Effect of hot flushes on cardiovascular autonomic responsiveness: A randomized controlled trial on hormone therapy

Maturitas 72 (2012) 243–248

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Effect of hot flushes on cardiovascular autonomic responsiveness: A randomized controlled trial on hormone therapy Hanna Hautamäki a , Petri Haapalahti b , Päivi Piirilä b , Pauliina Tuomikoski a , Anssi Sovijärvi b , Olavi Ylikorkala a , Tomi S. Mikkola a,∗ a b

Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland Department of Clinical Physiology and Nuclear Medicine, Helsinki University Central Hospital, Helsinki, Finland

a r t i c l e

i n f o

Article history: Received 5 December 2011 Received in revised form 26 March 2012 Accepted 3 April 2012

Keywords: Hot flush Vasomotor symptoms Menopause Autonomic nervous function Heart rate Blood pressure

a b s t r a c t Objectives: To compare the responses of heart rate and blood pressure to various autonomic tests in women with and without pre-treatment hot flushes during estradiol and estradiol + medroxyprogesterone acetate (MPA) use. Study design and main outcome measures: Hundred and fifty recently postmenopausal women (72 with and 78 without hot flushes) were randomized to receive transdermal estradiol (1 mg/day), oral estradiol (2 mg/day) alone or in combination with MPA (5 mg/day), or placebo for six months. Cardiovascular responsiveness was comprehensively assessed with controlled and deep breathing, active orthostatic test, Valsalva maneuver and handgrip test. Results: Hot flushes were accompanied with a significant reduction (−2.2 ± 0.7 vs. 1.3 ± 1.1 beats/min, p = 0.03) in resting heart rate during estradiol-only treatment; the route of estradiol administration was no factor in this regard. This effect was attenuated by the addition of MPA to oral estradiol. Hot flushes were also associated with reduced maximal heart rate in response to handgrip during the use of estradiolonly therapy (−2.2 ± 1.3 vs. 2.8 ± 1.5 beats/min, p = 0.038); again, the MPA addition eliminated this effect. Hot flushes were accompanied with lowered resting but augmented blood pressure responses to handgrip test during all hormone regimens, whereas in women without hot flushes estradiol-only regimen tended to elevate diastolic resting blood pressure. Conclusions: Hot flushes appear as determinants for cardiovascular responses to hormone therapy. Estradiol-only therapy causes beneficial changes in cardiovascular regulation in flushing women, and these are blunted, in part, by the addition of MPA. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Both heart rate and blood pressure serve as markers of the risk for cardiovascular morbidity [1,2]. These variables show marked fluctuations in women at the onset of menopause [3,4] when also a majority of women typically experience vasomotor hot flushes [4]. Autonomic nervous system is deeply involved both in the regulation of heart rate and blood pressure as well as vasomotor symptoms [5–8]. Female sex steroids, particularly estrogen, may reduce blood pressure [9,10] although data are not uniform [11–13]. Circulating natural progesterone at the end of menstrual cycle [14] or an addition of synthetic progestin to estrogen as a part of

∗ Corresponding author at: Helsinki University Central Hospital, Department of Obstetrics and Gynecology, Haartmaninkatu 2, PO Box 140, FIN-00029 HUS, Helsinki, Finland. Tel.: +358 50 4271187; fax: +358 9 471 71731. E-mail address: tomi.mikkola@hus.fi (T.S. Mikkola). 0378-5122/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.maturitas.2012.04.001

postmenopausal hormone therapy (HT) [15] may predispose women to an increased risk of cardiac arrhythmias. These may be results of direct effect of progesterone/progestin on sinus node or secondary consequences of changes in the autonomic nervous system affected by hormone therapy [11,16–18]. Recent data imply that menopausal hot flushes per se are determinants for cardiovascular health [19] as shown also in our previous studies on vascular function [20] and ambulatory blood pressure [21]. Furthermore oral estrogen combined with medroxyprogesterone acetate (MPA) showed an increased occurrence of arrhythmias compared with estrogen only therapy in women with pre-treatment hot flushes [22]. Therefore we wish to provide some more information on the possible mechanisms behind these findings. It is not known if hot flushes are factors for heart rate and blood pressure responses to various types of hormone therapy. To address this question we compared these responses to estradiol, given alone or in combination with MPA, in a placebo-controlled trial on recently postmenopausal women with or without hot flushes.

