Transdermal oestrogen reduces daytime blood pressure in hypertensive women

Journal of Human Hypertension (1998) 12, 323–327  1998 Stockton Press. All rights reserved 0950-9240/98 $12.00

ORIGINAL ARTICLE

Transdermal oestrogen reduces daytime blood pressure in hypertensive women K Manhem1, H Ahlm1, I Milsom2 and A Svensson1

¨ Departments of 1Medicine; and 2Obstetrics and Gynecology, Sahlgrens University Hospital, Goteborg, Sweden

The aim of this study was to investigate the acute effects of transdermally administered 17-␤-oestradiol on ambulatory blood pressure (BP) in hypertensive, postmenopausal women. Thirteen postmenopausal women with ongoing treatment for hypertension were included in this placebo-controlled, double-blind cross-over study. Ambulatory recordings of BP and heart rate were performed during 24 h on two occasions, separated by at least 1 week, after application of a patch containing either 100 ␮g per 24 h 17-␤-oestradiol or placebo. Serum oestradiol was increased (P⬍0.001) during active treatment (139.2 ± 21.1 pg/ml) compared with the baseline postmenopausal levels recorded during placebo (40.5 ± 2.2 pg/ml). No rise in BP was found in office BP

or during ambulatory recordings. Daytime BP pressure was acutely reduced by approximately 3 mm Hg during the 24 h of treatment with oestrogen (SBP n.s., DBP P⬍0.05), without any change in heart rate. Nocturnal dipping in SBP and DBP was present during placebo conditions, and there were no signs of an increase in dipping during treatment with 17-␤-oestradiol. This study supports previous evidence that hormone replacement therapy is safe in hypertensive women. The data in the present study also imply an acute, but small reduction of daytime BP due to transdermal oestrogen in hypertensive, postmenopausal women. Furthermore oestrogen did not blunt or increase the dipping phenomena during the night in these women.

Keywords: oestrogen; ambulatory monitoring; transdermal; acute effects

Introduction Essential hypertension is an independent risk factor for cardiovascular disease in women, and in older women the single most important factor.1 However, women experience a lower incidence rate of stroke and left ventricular hypertrophy at similar blood pressure (BP) levels compared to men.2 Several investigators have found that the menopause is accompanied by a steeper rise in systolic BP (SBP). However, the effect of the menopause on BP is difficult to evaluate in cross-sectional studies, since the menopause as well as BP are influenced by other factors such as body mass index (BMI), socio-economic class, and smoking.3 According to several epidemiological studies the prevalence of hypertension is not influenced by oestrogen use.4 Whether or not oestrogen treatment reduces BP in postmenopausal women is still under debate. The recently published PEPI trial5 did not demonstrate a significant lowering effect of hormone replacement therapy (HRT) on BP. On the other hand Barrett-Connor has previously stated that replacement therapy is associated with lower BP.6 However, postmenopausal HRT appears to result in small but measurable haemodynamic changes, with a mild lowering of systemic BP during normotensive

Correspondence: K Manhem, Department of Medicine, Sahlgrens ¨ University Hospital/Ostra, S-416 85 Gothenburg, Sweden Received 13 June 1997; revised and accepted 19 September 1997

conditions according to a recent review by Samaan and Crawford.7 Several earlier studies have investigated the influence of oestrogens on BP. No effect on BP or BP lability due to orally administered oestrogen treatment in an older population was found by Pfeffer and coworkers as early as 1979.8 A reduction in SBP was shown in a hypertensive population (n = 12) when treated with natural oestrogens for 3–6 months.9 A small reduction in SBP and diastolic BP (DBP) after 28 days of treatment with oral oestrogen given to normotensive postmenopausal women has previously been reported.10 An approximately 10 mm Hg reduction in ambulatory monitored SBP and DBP, during transdermal administration of 17-␤-oestradiol was found in a group of mild hypertensive untreated perimenopausal women, but no information was provided on when the recording was performed in relation to the start of treatment.11 A potentiating effect of the combination of oestrogen and progestin on BP reduction appeared after 1 week of treatment in a study including 12 normotensive postmenopausal women.12 On the other hand Lip, Beevers and coworkers have in several papers provided evidence of the safe use of HRT in hypertensive women.13–16 Thus there is evidence that HRT may influence BP levels and/or hypertension, but there is at present no convincing evidence of a clinically relevant effect in hypertensive women, nor is it known if the acute haemodynamic effects of oestrogen seen in animal experiments17 are true for HRT in women. The aim

