Arterial blood pressure (BP) increases with

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1 AJH 1998;11: ORIGINAL CONTRIBUTIONS Estradiol-17 Reduces Blood Pressure and Restores the Normal Amplitude of the Circadian Blood Pressure Rhythm in Postmenopausal Hypertension Giuseppe Mercuro, Sandra Zoncu, Davide Piano, Isa Pilia, Adriana Lao, Gian Benedetto Melis, and Angelo Cherchi After menopause, both systolic (SBP) and diastolic (DBP) blood pressure (BP) become higher in women than in men of the same age, suggesting that estrogen deficiency may influence the agerelated increase in BP. We studied 30 postmenopausal women (mean age, years; time from menopause, 2 5 years) affected by mild hypertension with no target-organ complications by means of 24-h BP monitoring. None of the group were undergoing estrogen replacement therapy or taking antihypertensive drugs. According to a randomized, double-blind protocol, subjects received patches of transdermal estradiol- 17 (E 2 ) or a matched placebo, with crossover after a 7-day washout period. In 12 patients the 24-h peak-to-trough variation in SBP and DBP amounted to less than 10% (nondippers). Administration of E 2 significantly decreased 24-h SBP and DBP in the whole cohort (P <.05). Furthermore, E 2 restored the expected reduction in BP during nighttime in the nondipper subgroup. It is well known that estrogen replacement therapy protects against the development of both cardiovascular diseases and stroke. Our data suggest that this activity could be attributed, at least in part, to the activity of E 2 in preserving physiologic circadian fluctuation of BP. Am J Hypertens 1998;11: American Journal of Hypertension, Ltd. KEY WORDS: Menopause, ambulatory blood pressure monitoring, essential hypertension, diurnal ABP profile, hormone replacement therapy. Received August 13, Accepted March 9, From the Institute of Cardiology and Department of Obstetrics and Gynecology, University of Cagliari, Cagliari, Sardinia, Italy. Address correspondence and reprint requests to Prof. Giuseppe Mercuro, MD, Institute of Cardiology, University of Cagliari, Via S. Giorgio, 12, Cagliari, Sardinia, Italy. Arterial blood pressure (BP) increases with age and women manifest a higher BP after the age of 60 years. 1 5 This rise is more accelerated in postmenopausal than in premenopausal women. 2 After menopause, the agerelated increase may cause BP to exceed normal limits 6 ; accordingly, hypertension is prevalent among postmenopausal women compared to age-matched male subjects. 7 The finding that surgically induced menopause, irrespective of subjects age, is associated with an accelerated increase of arterial BP 8,9 appears to indicate a direct involvement of estrogen insufficiency with the rapid increase in arterial BP after menopause. On the other hand, a significant association between the reduction of the magnitude of the BP nighttime dip and future cardiovascular events has been demonstrated in women with essential hypertension. 10 We previously stated that the administration of estradiol- 17 (E 2 ) exerts beneficial effects, both in lowering el by the American Journal of Hypertension, Ltd /98/$19.00 Published by Elsevier Science, Inc. PII S (98)00096-X

