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Interaction between cardiovascular autonomic control and sex hormones in perimenopausal women under menopausal hormone therapy

Kiselev, Anton R.a,c; Neufeld, Irina W.b; Bobyleva, Irina V.b; Prokhorov, Mikhail D.d; Karavaev, Anatoly S.c,d

Cardiovascular Endocrinology & Metabolism: September 2018 - Volume 7 - Issue 3 - p 58–63
doi: 10.1097/XCE.0000000000000153
Original Article

Objective The aim of this study was to assess the dynamical interaction between the cardiovascular autonomic control and sex hormones in perimenopausal women under menopausal hormone therapy (MHT).

Patients and methods Seventy women (age: 51.6±2.1 years) were treated with MHT. Standard time and frequency domain measures of heart rate variability (HRV) and index S of synchronization between the slow oscillations in HRV and photoplethysmographic waveform variability were studied during a 6-week treatment with MHT. We assessed also the dynamics of the following sex hormones: estradiol, follicle-stimulating hormone, dehydroepiandrosterone sulfate, and testosterone.

Results MHT increased estradiol and decreased follicle-stimulating hormone. Hot flashes and index S were significantly decreased under MHT (P<0.05). Other autonomic indices were not significantly changed (P>0.05). Changes of index S did not correlate with changes of sex hormones and hot flushes (P>0.05).

Conclusion The obtained results may indicate the independence of heart autonomic control (assessed by HRV measures) from women’s hormonal status. However, any changes in sex hormones contribute to changes in the systemic control of circulation, which is assessed by index S.

Departments of aInnovative Cardiological Information Technology, Institute of Cardiological Research

bObstetrics and Gynecology, Saratov State Medical University

cDepartment of Dynamic Modeling and Biomedical Engineering, Saratov State University

dLaboratory of Nonlinear Dynamics Modeling, Saratov Branch of the Institute of Radio Engineering and Electronics of Russian Academy of Sciences, Saratov, Russia

Correspondence to Anton R. Kiselev, MD, DSc, a/ya 4440, Saratov 410004, Russia Tel: +78 452 393 978; fax: +78 452 511 534; e-mail:

Received December 5, 2017

Accepted February 20, 2018

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Women are known to have lower total heart rate variability (HRV) and lower power of slow oscillations than men. These sex-related differences diminish with age, especially at the time of menopause, which may suggest a potential hormonal influence on the autonomic nervous system 1. In our previous cross-sectional study 2, we did not find a clinically important relationship between the cardiovascular autonomic indices [standard indices of HRV and index S of synchronization between the low-frequency (LF) oscillations in HRV and photoplethysmographic waveform variability (PPGV)] and menopausal status assessed by the level of sex hormones, menopause time, and hot flashes in women. Low correlation between the index S and some sex hormones has been shown, which has no clinical importance 2. However, individual dynamical features of the relationship between the cardiovascular autonomic control and indices of clinical status of perimenopausal women, for example, sex hormone levels, were not studied in Neufeld et al. 2. It was the main limitation of this previous study 2.

Мenopausal hormone therapy (MHT) is used as an effective approach for the treatment of menopausal disorders, owing to the reduction of circulating estrogen levels 3–5. Some authors have recommended MHT for cardiovascular prevention in addition to treatment of menopausal disorders 3,5. However, the recent meta-analysis performed by Yang et al. 6 has not supported this concept.

It is known that autonomic dysfunction is an important factor for the evaluation of risk of cardiovascular events in patients with cardiovascular diseases 7,8. The relationship between MHT and cardiovascular autonomic control is poorly understood. The results of studies in this field are controversial 9–17.

The aim of the present study is to assess the dynamical interaction between the cardiovascular autonomic control and sex hormones in perimenopausal women under MHT.

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Patients and methods


This study was approved by the Ethics Committee of the Saratov Research Institute of Cardiology in Saratov, Russia, and informed consent was obtained from all participants. Our study included 70 perimenopausal women aged 51.6±2.1 years (mean±SD), who needed MHT 18. The women were using MHT to reduce menopause symptoms such as hot flashes, night sweats, irritability, mood swings, and depression. Cardiovascular, gynecological, and other clinical characteristics were accessed in all women. Only the patients aged between 46 and 55 years were enrolled in our study. Women with hypertension did not have prior treatment with β-blockers or calcium channel blockers during 7 days before the start of the study.

The patients were not included in our study, if they matched the following criteria:

  • rhythm other than sinus that could impede the analysis of HRV,
  • endocrine pathology, excluding diabetes mellitus,
  • valvular defect of the heart,
  • chronic gastrointestinal diseases (hepatitis, gastric ulcer, duodenum disease, and cholecystitis), chronic diseases of kidneys, neurological or respiratory disorders, and other chronic diseases in the stage of exacerbation,
  • contraindications to MHT,
  • history of polycystic ovary syndrome,
  • patient’s refusal from MHT.