17-␤-oestradiol in postmenopausal hypertensive women K Manhem et al

324

of this study was to investigate the acute effects of transdermal 17-␤-oestradiol on ambulatory BP in hypertensive, postmenopausal women.

Materials and methods Subjects Thirteen non-smoking postmenopausal women, mean age 62 years (range 56–70), were recruited from our out-patient hypertensive clinic. All the women were currently taking hypertensive treatment and had been doing so for a mean time of 10 years (range 1–22). Two patients were on adequate thyroid substitutional therapy and none were diabetic or hyperlipidaemic. None of the women investigated had ever been on any kind of hormonal substitution. The BMI of the group was 30.5 kg/m2 (range 23–38 kg/m2) while waist/hip (W/H) ratio was 0.87 (range 0.76–0.98). None of the subjects had used acetyl salicylic acid (ASA) during the last 10 days (Table 1). Informed consent was obtained from each subject and the study was approved by the Eth¨ ics Committee of the University of Goteborg and performed in accordance with the Helsinki Declaration of Health.

sphygmomanometer (Tonometer, model Minimus, Speidel & Keller, Jungingen, Germany) and blood samples were obtained without stasis from the indwelling venous cannula. A placebo or a 100 ␮g per 24 h 17-␤-oestradiol patch (Estraderm, CibaGeigy) was then applied in a randomised fashion. Twenty-four hours later (day 2) the patients returned to the laboratory and BP recordings and blood samples were collected in the same manner as during day 1. Twenty-four hour ambulatory BP and heart rate (HR) monitoring (Spacelab 90202, Redmond, WA, USA) was then started and recordings were made 3 times per hour throughout the 24 h. In the morning of day 3 the patients returned to the laboratory for removal of the patch and the ambulatory device. The second investigation was performed 2 weeks later in the same manner using the type of patch not used during the first investigation. Serum oestradiol was assessed by radioimmunoassay (The Abbot IMx Estradiol Assay, Diagnostics Division, Abbot Park, IL 60064, USA) from blood samples taken during treatment with both the oestradiol patch and the placebo patch (see above). Data analysis

Study design A placebo-controlled, double-blind crossover study design was used and all patients performed two 24-h ambulatory recordings (Figure 1). During day 1 they entered the laboratory in the morning after a period of 12 h fasting. After verbal information, a venous cannula was inserted into an antecubal vein (Venflon; Viggo, Helsingborg, Sweden) and the patient was left alone in a supine position in a quiet room for 30 min. BP was then recorded with a

During ambulatory monitoring, 1-h means of heart rate, systolic and diastolic BP were compared. Day (6.00 am–11.00 pm) and night (11.00 pm–6.00 am) recordings were analysed separately. To evaluate if a dipping phenomena was present the 6-h period 0.00–06.00 was compared with the rest of the 24 h. Standard statistical methods were used. The 24h ambulatory recordings were analysed by two-way analysis of variance for repeated measures taking into account subjects, treatment, and time. The

Table 1 Study population, basal characteristics Age (years)

65 59 56 60 59 67 69 62 57 58 64 62 68

Treatment

Duration of treatment (years)

BMI

W/H

Office SBP/DBP (mm Hg)

Mean SBP/DBP day (mm Hg)

Mean SBP/DBP night (mm Hg)

Atenolol Metoprolol Furosemide Atenolol Felodipine Enalapril Felodipine Amiloride Furosemide Doxazosin Quinapril/ hydrochlortiazide Hydrochlortiazide Metoprolol Isradipine Felodipine Captopril Lisinopril Atenolol Felodipine Felodipine Lisinoprile Felodipine Hydrochlortiazide

