Arterial pathology is a major contributor to cardiovascular disease, morbidity and mortality. Women are at higher risk of cardiovascular disease after menopause. Arterial stiffness determined by pulse wave velocity, increases with age both in men and women, whereas arterial compliance in premenopausal women is greater than in men of similar age. This difference is lost in the postmenopausal years, with evidence of rapid decline in arterial compliance in the perimenopausal period. Loss of hormonal modulation is a likely explanation for reduced arterial compliance in postmenopausal women. Long-term treatment with hormone replacement therapy (HRT) may be expected to partially reverse the increase in arterial stiffness. The aim of the study was to analyse the effect of HRT on blood pressure and arterial compliance in postmenopausal women with arterial hypertension receiving hypotensive drugs. The results in the present study of postmenopausal women with mild to moderate arterial hypertension receiving HRT showed only a transient tendency towards lower blood pressure. In our study HRT was found to improve arterial compliance at 3 months after HRT, and the effect was maintained throughout 12 months. The increased arterial compliance in women receiving HRT was independent of blood pressure. In parallel with decreasing pulse wave velocity women receiving HRT had lower total and low-density lipoprotein cholesterol. The conclusions were that after 1 year HRT in postmenopausal women with arterial hypertension improves circadian blood pressure pattern, but it does not affect significantly blood pressure values and variability. The present study also shows that HRT significantly inhibits age-related rigidity of large arteries.
Arterial hypertension is one of the major coronary risk factors for increasing morbidity and mortality from cardiovascular diseases in women after menopause. In postmenopausal women both systolic and diastolic blood pressure is higher than in men matched for age, suggesting that oestrogen deficiency may influence the age-dependent rise in blood pressure. This is confirmed by the fact, that surgical menopause, independent of age is associated with accelerated blood pressure increase.1 The incidence of hypertension in postmenopausal women also rises progressively, becoming a more frequent disorder than in age-matched men.
The expected effect of hormone replacement therapy (HRT) to interrupt or delay the development of cardiovascular disorders in postmenopausal women was confirmed in first clinical studies.2 However, despite circumstantial evidence showing the advantages of HRT in various clinical aspects, the role of HRT in the prevention of cardiovascular diseases has not yet been clearly defined. Although HRT has been proved to reduce the risk for the development of cardiovascular diseases, at least in some postmenopausal women, its cardioprotective mechanism has not been fully elucidated. Oestrogens have a favourable influence on plasma lipids,3 however it is estimated that alterations in the lipoprotein profile account for only 25 to 50% of the observed risk reduction, suggesting that other factors may play a role. One of them may be the direct effect of oestrogens on the vascular wall.4
With normal aging major changes occur in the arteries causing their rigidity, which decreases their distensibility and compliance independent of the elevated blood pressure. The process of aging involves the whole vascular bed, but it is most pronounced in elastic arteries. The arterial wall thickens and the diameter increases. In central arteries the lumen is mainly increased, whereas in peripheral arteries the wall is thicker. For this reason the ratio of the wall thickness to the arterial lumen varies depending on the vascular segment. Age-related changes that occur in the media are the thickened muscular layer, cracking and fragmentation of elastic layers, in which fibres become thinner and lacerated. As a result the artery is less distensible, its lumen is increased, which inhibits the reduction in compliance, but according to Laplace's law, it increases the wall stress, which is then propagated to less distensible collagen fibres.
Although arterial compliance in women before menopause is greater than in age-matched men, the difference disappears after menopause due to suddenly decreased vascular compliance in perimenopausal women.5
Postmenopausal women more frequently have other atherosclerotic risk factors, ie hyperlipidaemia, insulin resistance and arterial hypertension. Advanced age, menopause and hypertension independently contribute to the increase of stiffness, the decrease of distensibility and compliance and to the impairment of the buffer role of large arteries.6 This induces alterations in pulse wave velocity, and causes disproportionate increase of systolic and decrease of diastolic blood pressure.7 As a consequence there is a wider gap between the systolic and diastolic blood pressure, ie pulse pressure, which is an independent risk factor for cardiovascular complications, especially myocardial infarction in hypertensives. The increased rigidity of the vessels indirectly causes alterations in left ventricular afterload and diastolic perfusion, which cause myocardial ischaemia.
Asmar et al8 demonstrated that pulse wave velocity in hypertensives is affected by age and blood pressure as well as plasma total cholesterol. Excessive cholesterol concentration has been implicated in vascular endothelial dysfunction leading to diastolic impairment.
Most studies analysing the effect of HRT on blood pressure or vascular compliance have been carried out in healthy women. Much less attention has been focused on women with arterial hypertension.