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2. Methods

at the end of the 6 month period of HT regimen. These tests which have been described in more detail earlier [23], are briefly:

2.1. Study population One hundred fifty healthy, non-smoking women (mean age 53.2 ± 0.2 years, time since menopause 19.5 ± 0.8 months) were included in to this trial, as reported previously [23]. Hot flushes, recorded prospectively for two weeks in a diary, were rated with a hot flush weekly weighted score (HFWWS) [24]. Women with ≥7 moderate/severe hot flushes/day (n = 72) were classified as “women with hot flushes” and women reporting only ≤3 mild hot flushes/day not interfering daily activity or no hot flushes at all (n = 78) were classified as “women without hot flushes”. Women were treated with a double-blind, double-dummy technique either with transdermal estradiol hemihydrate gel 1 mg/day or oral estradiol valerate 2 mg/day, alone or combined with medroxyprogesterone acetate 5 mg/day (E + MPA) or with placebo for six months (Fig. 1). This study was approved by the Helsinki University Women’s Hospital Ethics Committee, and registered in the National Agency for Medicine (EudraCT 2004005091-16) and the U.S. National Institutes of Health Clinical Registry (No. NCT00668603). The study was conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki, and written informed consent was obtained from all participants.

1. Controlled breathing. A 5-min baseline recording while breathing quietly at 15 cycles/min to assess the resting heart rate under controlled conditions. 2. Deep breathing. Six timed deep breathing cycles (inspiration + expiration) in 1 min with simultaneous measurement of heart rate alterations. 3. Active orthostatic test. The women quickly stood up from a supine position and remained standing still for 8 min. Blood pressure was measured at 0.5, 1, 3, 5 and 8 min while standing. 4. Valsalva maneuver. After maximal inspiration, forced expiration against a resistor with airway pressure of 40 mmHg was maintained for 15 s. 5. Sustained handgrip. With their dominant hands, the women squeezed a dynamometer at 30% of predetermined maximal handgrip strength for 3 min. Blood pressure was measured before and at 1, 2 and 3 min during the sustained grip. The tests were carried out in the order given above to minimize carry-over effects. Blood pressure was measured manually with a calibrated sphygmomanometer. A 12-lead ECG was recorded continuously during all tests and the signals were digitized at 200 Hz (WinAcq, Absolute Aliens Co., Turku, Finland) and stored on a disk for processing.

2.2. Cardiovascular autonomic function tests

2.3. Data processing

To obtain a comprehensive view of cardiovascular autonomic responsiveness, each individual underwent the following well established tests for cardiovascular autonomic function before and

Processing of data has been reported in detail earlier, briefly; an experienced physiologist blind to the hot flush status reviewed the heart rate responses with biosignal analysis software (WinCPRS

Fig. 1. Flow chart of the study.

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version 1.3, Absolute Aliens Co., Turku, Finland). Automatic R-wave detection was followed by manual editing of data to exclude occasional artifacts and ectopic beats with linear interpolation. Maximal changes of heart rate and blood pressure from baseline were calculated. The heart rate responses in the autonomic tests were further quantified by using standard calculated indices. During deep breathing, the magnitude of respiratory sinus arrhythmia was quantified by the deep breathing difference, defined as maximum R-R interval (minimum heart rate) during expiration minus the minimum R-R interval (maximum heart rate) during inspiration [25]. The initial acceleration and subsequent deceleration of heart rate in response to orthostatic challenge was quantified by the 30/15 ratio (defined as the longest R-R interval between the 21st and 45th heart beat divided by the shortest interval between the 5th and 25th heart beat after standing up) [26]. Valsalva ratio (maximum instantaneous R-R interval after the strain divided by the minimum R-R interval during strain) and the Tachycardia ratio (minimum R-R interval during strain divided by mean R-R interval before the strain) were calculated from the heart rate responses to the Valsalva maneuver [27].