6 17

28 31

0.93 0.87

151/82 163/82

131/79 169/96

127/75 147/75

17

33

0.93

139/78

123/79

124/67

1 2

29 38

0.78 0.98

155/87 142/62

114/77 143/90

126/79 134/88

2

36

0.86

167/83

139/79

160/85

8 20

30 32

0.96 0.87

144/72 164/101

141/72 149/91

134/66 148/86

22

32

0.83

130/71

133/71

132/70

5 15

25 29

0.84 0.84

144/75 158/95

134/85 133/86

119/73 123/80

5

30

0.91

149/86

122/70

119/65

10

23

0.76

135/75

135/80

146/78

17-␤-oestradiol in postmenopausal hypertensive women K Manhem et al

P⬍0.05, SBP n.s.), but there was no influence of oestrogen on HR (Figure 2). Daytime registered BP was reduced by approximately 3 mm Hg during oestrogen treatment (Figure 1). During night registration neither BP nor heart rate differed significantly when comparing oestrogen and placebo. In accordance with these findings the mean DBP during the daytime was reduced during treatment with oestrogen compared to placebo (DBP daytime oestrogen: placebo P⬍0.05). Dipping phenomena were present during both treatment with placebo and oestrogen, although the difference in mean SBP (sleep/waking period) during oestrogen was not statistically significant (Table 2). However, the ⌬-values for SBP and DBP comparing strict night and day did not differ when comparing placebo and oestrogen treatment, indicating that dipping phenomena were not influenced by oestrogen exposition (Table 2). No difference in office BP or heart rate in response to oestrogen was found (Table 1).

Discussion In the present study we did not find any indication of acute hypertensive effects due to oestradiol in a group of hypertensive postmenopausal women. On

Figure 1 Twenty-four-hour ambulatory recordings of heart rate, systolic and diastolic BP during placebo conditions and oestrogen treatment in 13 hypertensive women. Mean and s.e.m.

Greenhouse–Geiser correction was applied. When testing mean BP comparing day/night and office BP, Student’s t-test for paired tests was used. All tests were considered significant at P⬍0.05.

Results During treatment with the placebo patch all the women had a serum oestradiol concentration within the postmenopausal range (⬍50 pg/ml). Serum oestradiol was increased (P⬍0.001) during treatment with the oestradiol patch (139.2 ± 21.1, range 67.6– 372.9 pg/ml) compared to treatment with the placebo patch (40.5 ± 2.2, range 21.6– 48.6 pg/ml). During the entire 24-h registration there was no significant effect of treatment on BP or heart rate (ANOVA: HR, SBP, DBP for all n.s.) (Figure 1). However, oestrogen treatment significantly influenced ambulatory day-time BP recordings (ANOVA: DBP

Figure 2 Daytime (06.00–23.00) ambulatory recordings of systolic and diastolic BP during placebo conditions and oestrogen treatment in 13 hypertensive women. Mean and s.e.m.

325

17-␤-oestradiol in postmenopausal hypertensive women K Manhem et al

326

Table 2 Blood pressure differences: (06.00–23.00)/(24.00–05.00)

⌬ ‘day/night’ SBP – placebo DBP – placebo SBP – oestrogen DBP – oestrogen

6.3 7.1 2.8 4.3

mm Hg mm Hg mm Hg mm Hg

Significance P⬍0.05 P⬍0.001 n.s. P⬍0.01

SBP, difference (⌬) oestrogen/placebo, n.s. DBP, difference (⌬) oestrogen/placebo, n.s.