Anthropometric and clinical characteristics of studied women are presented in Table 1.

Table 1

Table 1

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Design of study

This is a nonrandomized study with no placebo control group.

Seventy women were treated with MHT. As a drug for MHT, we used 17-β-estradiol and dydrogesterone (Femoston, 17-β-estradiol/continuously, and dydrogesterone/sequentially) one time per day with one tablet at 8:00–8:30 a.m. During this study, hypertensive women received treatment only with diuretics. During this study, hypertensive women received treatment only with diuretics.

To examine the cardiovascular autonomic control, we simultaneously recorded the signals of ECG and photoplethysmogram (PPG). The level of the following sex hormones was assessed: estradiol, follicle-stimulating hormone (FSH), dehydroepiandrosterone sulfate, and testosterone. The ECG and PPG signals and sex hormones were analyzed at the following checkpoints of our study:

  • before the start of the treatment (stage A),
  • after 3-week treatment with MHT (stage B),
  • after 6-week treatment with MHT (stage C).
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Signal recording

To examine the cardiovascular autonomic control, we carried out HRV analysis and estimated a degree of synchronization between the LF oscillations in HRV and PPGV. PPG signal measured on the middle finger of the patient’s hand and ECG were simultaneously recorded at rest. Both signals were recorded within 10 min in supine position.

All patients were investigated in the afternoon fasting under spontaneous breathing. The ECG and PPG signals were measured in a quiet, temperature-controlled room. All signals were sampled at 250 Hz and digitized at 14 bits. The record of respiration was used to control the evenness of breathing. We excluded the series with forced inspiration and delays in breathing from the analysis. For further analysis, only ECG and PPG records without artifacts, extrasystoles, and considerable trends were left.

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Signal processing

We analyzed HRV in the frequency domain and time domain using heart rate and PPG signals simultaneously recorded within 10 min. We evaluated the following time domain HRV parameters: mean heart rate, SD of the NN interval, coefficient of variation, square root of the mean squared differences of successive NN intervals, and proportion derived by dividing NN50, the number of interval differences of successive NN intervals greater than 50 ms, by the total number of NN intervals 7.

Total power (0–0.5 Hz) and power of high-frequency (HF; 0.15–0.4 Hz) and LF (0.04–0.15 Hz) bands of the HRV spectrum were analyzed 7. Power of LF and HF bands was presented in percentages of total power (LF% and HF%). LF/HF ratio was also calculated 7.

To estimate the synchronization between the LF oscillations in HRV and PPGV, we used the method proposed by us recently 19. Index S defines the relative time of synchronization between the considered slow oscillations.

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Statistical analysis

Continuous variables are reported as medians with interquartile ranges (lower and upper quartiles). Categorical data are presented as frequencies and percentages. The obtained estimations were considered statistically significant, if P was less than 0.05. For a statistical analysis, the software package Statistica 6.1 (StatSoft Inc., Tulsa, Oklahoma, USA) was used.

We applied the Shapiro–Wilk test to check whether the data are approximately normally distributed. As these data occur to be non-normal, their further analysis was carried out using nonparametric statistical methods. To compare the variables between patients’ groups, we used the Mann–Whitney test. To compare the variables within one patients’ group, we used the Wilcoxon test. Paired relationships between the continuous variables were assessed using Spearman’s correlation coefficients (0.68–1.0 is high correlation, 0.36–0.67 is moderate correlation, and ≤0.35 is low correlation 20). Multiple regression analysis with sigma-restricted parameterization was used to study the multivariate effects for continuous and categorical variables.

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MHT increased estradiol and decreased FSH (Table 2). The dynamics of testosterone and dehydroepiandrosterone sulfate did not have a clear trend (increase or decrease) under treatment that hampers its interpretation (Table 2). The frequency of hot flashes was significantly decreased under the 6-week treatment to 22.9% (P<0.001 for pairs ‘initial state vs. state after treatment’). We found a statistically significant decrease of index S during MHT (Table 3). Other autonomic indices were not significantly changed under treatment (Table 3).

Table 2

Table 2

Table 3

Table 3

Correlation analysis was used to study the association between the cardiovascular autonomic indices, sex hormones, and hot flushes during MHT. We found no correlation between the hot flushes and all studied autonomic indices (P>0.1). Even the index S, which appreciably varied during MHT, did not correlate with hot flushes (Spearman’s R=0.06, P=0.680). Index S was associated only with estradiol and FSH (Fig. 1). Other autonomic indices had no significant pair correlation with the level of sex hormones (P>0.05).