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3. Results At baseline the study groups were comparable except that women with hot flushes showed a slightly shorter time period (16.9 ± 1.2 vs. 21.9 ± 1.1 months, p = 0.001) since the onset of menopause. Of the 150 women at baseline, 138 (92%) completed the study protocol and underwent cardiovascular autonomic nervous testing at 6 months (Fig. 1). Twelve women discontinued the trial (10 withdrew consent, 2 discontinued due to spotting) and these women were evenly distributed between the different treatment groups (Fig. 1). Active treatments reduced (p < 0.05 for all) hot flushes effectively, but also placebo caused a modest 26% reduction in HFWWS from baseline. Oral and transdermal estradiol treatments were carefully compared with each other with regard to the outcome measures and no differences between these regimens emerged. Thus, these groups were combined and analyzed as a single estradiol-only (E) treatment. 3.1. Heart rate responses

2.4. Statistical analyses The Shapiro–Wilk test was used to assess the normality of the variables. Normally distributed data were compared by means of Student’s t test or one-way analysis of variance. Mann–Whitney U or Kruskall–Wallis tests were used to compare non-normally distributed data. A paired-samples t-test or Wilcoxon’s signed rank test were used for within group comparisons of treatment effects. Two-way between groups ANOVA with analysis of covariance was used to explore the impact of hot flushes on the cardiovascular autonomic nervous testing variables during HT. Due to the multicollinearity between the investigated variables an univariable instead of multivariable approach was used. The effect of treatment was assessed as the absolute change at six months controlling for possible confounding factors (the baseline value of the variable in question, time since last menstruation, the levels on estradiol) expressed as percentages from baseline. A two-tailed value of p < 0.05 was considered statistically significant. Data are expressed as mean and standard error of mean regardless of the distribution pattern. All analyses were performed by using SPSS 16.0 software for Windows (SPSS Inc., Chicago, IL, USA).

Pre-treatment hot flushes were associated with a significant reduction in resting heart rate in women receiving E treatment (−2.2 ± 0.7 vs. 1.3 ± 1.1 beats/min, p = 0.03) (Fig. 2a). The addition of MPA prevented this reduction and caused even a small elevation in heart rate, but only in women with pre-treatment flushing (Fig. 2a). In women without hot flushes both active treatments showed a tendency toward reduced heart rate, but no significant changes emerged (Fig. 2a). Pre-treatment hot flushes were accompanied with decreased maximal heart rate responses during handgrip strain in women receiving E (−2.2 ± 1.3 vs. 2.8 ± 1.5 beats/min, p = 0.038), but not with E + MPA, treatment (Fig. 2b). Moreover, in these women E + MPA caused a significant increase in maximal heart rate compared to the decrease seen with sole E treatment (3.1 ± 1.4 vs. −2.2 ± 1.3 beats/min, p = 0.02). Pre-treatment hot flushes, or hormonal treatments, were no determinants for the responses of maximal heart rate to the active orthostatic testing or Valsalva strain (data not shown). Neither hot flushes nor hormonal treatments affected the deep breathing-induced oscillations of heart rate, the Valsalva- or Tachycardia ratios during Valsalva strain, or the 30/15 ratio during orthostatic testing (Table 1).

Fig. 2. Absolute change in (a) resting heart rate and (b) maximal heart rate response in Handgrip test, in postmenopausal women with and without hot flushes after six months of hormone therapy. Data are expressed as mean ± standard error of mean. E: estradiol-only. E + MPA: estradiol + medroxyprogesterone acetate.