The purpose of the present study was to analyse the effect of HRT on blood pressure values and profile, and arterial compliance in postmenopausal women with arterial hypertension receiving hypotensive drugs.
Materials and methods
The study was designed for women treated in the Outpatient Unit of the I Cardiac Department, Jagiellonian University Medical College, Poland. A group of 76 women (mean age 52.5 ± 5.8 years) with natural menopause and primary mild to moderate arterial hypertension with a duration of 5.9 ± 5.0 years entered the study. Mean time of amenorrhea was 54.2 ± 47.4 months, FSH >21 U/l (mean 74.6 ± 27.1), oestradiol <50 pg/ml (mean 17.3 ± 9.5). Table 1 summarises anthropometric parameters and blood pressure in the study population.
The subjects with coronary artery disease, heart failure, diabetes, obesity, coagulation disorders, liver damage and imminent neoplastic process were excluded from the study. Hypotensive treatment consisted of beta-blockers, calcium antagonists, diuretics and angiotensin-converting enzyme (ACE) inhibitors. The type and doses of the hypotensive agents remained unaltered during 12-month of follow-up (see Table 2). None of the patients had been receiving HRT before.
After a gynaecological examination, women with a low level of hormones and/or severe oestrogen deficiency symptoms were offered transdermal hormone substitution with 17β-oestradiol and norethisterone acetate (Estracomb TTS 50, Novartis). Forty women who accepted the treatment received HRT, whereas 36 women who were afraid of taking HRT did not receive the treatment. The study protocol was approved by the Jagiellonian University Ethics Committee. The enrolled patients were informed about the aim of the study and gave their written consent.
24-h noninvasive ambulatory blood pressure monitoring (ABPM)
At baseline and at 3 and 12 months all patients underwent 24-h ABPM using an oscillometric recorder SpaceLabs 90207 (SpaceLabs Inc, Redmond, WA, USA) with recordings every 20 min in the day (6.00–22.00) and every 30 min at night (22.00–6.00). Day and night time intervals were defined arbitrarily for all patients. The recorder was mounted between 8.00 and 9.00. If the difference between the automatic and routine measurement using a mercury sphygmomanometer did not exceed 5 mm Hg the cuff was assumed to be appropriately placed. The cuff was placed on the left arm except for left-handed persons and those with previously recorded higher blood pressure on the right arm. The patients were not aware of the recorded blood pressure values. The measurements automatically designated as erroneous, those for which the difference between the systolic and diastolic blood pressure was below 20 mm Hg or mean blood pressure was >25% higher than the previous and subsequent measurement and those with heart rate >160 bpm were excluded from analysis. The circadian blood pressure profile and day and night blood pressure values as well as the day–night blood pressure difference were examined from ABPM.
We also measured mean systolic and diastolic blood pressure for the entire 24 h and separately for the day and night, mean nocturnal systolic and diastolic blood pressure fall with respect to the daytime, and we analysed blood pressure variability from standard deviations of all blood pressure measurements in the entire 24 h.
Pulse wave velocity (PWV)
Pulse wave velocity was measured using the Complior device (Complior, Colson, Garges les Genosse, France). Pressure-sensitive transducers TY-306-Fukuda (Fukuda, Tokyo, Japan) were placed over the right carotid artery and right femoral artery. PWV was calculated as the ratio of the distance between the transducers and time between pulse wave nadir recorded over the carotid artery and femoral artery. PWV was averaged from at least 20 correct single measurements.5
Total cholesterol, high-and low-density lipoprotein (HDL/LDL) cholesterol and triglycerides were measured at baseline and at 3 and 12 months. Total cholesterol and triglycerides were measured with the enzymatic-colorimetric method CHOD-PAP using Boehringer Mannheim kits on RA 1000. HDL cholesterol was measured after precipitation of lipid fractions with heparin and MN2+. LDL cholesterol was calculated according to Friedewald formula.
FSH and oestradiol were measured using the MEIA kits, Abbott (sensitivity: for oestradiol 1 ng/ml, for FSH 0.5 mIU/ml) at the same time intervals as the remaining biochemical parameters.
Basic statistics such as means and standard deviations, and normal distribution were analysed. Intergroup differences were tested using χ2 test, Student's t-test and one-way variance analysis. Only two-side tests were used. A P < 0.5 was considered as statistically significant. Statistical analysis was done using Statistica 5.0 PL for Windows.
At baseline the study groups did not differ in age, BMI, waist/hip ratio, duration of hypertension, blood pressure, lipid profile or pulse wave velocity (Table 1).
At 3 months women receiving HRT showed a tendency towards lower systolic and diastolic blood pressure. At 12 months blood pressure values did not differ from those at baseline in either group (Table 3).