Fig. 1

Fig. 1

We studied the details of multiple interactions between the index S and sex hormones in stages of our study. The best multiple regression model with index S as the dependent variable and all sex hormones as predictor variables has R 2=0.24, P=0.102, which is not statistically significant. The multiple analysis has shown that testosterone is a predictor variable that is most associated with index S. The standardized (β) regression coefficient of testosterone is 0.32.

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We found no significant dynamics of most cardiac autonomic indices under MHT, except the synchronization of LF oscillations in HRV and PPGV estimated by index S. MHT decreased this synchronization, which is a marker of the status of systemic autonomic regulation in cardiovascular system. Index S characterized the degree of synchronization between the slow processes in baroreflector regulation of blood pressure (by total vascular conductance) and chronotropic regulation of the heart. We found no other studies on this synchronization in women under MHT.

Our results on time and frequency domain measures of HRV are consistent with the study by Hautamäki et al. 21. These authors have shown that MHT do not significantly modify the HRV responses in women with or without hot flushes. In our study, the decrease of hot flushes was not associated with dynamics of studied cardiovascular autonomic measures. The absence or very low power of relationship between MHT and cardiovascular autonomic control was previously reported also by some authors 22–25.

Our results are not consistent with some studies. For example, Perseguini et al. 13 reported an increase of cardiac sympathetic modulation under MHT, accessed by LF and LF/HF. In the study by Rosa Brito-Zurita et al. 14, estrogen increased the parasympathetic tone in cardiovascular control that contradicts the results of Perseguini and colleagues. Magri et al. 26 reported that MHT seems to play a positive role in the autonomic modulation of cardiac function through a shift of LF/HF ratio values toward those in young patients.

Yang et al. 27 reported a decrease of LF% in perimenopausal women treated with estrogens, but not in women treated with combined estrogen–progestin substitution therapy. In this last group of women, the combined estrogen–progestin substitution therapy had no effect on HRV. However, Farag et al. 11 obtained the contradictory results. In our study, all women were treated with estrogen–progestin drug (17-β-estradiol and dydrogesterone).

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In our study, we did not reveal a clinically important relationship between the changes of time and frequency domain measures of HRV and dynamics of sex hormones under MHT. Synchronization between the LF oscillations in HRV and PPGV was significantly decreased under treatment. However, this decrease of synchronization did not correlate with the dynamics of sex hormones profile and hot flushes.

In our opinion, these results may indicate the functional independence of heart autonomic control, assessed by HRV measures, from the regulatory system of women’s hormonal status. At the same time, any changes in women’s hormonal status, for example, under MHT, contribute to the changes in the systemic regulation of blood circulation, assessed by the index of synchronization between the LF oscillations in HRV and PPGV. Clinical impact of the presented results needs to be clarified in future studies.

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Study limitations

This is a nonrandomized study with no placebo control group, which is a weakness of the study design.

Because of the small number of women in the studied group, we have not investigated the impact of hypertension on the relationship between the cardiovascular autonomic control and sex hormones under MHT.

We studied a mixed group of women in terms of mensis status. Part of the studied women have mensis, but they have been prescribed treatment with MHT because of the perimenopausal disorders. During women’s stratification based on mensis, we found no significant impact of mensis on our statistical results. We believe that levels of sex hormones are a key factor in determining the menopausal status (mensis disorders, hot flushes, etc.) in women. Thus, we studied only the interaction between sex hormones profile and cardiovascular autonomic control in mixed group of perimenopausal women.

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Conflicts of interest

There are no conflicts of interest.