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Table 1 Effect of hormone therapy on deep breathing difference, 30/15 ratio, Valsalva and Tachycardia ratio in women with and without hot flushes, expressed as absolute changes from levels before treatment. Data are presented as mean ± standard error of mean. There were no differences between groups. Presence of pre-treatment hot flushes

Estradiol and MPA

Estradiol

Placebo

Yes

No

Yes

No

Yes

No

Deep breathing test  of deep breathing difference (beats/min)

(n = 35) −0.9 ± 0.7

(n = 35) −2.1 ± 1.2

(n = 18) 1.1 ± 1.0

(n = 16) −0.7 ± 1.2

(n = 16) 1.6 ± 1.4

(n = 17) 0.8 ± 1.2

Active ortostatic test  of 30/15 ratio

(n = 35) −0.04 ± 0.3

(n = 35) −0.01 ± 0.04

(n = 18) −0.02 ± 0.06

(n = 16) −0.06 ± 0.07

(n = 16) −0.05 ± 0.04

(n = 17) 0.03 ± 0.05

Valsalva test  of Valsalva ratio  of Tachycardia ratio

(n = 33) −0.02 ± 0.05 0.01 ± 0.01

(n = 34) −0.03 ± 0.04 0.02 ± 0.01

(n = 16) 0.01 ± 0.07 0.02 ± 0.02

(n = 15) 0.08 ± 0.1 0.00 ± 0.01

(n = 13) −0.04 ± 0.08 0.00 ± 0.02

(n = 13) 0.09 ± 0.06 −0.02 ± 0.02

MPA: medroxyprogesterone acetate.

Table 2 Effect of hormone therapy on resting blood pressure and maximal blood pressure response to Handgrip test in women with and without hot flushes, expressed as absolute changes (mmHg) from levels before treatment. Data are presented as mean ± standard error of mean. Presence of pre-treatment hot flushes Change of resting blood pressure (mmHg) Systolic Diastolic

Estradiol

Estradiol and MPA

Placebo

Yes n = 35

No n = 34

Yes n = 16

No n = 16

Yes n = 17

No

−5.4 ± 2.4 −4.0 ± 1.2*

−1.9 ± 2.5 0.9 ± 1.5*

−9.9 ± 3.8 −5.0 ± 2.0

−2.4 ± 3 −1.2 ± 1.8

−8.9 ± 2.8 −3.9 ± 2.1

−1.1 ± 2.4 −1.3 ± 2.1

7.6 ± 4.3 4.8 ± 2.3

1.4 ± 3.7 2.3 ± 1.7

5.4 ± 4.8 3.5 ± 2.3

−3.4 ± 2.7 0.8 ± 1.9

Change of maximal blood pressure during Handgrip test (mmHg) Systolic 5.5 ± 2.7 Diastolic 5.1 ± 1.5**

−2.4 ± 2.2 −2.3 ± 1.4**

n = 18

MPA: medroxyprogesterone acetate. * p = 0.045. ** p = 0.003 for the differences between women with and without hot flushes within treatment group.

3.2. Blood pressure responses Pre-treatment hot flushes were associated with reductions in resting blood pressure following hormone treatments (Table 2). Only E treatment showed a significant difference for diastolic blood pressure when compared between flushing and non-flushing women (Table 2). In flushing women also placebo reduced blood pressure (Table 2). Pre-treatment hot flushes were accompanied with significantly increased blood pressure elevation during handgrip strain in women who received E treatment (Table 2). No such difference between flushing and non-flushing women was seen for E + MPA treatment (Table 2). In women with pre-treatment hot flushes systolic and diastolic blood pressure responses during active orthostatic test were similar in all study groups (Fig. 3).

comparisons, we had limited number of women in our study. Also as one limitation we acknowledge that we studied healthy lean white women and thus, our results may not be generalized to overweight women or women of other ethnic background. It has been shown previously that conjugated equine estrogen treatment may lower heart rate and blood pressure responses, but the impact of hot flushes was not evaluated in that study [31]. We show here that the potentially beneficial effects of estradiol on autonomic nervous function are seen particularly in women with pre-treatment hot flushes. In this regard the route of the estradiol does not appear to be relevant since we did not detect any differences between oral and transdermal estradiol treatments. Our findings suggest that a shift toward sympathetic dominance at menopause [32,33] may be prevented by E treatment in women

