 3 and 12 months of follow-up in the control group (filled circles) and the HRT group (open circles). Horizontal lines represent means; P values are taken from nonpaired Student t test); P (ANOVA) systolic/diastolic.3/.2 for the HRT group, and.1/.5 for the control group (N 11 for the control group, N 13 for the HRT group). [5.7] after 1 year of treatment, P [ANOVA].005/.003). In the control group there was an increase in ABPM values during the study period (from [11.2]/71.3 [7.4] to [10.1]/72.5 [7.2] after 1 year, P [ANOVA].054/.02). The interaction between therapy and time for ambulatory blood pressures was significant P [ANOVA].001 and.0001 for 24-h systolic and 24-h diastolic blood pressures, respectively, indicating that blood pressure changes over time differed significantly between the HRT and the control groups. Analysis of ABPM-values during the waking and the sleeping periods revealed similar results to the analysis of 24-h mean values (data not shown). Changes in blood pressures over time did not differ between the two dydrogesterone subgroups (P FIGURE 2. Changes in systolic and diastolic 24-h ambulatory blood pressures from baseline at 3 and 12 months of follow-up in the control group (filled circles) and in the HRT group (open circles). Horizontal lines represent means; P-values are taken from nonpaired Student t test); P (ANOVA) systolic/diastolic.005/.003 for the HRT group,.054/.02 for the control group (N 11 for the control group, N 13 for the HRT group). [ANOVA].77). When the missing values were replaced by the previous ones in time, the ANOVA analysis yielded similar results (data not shown). Results of the linear regression analysis, which was performed to study the relationship between BMI and blood pressure in the control group, showed that the increase in blood pressure could not be attributed to the increase in BMI ( 5.6, P.3 for systolic changes, and 4.9, P.3 for diastolic changes). DISCUSSION Menopause is associated with a large increase in the risk of cardiovascular diseases and an increase in blood pressure, although the latter issue is somewhat controversial. 1,11,16 We performed a prospective, ran-

5 AJH OCTOBER 1998 VOL. 11, NO. 10, PART 1 ABPM DECLINES DURING POSTMENOPAUSAL HRT 1151 domized study on the effects of HRT on blood pressure in 29 postmenopausal women. After randomization, the treatment and the control groups did not differ significantly with respect to age, BMI, serum creatinine, hemoglobin level, duration of amenorrhea, and blood pressures. During the study, some changes in office blood pressures were observed, but a steady change did not occur. These results are in concordance with those of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, which found slight decreases in systolic (office) blood pressures during the first year of treatment that were not statistically significant. 12 However, in the present study, ABPM, a more accurate technique for blood pressure determination, was used as well. ABPM results did not differ significantly between the HRT and the control groups at baseline. In the control group, ambulatory blood pressures increased at 3 and 12 months of follow-up. This increase in blood pressures could not be explained by the (small) increase in BMI. In the HRT group, an ongoing decrease in blood pressures was observed at 3 and 12 months. ANOVA for repeated measurements confirmed the conclusion that time effects differed between the two groups. Blood pressure changes in the HRT group were not attributable to a decline in hemoglobin concentration (due to uterine withdrawal bleeding) or changes in BMI. The initial rise of ABPM values in the control group and the initial decline in the HRT group might partially be due to regression to the mean; the results of the unpaired Student t test (P.002), however, indicate that the chance that this explanation is true is 0.2%. In addition, regression to the mean is an extremely unlikely explanation for the further decline in blood pressures in the HRT group at 12 months. The reason why ABPM detects small blood pressure changes during HRT, whereas office measurements fail to demonstrate these effects, might at least partially be the greater number of blood pressure measurements, which provides more accurate estimates of the blood pressure. In the present study, this is illustrated by the variances of changes in office pressure, which are comparable with the results of the PEPItrial, 12 but which were 1.5 to 2 times higher than the variances of changes of the ABPM registrations (as reflected by the confidence intervals in Table 2). The results of the office blood pressure changes during HRT in the present study are in concordance with the results of the PEPI trial, suggesting that effects on blood pressure are comparable in both studies. However, in the present study, ABPM in the HRT group showed a significant decline in blood pressures of 5.5/4.2 mm Hg. Changes in blood pressures during the waking and sleeping periods were similar. To detect declines of 4 to 5 mm Hg in blood pressure with a power of 90%, the PEPI trial would have needed 200 patients/group, whereas the groups consisted of only 175 patients. Therefore, the absence of significant changes in blood pressures in this trial could be explained by a lack of statistical power. Different effects of ERT or HRT on blood pressure may be due to the composition of the pharmacotherapeutical agent or the route of its administration. A previous observational study showed a blood pressure decline, determined with ABPM, during transdermal ERT, not with oral ERT. 14 The compound used in the present study, 17 -estradiol, seems to have vasodilating and blood pressure-lowering properties The mechanism of this vasodilation and blood pressure lowering is not fully understood. Potential mechanisms are the increase of the activity of PGI 2 (a vasodilating prostaglandin) and nitric oxide, and the observed decreases in plasma endothelin and renin levels during ERT Determination of these mechanisms was not within the scope of the present study. Our data raise the possibility that subtle blood pressure changes may at least be partially responsible for the unexplained part of the decline in cardiovascular risk with HRT. If confirmed by other studies, the findings of the present study may be relevant for clinical practice. Although it has been shown that HRT does not induce an elevation of blood pressure in hypertensive postmenopausal women, 13 in clinical practice HRT has often been withheld from hypertensive patients. If the blood pressure lowering effects of HRT can be confirmed in larger studies and in hypertensive postmenopausal women, HRT should be considered as initial therapy for the increased cardiovascular risk in these patients. Some issues remain to be elucidated. In the PEPI trial a (nonsignificant) increase in blood pressure was observed in the second year of HRT. 12 Another study in hypertensive postmenopausal women did not observe an ongoing increase after 1 year of HRT: even after 3 years of HRT, office blood pressures were not different from baseline. 13 Therefore, further studies should be performed to confirm the observation of the present study that ambulatory blood pressures fall during the first year of HRT. Additionally they should explore ambulatory blood pressures after 1 year of HRT. In conclusion, ambulatory not office blood pressures decline during hormone replacement therapy (micronized 17 -estradiol and dydrogesterone) in postmenopausal women. Larger studies using ABPM for determination of blood pressures are needed to confirm these results and to explore the course of ambulatory blood pressures after 1 year of HRT.

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