the contrary this study has demonstrated a daytime reduction of approximately 3 mm Hg in SBP and DBP, without any change in HR, during the acute administration of transdermal oestrogen. Furthermore, a maintained nocturnal dipping phenomenon was still apparent during oestrogen treatment. It is believed that oestrogen acts as a vasodilator via several different mechanisms, eg, directly via endothelium-dependent and -independent mechanims,18,19 via calcium-channel blocking-like effects20 and via interaction with the renin-angiotensin system.21 Oestrogen also elicits an effect on prostacyclin production which also has a vasodilating potential.22 It is well known that oestrogen influences the renin-angiotensin system,23 but acute antihypertensive effects via this system have not been well documented. The difference in BP response seen with the oestrogens available in oral contraceptives compared to oestrogens used during HRT could be explained by differences in doses, types and administration of the oestrogen used, but also by the fact that an influence on the renin-angiotensin system can be dual with vasodilation by pro-renin, and vasoconstriction by renin.24 Recently, an acute effect of oestrogen replacement on BP via l-NMMA (nitric oxide synthetase inhibitor) was demonstrated in transgenic hypertensive rats but not in normotensive rats, indicating an endothelium-dependent effect of oestrogen on genetically renin-dependent hypertension.25 The findings of an acute effect on BP 24 h after transdermal application indicates a mechanism which involves vasodilation through direct effects on receptor levels. An increase in peripheral blood flow induced by the acute administration of sublingual oestrogen has also recently been reported.26 Oestrogen receptors in the heart and large vessels are well defined.27,28 What is even more interesting is the difference in effect on BP during the daytime compared to night-time recordings. Growth hormone and cortisol are two important hormones with a circadian variation,29 and insulin secretion is in part affected by this variation.30 The haemodynamic changes observed in the present study could perhaps be a result of these circadian variations. The central nervous system integrates both haemodynamic and humoral responses to support BP elevation.31 Further, heart rate is known to be a marker of sympathetic activity, and the oestrogen-induced changes in the present study were present when mean heart was elevated.32 Our data may indicate an effect of oestrogen on vasodilatation via the sympathetic system. When HR is maintained on a higher

level the difference in BP is present, but during the night-time, when the sympathetic system is less activated, the effect of oestrogen will not be so large. In animal experiments oestrogen has been shown to be a control factor in the release of adrenaline.33 An effect of oestrogen on ␣-adrenergic activity in animal studies is well known.34 A direct vasodilator effect by oestrogen on the arterial wall mediated by a decrease in the release of noradrenalin has been suggested by Mercuro and co-workers35 since vasodilatation during oestrogen exposion was parallel to a decrease in venous plasma noradrenalin. We have in previous studies found an increased HR and BP in response to mental stress during the luteal phase of the menstrual cycle in premenopausal women.36,37 The present findings imply a difference in oestrogen effect in post compared to pre-menopausal women. Moreover, a difference in the effect on BP regulation of endogenous compared to exogenous oestrogen may also be present. The association of vasomotor lability with the decline of oestrogen levels during the climacteric period is well documented,38 but the cause of this lability is not well understood. Climacteric symptoms may indicate an interaction between steroid hormones and sympathetic regulation. Twenty-four-hour ambulatory recordings of BP are highly reproducible39 and ambulatory BP is an independent predictor of prognosis in essential hypertension.40 Furthermore, the absence of dipping phenomena indicates an increased risk of cardiovascular events,40 and the non-dipping phenomenon seems to be especially harmful in women. The group investigated in the present study were all true hypertensives with a history of sustained hypertension for several years. In this respect our study population represents a normal female hypertensive group where nocturnal dipping in BP was not blunted by the intervention of oestrogen. In conclusion we did not find any sign of an elevation of BP due to oestradiol, rather we found an acute mild BP reducing effect of transdermal oestrogen in postmenopausal hypertensive women during daytime activation without any change in HR. This effect was seen within 24 h of starting oestrogen treatment. Furthermore nocturnal dipping was preserved, without any increase in BP change from day to night during oestrogen administration. These findings reinforce the concept of an acute positive effect of HRT in treatment of hypertensive postmenopausal women, and may in part contribute to the positive effects of HRT on cardiovascular control. However, the possible protective effects of oestrogen on BP during long-time treatment must be elucidated in randomised prospective studies.

Acknowledgements This study was supported by grants to Dr K Manhem from the Swedish Medical Society and the Swedish Heart Lung Foundation. We also thank Margareta Olsson RN for skilful technical assistance.

17-␤-oestradiol in postmenopausal hypertensive women K Manhem et al

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