4. Discussion Our results show that pre-treatment hot flushes are accompanied with reduced resting heart rate during the use of E treatment. This potentially beneficial effect was attenuated by the addition of MPA to estradiol. Furthermore, in women with pre-treatment hot flushes all treatments lowered resting blood pressure and increased the maximal blood pressure response to sustained strain. This study gives further information on the impact of prospectively recorded hot flushes on HT-induced changes in cardiovascular autonomic function. We evaluated autonomic cardiovascular responsiveness with five established tests commonly used in clinical assessment of autonomic function [28–30]. This comprehensive approach may be regarded as one strength of our study. Other strengths include a careful prospective recoding of hot flushes, and a placebocontrolled trial design. However, we admit that in view of the large variation in autonomic function measures and of multiple

Fig. 3. Blood pressure during Active orthostatic test in postmenopausal women with hot flushes after six months of hormone therapy. There were no differences between groups. Data are presented as mean ± standard error of mean. E: estradiol-only. E + MPA: estradiol + medroxyprogesterone acetate.

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who report hot flushes before the initiation of HT. Our data cannot deduce whether this effect is a secondary consequence of disappearance of hot flushes or whether sympathetic over activity somehow enforces possible direct effect of estradiol on the heart rate. Progestin may have deleterious effect on heart rate [15]. Therefore it was of interest that MPA appeared to attenuate the heart rate reducing effect of estradiol. Large placebo-controlled trials with conjugated equine estrogen and MPA, such as HERS and WHI, showed a number of adverse cardiovascular events [34,35]. Several explanations have been suggested including the effect on heart rate possibly predisposing to arrhythmias [22]. Our results further support the potentially harmful effect of MPA on cardiovascular autonomic function, although we admit that no arrhythmias could be recorded in our healthy volunteers. Increase in blood pressure often seen at the menopausal transition [2] has been mainly connected to the reduced elasticity of the vascular wall. Since estrogen has direct vasodilatory effects [36] HT has been associated to reduced blood pressure in some [9,10,16,31] but not in all [11,12,18] studies. We have shown that estradiol use reduces ambulatory blood pressure, but only in women with pre-treatment hot flushes [21]. This finding was confirmed by the present data on significant falls in resting blood pressure in response to hormone treatment but only in women with pretreatment flushing. In contrast, isometric exercise induced rises in blood pressure were higher in women with flushes and receiving estradiol-only therapy. All this may imply that restoring the balance in sympathetic tone due to the elimination of hot flushes may improve the reactivity of the vasculature to physical strain. The fact that also placebo treatment reduced blood pressure could be partly due to a true placebo-effect [37] and perhaps partly to the testing environment being more familiar at the second assessment. Both of these mechanisms could influence the autonomic nervous system assessment [37]. 5. Conclusions Hot flushes in recently postmenopausal women are accompanied with reduced heart rate response to sympathetic challenge during the use of E treatment. Hot flushes are also associated with reduction in resting blood pressure and elevations in isometric exercise-induced blood pressure response during E treatment. The addition of MPA to estradiol blunts these responses in women with pre-treatment hot flushes. The findings may be, in part, results of the effect of estradiol eliminating the hot flush-related sympathetic over activity. The clinical significance of our findings calls for further studies with larger numbers of women and also other progestins than MPA. Contributors Hautamäki, Hanna: design of the study, clinical examination of patients and collecting data, processing and analyzing the data, statistical analyses, drafting and revising the manuscript. Haapalahti, Petri: design of the study, processing and analyzing the data, revising the manuscript. Piirilä, Päivi: clinical examination of patients and review and editing raw data, processing and analyzing the data, revising the manuscript. Tuomikoski, Pauliina: design of the study, clinical examination of patients, statistical analyses, revising the manuscript. Sovijärvi, Anssi: design of the study, processing and analyzing the data, revising the manuscript. Ylikorkala, Olavi: design of the study, processing and analyzing the data, revising the manuscript.