Blood pressure variability defined as standard deviation (SD) of all measurements in the entire 24 h did not differ significantly at 3 months and 12 months after HRT (Table 4). In women not receiving HRT blood pressure variability did not change significantly, either.
Nocturnal blood pressure fall did not change significantly during a 3- and 12-month HRT as compared with baseline values. Similar in the non-HRT group there were no significant changes. In a subgroup of non-dippers (nocturnal systolic and/or diastolic blood pressure fall below 10%) there was a tendency towards restoration of circadian rhythm in women receiving HRT (for systolic blood pressure 2.7 ± 4.0 vs 4.9 ± 7.6 vs 3.0 ± 10.8%; for diastolic blood pressure 8.4 ± 1.0 vs 8.8 ± 2.9 vs 12.9 ± 4.7%).
At 3 months in those women receiving HRT systolic blood pressure was significantly lower at two time points, ie 11.00 and 15.00. At 12 months systolic blood pressure was significantly lower at night: 0.00, 1.00, 2.00 and 5.00 (Figure 1). In this group diastolic blood pressure at one year was also lower at night: 0.00, 1.00 and 4.00 (Figure 3). The circadian systolic and diastolic blood pressure profile in hypertensive women with HRT (Figures 2 and 4) did not differ significantly from baseline values either at 3 or 12 months.
In women receiving HRT, PWV was significantly lower at 3 months. This decrease was maintained at 12 months (Table 5). In contrast, in women not receiving HRT this parameter did not change significantly.
At baseline the study groups did not differ significantly in total cholesterol, HDL and LDL cholesterol or triglycerides (Table 1). In women receiving HRT at 3 and 12 months there was a significant decrease in total cholesterol, LDL cholesterol, whereas HDL cholesterol and triglycerides did not change. In women without HRT total cholesterol, LDL and HDL cholesterol, and triglycerides did not change. Table 6 summarises the differences in lipid profiles between the study groups at 3 and 12 months.
In the present study postmenopausal women with mild to moderate arterial hypertension receiving hypotensive agents and HRT showed only a transient tendency towards lower blood pressure.
The present findings are in accordance with the results of Lip et al9 who in a prospective open study in 75 hypertensive women receiving hypotensive treatment together with HRT did not find significant differences in blood pressure. In our study we did not observe body weight gain, in contrast to Lip et al9 who demonstrated a progressive weight gain during hormonal substitution. In the light of epidemiological evidence suggesting that body weight gain is an important factor for blood pressure increase and increased incidence of hypertension in postmenopausal women it may be supposed that HRT really caused blood pressure fall in this group of patients.
Modena et al10 when evaluating the effect of transdermal oestrogen replacement therapy combined with hypotensive treatment on the modification of risk factors in a group of 100 postmenopausal women with arterial hypertension, did not observe blood pressure rise at 12 months after HRT. However, they found out that 17beta-oestradiol combined with hypotensive agents may reduce cardiovascular risk in women after menopause with arterial hypertension via a favourable effect on the metabolism of lipids, carbohydrates and left ventricular mass regression.
We can compare our own findings with a prospective study published by Szekacs et al.11 They studied a group of 34 postmenopausal women receiving hypotensive treatment and oral HRT (cycles of oestradiol + norgestrel). Blood pressure was assessed using 24-h ABPM. In women receiving HRT blood pressure was significantly lower, especially in the morning. No significant changes in blood pressure in our study, despite the same method of assessment, may be accounted for by a different route of drug administration and type of HRT. The systolic blood pressure fall in women receiving calcium antagonists was, however smaller as compared with other drug classes.
In the light of accumulating evidence showing that hypertensives with normal nocturnal blood pressure fall (dippers) have a smaller risk for cardiovascular and renal complications12 as compared with non-dippers, but with similar blood pressure during the day13 it is very important to evaluate the effect of HRT on nocturnal blood pressure. The 24-h ABPM revealed a higher 5-year mortality among women with spontaneous arterial hypertension in whom there was no nocturnal blood pressure fall as compared with women with dippers.13 Higher nocturnal blood pressure fall could partly account for the cardioprotective effects of oestrogens.
In our study the magnitude of nocturnal blood pressure fall did not change significantly during a year of HRT as compared with baseline values. However, in non-dippers there was a tendency towards restoration of the circadian rhythm only in women receiving HRT.
Mercuro et al14 evaluated the effect of a single administration of physiological doses of oestradiol on circadian blood pressure variations in a group of 30 postmenopausal women with mild arterial hypertension without target-organ complications. They demonstrated that transdermal oestradiol may restore the expected nocturnal blood pressure fall.
Butkevich et al15 confirmed these findings for oral oestrogens demonstrating a higher proportion of dippers and a higher nocturnal blood pressure fall in women receiving HRT as compared with those not receiving HRT.