2 910 MERCURO ET AL AJH AUGUST 1998 VOL. 11, NO. 8, PART 1 evated blood pressure levels and in maintaining a uniform blood pressure control over 24 h in postmenopausal women with hypertension occurring subsequent to cessation of ovarian function. 11 In the present study we examined the effect of acute administration of physiologic doses of E 2 on BP in a group of postmenopausal hypertensive women by means of ambulatory BP monitoring (ABPM). In particular, we studied the 24-h BP profile in the nondipper subgroup, whose nighttime ambulatory BP fell by less than 10%, with respect to daytime BP. MATERIALS AND METHODS Patients Thirty postmenopausal women (mean [ SD] age, years, range, years) with menopause occuring over the previous 2 to 5 years were studied. The postmenopausal status was clearly confirmed by an estradiol blood concentration 25 pg/ml, accompanied by a follicle-stimulating hormone (FSH) concentration of 20 IU/mL. Patients were affected by mild to moderate essential hypertension, 12 the onset of which had occurred 1 to 3 years earlier. All were free from target-organ complications. No subjects were receiving hormone replacement therapy. All antihypertensive drugs were withdrawn at least five drug half-lives before the study. Elevated BP values were confirmed after the washout period by a 24-h ABPM. No participant was characterized by further specific risk factors for cardiovascular disease, such as high total cholesterol and LDL, diabetes, obesity, or habitual smoking. Screening ABPM Before Study Protocol The present study was approved by the Ethical Committee of our university. Informed consent was obtained from all women. All subjects were weighed and measured. According to ABPM profiles, subjects were divided into two groups according to the presence (dippers) or absence (nondippers) of a nocturnal SBP and DBP decline greater than 10% of daytime values. At baseline, the comparison between dipper (n 18, 60%) and nondipper (n 12, 40%) hypertensive women showed no differences in age, time from menopause, body mass index, mean plasma levels of estradiol and FSH, office BP, heart rate, and routine laboratory tests (Table 1). Study Protocol According to a randomized, doubleblind, crossover protocol, nine dipper and six nondipper subjects applied patches of transdermal estradiol- 17 for a period of approximately 36 hours. Patches were rated to deliver 100 mg/day of E 2 (Estraderm TTS 100; Ciba-Geigy, Origgio, VA Italy). Subsequently, placebo patches were applied for an equivalent period of time; the remaining participants in the study received the drugs in the reverse order. The two experimental sessions were separated by a 1-week TABLE 1. DESCRIPTION OF DIPPER AND NONDIPPER HYPERTENSIVE WOMEN Dippers (n 18) Nondippers (n 12) Age (years) Time from menopause (years) BMI (kg/m 2 ) Estradiol-17 (pg/ml) FSH (IU/mL) Office blood pressure SBP (mm Hg) DBP (mm Hg) Pulse rate (beats/min) Serum glucose (mg/dl) Serum creatinine (mg/dl) Plasma total cholesterol (mg/dl) Plasma HDL (mg/dl) Plasma triglycerides (mg/dl) BMI, body mass index; FSH, follicle-stimulating hormone; SBP, systolic blood pressure; DBP, diastolic blood pressure. Values are means SD. washout period. In the 2 days immediately before each experimental session all subjects were required to abstain from smoking, drinking alcohol and coffee, and from undertaking severe physical exercise. The women wore the skin patches at home beginning at 11:00 pm. The following day subjects came to our laboratory from 8:00 to 9:00 am and underwent 24-h ABPM (ABP Monitor SpaceLabs Medical, Inc., Redmond, WA) at our clinic. The technique of ABPM was based on recommendations that emerged at the Fourth International Conference on ABPM in Leuven, Belgium, During the daytime, subjects were free to ambulate inside the hospital premises. Reclining and napping were not allowed. Identical standard varied meals were served to women during both experimental sessions. All women were required to retire to bed by 10:00 pm and to remain recumbent until 6:00 am the next morning. The sampling interval was 15 min between 6:00 am and 10:00 pm (daytime period) and 30 min between 10:00 pm and 6:00 am (nighttime period). Circulating E 2 levels were determined by radioimmunoassay. 14 Data Analysis The mean percentage of readings of ambulatory recordings excluded from analysis was 12 5% per ambulatory recording. All group data are reported as means SD. We tested the normal distribution of 24-h BP values for individual records by the Shapiro-Wilk test. The Student s t test for paired data was used when both records of the same subject were normally distributed. The Wilcoxon s signed-rank test was used if data were not normally distributed. All calculated P values were considered as significant when.05.

3 AJH AUGUST 1998 VOL. 11, NO. 8, PART 1 HYPERTENSION, MENOPAUSE, AND TRANSDERMAL ESTROGEN 911 RESULTS Characteristics of the Patients No patient showed left ventricular hypertrophy. Nevertheless, the nondipper subgroup was characterized by a nonsignificant higher myocardial mass. Mean plasma concentration of estradiol after placebo was pg/ml, subsequent to transdermal E 2 ; it was pg/ml (P.01). No E 2 -treated woman reported any adverse symptoms. Ambulatory Blood Pressure Monitoring Figure 1 shows a plot of hourly means for SBP, DBP, and pulse rate over a 24-h period in nondipper hypertensive women after placebo and E 2. The nocturnal reductions of SBP and DBP in the dippers were 8.4% and 13%, respectively, v 3.4% and 5.3% in nondippers (Table 2). Nighttime SBP and DBP measurements resulted in statistically lower values in the group of dipper hypertensives. Estradiol-17 treatment was associated with a reduction in both SBP and DBP values throughout the majority of the 24-h period when assessed by ABPM, both in dipper and nondipper subjects (Table 2). Compared with placebo, E 2 reduced daytime SBP and DBP and nighttime SBP in the dipper subgroup (Table 2), whereas in the nondippers only nighttime SBP and DBP were significantly lower after hormone treatment. Average 24-h and daytime pulse rates were reduced by E 2 only in dippers (P.05). In comparison with placebo, E 2 administration did not produce a significant difference in the dippers nocturnal fall of SBP ( 13 mm Hg v 11 mm Hg) and DBP ( 11 mm Hg v 12 mm Hg). On the other hand, we observed a greater fall in nighttime DBP in nondippers after E 2 ( 10 mm Hg, 10.8%) than after placebo ( 5mmHg, 5.2%; P.05), although nighttime SBP did not differ significantly after the two treatments ( 7mmHgv 5 mm Hg). Thus, E 2 removed the previously observed difference between nighttime DBP values in the dipper and nondipper subgroups. DISCUSSION Women are at higher risk of cardiovascular diseases after menopause. 15,16 The most important change observed in risk factors linked to the menopause is represented by an alteration in the serum lipid and lipoprotein concentrations. 17 However, other factors, such as an age-related rise in arterial BP, should also be considered. 1 Women are characterized by a lower systolic BP than men younger than the age of 40, whereas after middle age both systolic and diastolic BP become higher in women than in men. 1 5 It is still not clear whether or not ovarian insufficiency contributes to this rapid increase. However, it has been observed that in both natural and surgically induced menopause with oophorectomy this accelerated rise is further increased 16,18 and may produce abnormally FIGURE 1. Line graphs show hourly means for systolic blood pressure (top panel), diastolic blood pressure (middle panel), and pulse rate (bottom panel). Values are means 1 SD for placebotreated and means 1 SD for estradiol-17 treated women. high BP values. 6 After menopause, the incidence of arterial hypertension progressively increases in women compared with men, becoming prevalent in women compared with age-matched male subjects. 7 In itself, hypertension represents one of the major cardiovascular risk factors 2,7 and hypertensive females are 4 times more likely than age-matched normotensive subjects to develop cardiovascular diseases. 19 In this study, ABPM was performed to examine the diurnal BP variations and to evaluate the effect of physiologic doses of E 2 on the BP profile in women