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Mikkola, Tomi: design and supervision of the study, clinical examination of patients, processing and analyzing the data, writing and revising the manuscript. Competing interests No conflicts of interest to be reported. Funding This study was supported by unrestricted grants from the Finnish Society for Menopause Research, the Päivikki and Sakari Sohlberg Foundation and the Emil Aaltonen Foundation. Acknowledgements We thank Pia Ebert, MD, from the Department of Obstetrics and Gynaegology at Helsinki University Central Hospital for her contribution in clinical patient examinations and data gathering. References [1] Lahiri MK, Kannankeril PJ, Goldberger JJ. Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. Journal of the American College of Cardiology 2008;51(18):1725–33. [2] Barton M, Meyer MR. Postmenopausal hypertension: mechanisms and therapy. Hypertension 2009;54(1):11–8. [3] Collins P, Rosano G, Casey C, et al. Management of cardiovascular risk in the peri-menopausal woman: a consensus statement of European cardiologists and gynaecologists. European Heart Journal 2007;28(16):2028–40. [4] Nelson HD. Menopause. Lancet 2008;371(9614):760–70. [5] Deecher DC, Dorries K. Understanding the pathophysiology of vasomotor symptoms (hot flushes and night sweats) that occur in perimenopause, menopause, and postmenopause life stages. Archives of Women’s Mental Health 2007;10(6):247–57. [6] Svartberg J, von Muhlen D, Kritz-Silverstein D, Barrett-Connor E. Vasomotor symptoms and mortality: the Rancho Bernardo Study. Menopause 2009;16(5):888–91. [7] Allison MA, Manson JE, Aragaki A, et al. Vasomotor symptoms and coronary artery calcium in postmenopausal women. Menopause 2010;17(6):1136–45. [8] Thurston RC, Kuller LH, Edmundowicz D, Matthews KA. History of hot flashes and aortic calcification among postmenopausal women. Menopause 2010;17(2):256–61. [9] Christ M, Seyffart K, Tillmann HC, Wehling M. Hormone replacement in postmenopausal women: impact of progestogens on autonomic tone and blood pressure regulation. Menopause 2002;9(2):127–36. [10] Vongpatanasin W, Tuncel M, Mansour Y, Arbique D, Victor RG. Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation 2001;103(24):2903–8. [11] Vestergaard P, Hermann AP, Stilgren L, et al. Effects of 5 years of hormonal replacement therapy on menopausal symptoms and blood pressure-a randomised controlled study. Maturitas 2003;46(2):123–32. [12] Hunt BE, Taylor JA, Hamner JW, Gagnon M, Lipsitz LA. Estrogen replacement therapy improves baroreflex regulation of vascular sympathetic outflow in postmenopausal women. Circulation 2001;103(24):2909–14. [13] Enstrom I, Lidfeldt J, Lindholm LH, Nerbrand C, Pennert K, Samsioe G. Does blood pressure differ between users and non-users of hormone replacement therapy? The Women’s Health In the Lund Area (WHILA) Study. Blood Press 2002;11(4):240–3. [14] Wolbrette D. Gender differences in arrhythmias. Clinical Cardiology 2002;25(2):49–56. [15] Gokce M, Karahan B, Yilmaz R, Orem C, Erdol C, Ozdemir S. Long term effects of hormone replacement therapy on heart rate variability, QT interval, QT dispersion and frequencies of arrhythmia. International Journal of Cardiology 2005;99(3):373–9. [16] Beljic T, Babic D, Marinkovic J, Prelevic GM. Effect of estrogen replacement therapy on cardiac function in postmenopausal women with and without flushes. Gynecological Endocrinology 1999;13(2):104–12. [17] Rosano GM, Patrizi R, Leonardo F, et al. Effect of estrogen replacement therapy on heart rate variability and heart rate in healthy postmenopausal women. The American Journal of Cardiology 1997;80(6):815–7. [18] Farag NH, Nelesen RA, Parry BL, Loredo JS, Dimsdale JE, Mills PJ. Autonomic and cardiovascular function in postmenopausal women: the effects of estrogen versus combination therapy. American Journal of Obstetrics and Gynecology 2002;186(5):954–61. [19] Tuomikoski P, Ylikorkala O, Mikkola TS. Menopausal hot flushes and vascular health. Annals of Medicine 2011;43(4):283–91.

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