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1. Stein PK, Kleiger RE, Rottman JN. Differing effect of age on heart rate variability in men and women. Am J Cardiol 1997; 80:302–305.
2. Neufeld IW, Kiselev AR, Karavaev AS, Prokhorov MD, Gridnev VI, Ponomarenko VI, et al. Autonomic control of cardiovascular system in pre- and postmenopausal women: a cross-sectional study. J Turk Ger Gynecol Assoc 2015; 16:11–20.
3. Gambacciani M, Levancini M. Hormone replacement therapy: who should be treated? Minerva Ginecol 2015; 67:249–255.
4. Fishman JR, Flatt MA, Settersten RA Jr. Bioidentical hormones, menopausal women, and the lure of the ‘natural’ in U.S. anti-aging medicine. Soc Sci Med 2015; 132:79–87.
5. Whayne TF Jr, Mukherjee D. Women, the menopause, hormone replacement therapy and coronary heart disease. Curr Opin Cardiol 2015; 30:432–438.
6. Yang D, Li J, Yuan Z, Liu X. Effect of hormone replacement therapy on cardiovascular outcomes: a meta-analysis of randomized controlled trials. PLoS One 2013; 8:e62329.
7. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996; 93:1043–1065.
8. Kiselev AR, Gridnev VI, Prokhorov MD, Karavaev AS, Posnenkova OM, Ponomarenko VI, et al. Evaluation of 5-year risk of cardiovascular events in patients after acute myocardial infarction using synchronization of 0.1-Hz rhythms in cardiovascular system. Ann Noninvasive Electrocardiol 2012; 17:204–213.
9. Boschetti M, Casu M, Moretti S, Teti C, Albanese V, Albertelli M, et al. Autonomic nervous system and cardiovascular risk assessment during one year of growth hormone (GH) replacement therapy in adults with GH deficiency. Hormones (Athens) 2014; 13:1–8.
10. 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; 9:127–136.
11. 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. Am J Obstet Gynecol 2002; 186:954–161.
12. Neves VF, Silva de Sá MF, Gallo L Jr, Catai AM, Martins LE, Crescêncio JC, et al. Autonomic modulation of heart rate of young and postmenopausal women undergoing estrogen therapy. Braz J Med Biol Res 2007; 40:491–499.
13. Perseguini NM, de Medeiros Takahashi AC, Milan JC, dos Santos PR, Neves VF, Borghi-Silva A, et al. Effect of hormone replacement therapy on cardiac autonomic modulation. Clin Auton Res 2014; 24:63–70.
14. Rosa Brito-Zurita O, Posadas-Romero C, Hermosillo AG, Zamora-Gonzalez J, Hernandez-Ono A, Cardoso-Saldana G, et al. Estrogen effect on heart rate variability in hypertensive postmenopausal women. Maturitas 2003; 44:39–48.
15. Virtanen I, Polo O, Polo-Kantola P, Kuusela T, Ekholm E. The effect of estrogen replacement therapy on cardiac autonomic regulation. Maturitas 2000; 37:45–51.
16. Virtanen I, Polo O, Saaresranta T, Kuusela T, Polo-Kantola P, Ekholm E. Medroxyprogesterone improves cardiac autonomic control in postmenopausal women with respiratory insufficiency. Respir Med 2004; 98:126–133.
17. Wyss JM, Carlson SH. Effects of hormone replacement therapy on the sympathetic nervous system and blood pressure. Curr Hypertens Rep 2003; 5:241–246.
18. Panay N, Hamoda H, Arya R, Savvas M. British Menopause Society and Women’s Health Concern. The 2013 British Menopause Society & Women’s Health Concern recommendations on hormone replacement therapy. Menopause Int 2013; 19:59–68.
19. Kiselev AR, Karavaev AS, Gridnev VI, Prokhorov MD, Ponomarenko VI, Borovkova EI, et al. Method of estimation of synchronization strength between low-frequency oscillations in heart rate variability and photoplethysmographic waveform variability. Russ Open Med J 2016; 5:e0101.
20. Taylor R. Interpretation of the correlation coefficient: a basic review. J Diagn Med Sonogr 1990; 1:35–39.
21. Hautamäki H, Mikkola TS, Sovijärvi AR, Piirilä P, Haapalahti P. Menopausal hot flushes do not associate with changes in heart rate variability in controlled testing: a randomized trial on hormone therapy. Acta Obstet Gynecol Scand 2013; 92:902–908.
22. Carnethon MR, Anthony MS, Cascio WE, Folsom AR, Rautaharju PM, Liao D, et al. Prospective association between hormone replacement therapy, heart rate, and heart rate variability. The Atherosclerosis risk in communities study. J Clin Epidemiol 2003; 56:565–571.
23. Fernandes EO, Moraes RS, Ferlin EL, Wender MC, Ribeiro JP. Hormone replacement therapy does not affect the 24-hour heart rate variability in postmenopausal women: results of a randomized, placebo-controlled trial with two regimens. Pacing Clin Electrophysiol 2005; 28:S172–S177.
24. Niskanen L, Laitinen T, Tuppurainen M, Saarikoski S, Kröger H, Alhava E, et al. Does postmenopausal hormone replacement therapy affect cardiac autonomic regulation in osteoporotic women? Menopause 2002; 9:52–57.
25. Weissman A, Lowenstein L, Porat M, Geva A, Rosenstein Y. The effect of hormone replacement therapy cessation on heart rate variability in postmenopausal women. Clin Auton Res 2005; 15:411–413.
26. Magri F, Gabellieri E, Busconi L, Guazzoni V, Cravello L, Valdes V, et al. Cardiovascular, anthropometric and neurocognitive features of healthy postmenopausal women: effects of hormone replacement therapy. Life Sci 2006; 78:2625–2632.
27. Yang SG, Mlček M, Kittnar O. Estrogen can modulate menopausal women’s heart rate variability. Physiol Res 2013; 62:S165–S171.

autonomic control; heart rate variability; low-frequency oscillations; perimenopause; sex hormones; synchronization

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