In contrast to our study the previously mentioned study by Mercuro et al14 was an acute trial, whereas Butkevich et al15 obtained only a single 24-h ABPM in relatively older women. Additionally, in their study women receiving HRT had a significantly lower body mass index as compared with those not receiving HRT, which may have had a significant effect on blood pressure. The duration of HRT before the onset of the study was also different. Larger prospective studies are necessary to determine the effect of HRT on nocturnal dipping in postmenopausal women.
It is well-known that cardiovascular events are more frequent in the morning hours.16 It may be associated with the increased sympathetic nervous activity and blood pressure rise in the ‘stressful’ morning hours. Our findings that HRT decreases blood pressure in the morning may be of major clinical importance indicating a possibility of reducing the cardiovascular risk in patients with arterial hypertension.
Arterial hypertension in most cases is associated with dyslipidaemia, which is an independent cardiovascular risk factor. In our study we also observed a favourable modification of plasma lipid profile. At 3 months in women receiving HRT total cholesterol and LDL cholesterol decreased. This is in accordance with the results obtained by other investigators.10,17,18
In our study HRT was found to improve arterial compliance already at 3 months after HRT, and the effect was throughout 12 months. The increased arterial compliance in women receiving HRT was independent of blood pressure.
Blacher et al19 evaluated changes in arterial compliance after HRT combined with an ACE inhibitor (moexipril) in postmenopausal women with mild to moderate hypertension. Both PWV and pulse pressure significantly decreased after moexipril. The changes were similar in women with and without HRT.
Our study in contrast to a single comparison of those receiving and not receiving HRT by McGrath et al20 is continuous and prospective, allowing for monitoring changes in arterial compliance after HRT in a relatively long time of 12 months.
When looking for the factors that might affect PWV we found parallel changes in both systolic and diastolic blood pressure as compared with changes in PWV in the consecutive time intervals of follow-up, ie a tendency to decrease at 3 months and return of baseline values at 1 year. The changes in blood pressure showed a trend without statistical significance and it is hardly a good explanation of PWV changes in our own study.
A similar tendency, but in the opposite direction, was observed for blood nitrate/nitrite levels at rest. The relationship between vascular compliance and altered endothelial function has been reported mainly with respect to muscular arterial compliance. This is justified, because these arteries contain effector cells for endothelial vasoactive substances. It is, however difficult to explain lower PWV and improvement of large elastic arteries in our study.
It is possible that oestrogen-generated nitric oxide has an influence on compliance not via the action on large arteries but via the myocardium modifying such haemodynamic parameters as filling pressure and stroke volume, because one of the basic methods to assess vascular compliance is to calculate the ratio of stroke volume to pulse pressure.
Because in parallel with decreasing PWV in women receiving HRT there was decreased total and LDL cholesterol in blood serum we may suspect that it is one of the mechanisms responsible for the improved compliance in the study group.
Our results are in accordance with the findings of other investigators.6,21,22 Rajkumar et al6 demonstrated improved compliance after HRT showing simultaneously that it is associated with lower PWV in large elastic arteries. These observations were confirmed in a randomised study by Giraud et al23 Also Nagai et al22 demonstrated positive effects of HRT, reducing arterial stiffness by 21% in those receiving HRT as compared with the subjects not receiving HRT. Other investigators also reported a 13% difference in vascular stiffness between women receiving HRT or not and a 7% increase at 4 weeks after HRT withdrawal.6
Our results are not in accordance with the results of Angere et al23 and Teede et al24 who did not find improved vascular compliance after a years HRT in the whole study population except for smoking women.
Smoking reduces carotid arterial distensibility by about 33%.25 This is a result of sympathetic activity, increased tension of vascular smooth muscle and altered endothelial-dependent vasodilating function.26
HRT may counteract these changes27 through increased production of nitric oxide,28 shifting autonomic balance towards increased vagal tone,29 increased expression of the gene for prostacyclin and nitric oxide synthases and through inhibition of vascular smooth muscle cell proliferation and acceleration of endothelial cell growth.30
Perhaps the increased arterial compliance in our study is associated with greater vasodilating dysfunction in arterial hypertension, similar to smoking women.
One-year combined HRT in postmenopausal women with arterial hypertension improves circadian blood pressure pattern, but it does not affect significantly blood pressure values and variability. The present study also shows that HRT significantly inhibits age-related rigidity of large arteries.
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Cite this article
Kawecka-Jaszcz, K., Czarnecka, D., Olszanecka, A. et al. The effect of hormone replacement therapy on arterial blood pressure and vascular compliance in postmenopausal women with arterial hypertension. J Hum Hypertens 16, 509–516 (2002). https://doi.org/10.1038/sj.jhh.1001431
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