4 912 MERCURO ET AL AJH AUGUST 1998 VOL. 11, NO. 8, PART 1 TABLE 2. AMBULATORY BLOOD PRESSURE MONITORING IN DIPPER AND NONDIPPER POSTMENOPAUSAL HYPERTENSIVE WOMEN AT BASELINE AND AFTER PLACEBO OR ESTRADIOL-17 Dippers (n 18) Nondippers (n 12) Basal Placebo E 2 Basal Placebo E 2 24-h SBP (mm Hg) * * DBP (mm Hg) * * PR (bpm) * Daytime SBP (mm Hg) * DBP (mm Hg) PR (bpm) * Nighttime SBP (mm Hg) * # * DBP (mm Hg) # 82 3 PR (beats/min) DBP, diastolic blood pressure; SBP, systolic blood pressure; E 2, estradiol-17 ; PR, pulse rate. *P.05, P.01 v respective placebo; P.05 v dippers basal; #P.05 v dippers placebo; P.05 v dippers E 2. with mild hypertension occurring subsequent to menopause. The nondipper subjects were defined as those whose nocturnal decrease of systolic BP was less than 10% of daytime BP. Present results, confirming a previous observation, 11 showed that E 2 is effective in lowering elevated BP levels in women with postmenopausal essential hypertension. Furthermore, estrogen demonstrated beneficial effects in both dipper and nondipper subjects. A decrease in BP during sleep occurs in normal subjects and in patients with uncomplicated essential hypertension. Patients with a flattened diurnal ABP profile are subject to increased risk for target-organ damage. The nondipping pattern may be a sufficient determinant of left ventricular wall thickening 20 and can be associated with hypertensive target-organ damage such as silent stroke, Binswanger s dementia, 21 and faster progression of renal insufficiency in renal hypertensive subjects. 22 A blunted or absent nocturnal fall of ABP has been found to be associated with higher future cardiovascular morbid events among women with ambulatory hypertension, 10,23 even though we did not distinguish between premenopausal and postmenopausal subjects. Slightly less than one-third of all patients with essential hypertension revealed an impaired nocturnal decline of BP. 24,25 Our study demonstrates a greater existence of this phenomenon (about 40%) among postmenopausal women, although the modest number of cases examined requires further confirmation. Estradiol-17, in addition to lowering elevated BP levels and maintaining a uniform BP control over 24 h, was able to restore a physiologic nocturnal fall in nondipper hypertensive postmenopausal women. The present findings seem to suggest a mechanism of increased cardiovascular risk after menopause. A persistent pressure overload, expressed by a blunted nocturnal reduction in BP, might increase the progression of hypertensive organ damage and could be responsible, at least in part, for a higher incidence of cardiovascular events. Larger scale studies are necessary to verify whether ovarian dysfunction is able to promote a flattened BP curve and transform a dipper into a nondipper profile in both normotensive and hypertensive women, with important implications in end-organ damage. Estrogen replacement therapy in menopause protects against osteoporosis and alleviates irritating menopausal symptoms. In the light of the present findings, the hormone treatment might contain a beneficial cardioprotective activity in patients with diurnal BP problems showing signs or symptoms of cessation of the ovarian function. ACKNOWLEDGMENTS We gratefully acknowledge Angela Pisanu and Rita Figus for their technical support and Maria Leo for her excellent graphic assistance. REFERENCES 1. Landahl S, Bengtsson C, Sigurdsson JA, et al: Agerelated changes in blood pressure. Hypertension 1986; 8: Staessen J, Bulpitt CJ, Fagard R, et al: The influence of menopause on blood pressure. J Hum Hypertens 1989; 3: Kotchen JM, McKean HE, Kotchen TA: Blood pressure trends with aging. Hypertension 1982;4(suppl III): Sigurdsson JA: High blood pressure in women. A

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