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Reprint requests: Giuseppe Paolisso, M.D., Department of Geriatric Medicine and Metabolic Diseases, IV Internal Medicine, Piazza Miraglia 2, I-80138 Naples, Italy (FAX: 39-81-5665051)
Objective: To evaluate the effects of tibolone on heart rate variability and plasma free fatty acid levels in postmenopausal women.
Design: Randomized, placebo-controlled trial.
Setting: University hospital.
Patient(s): Thirty postmenopausal women.
Intervention(s): Tibolone, 2.5 mg/d, or placebo for 4 months.
Main Outcome Measures: Variability in heart rate and changes in the lipid profile.
Result(s): Anthropometric data were unchanged throughout the study. Compared with placebo, long-term tibolone administration was associated with a decrease in plasma levels of low-density lipoprotein cholesterol, triglyceride, and free fatty acid and homeostasis model assessment index. Furthermore, tibolone administration was associated with an increase in RR interval, total power, and high frequency and decrease in low frequency and the low frequency/high frequency ratio. Finally, the δ decrease in plasma free fatty acid levels correlated with δ low frequency/high frequency ratio independently of age, δ body mass index, δ homeostasis model assessment index, and low-density lipoprotein cholesterol levels.
Conclusion(s): Long-term tibolone administration improves the ratio of cardiac sympathetic tone to parasympathetic tone in postmenopausal women.
The Writing Group for the PEPI Trial Effect of estrogen/progestin regiment on heart disease risk factors in postmenopausal women the Postmenopausal Estrogen/progestin Interventions (PEPI) trial.
The Writing Group for the PEPI Trial Effect of estrogen/progestin regiment on heart disease risk factors in postmenopausal women the Postmenopausal Estrogen/progestin Interventions (PEPI) trial.
), a synthetic steroid [(7α, 17α)-17 hydroxy-7-methyl-19-norpregn-(10)-en-20-yn-3-one] with estrogenic and some progestogenic and androgenic properties (
), tibolone may influence cardiac sympathetic nervous activity through a change in plasma free fatty acid concentration. We therefore assessed the efficacy of long-term tibolone administration (2.5 mg/d for 4 months) on plasma free fatty acid concentrations and on cardiac autonomic nervous activity, as assessed by heart rate variability (
Task Force of the European Society of CardiologyNorth American Society of Paging and Electrophysiology Heart rate variability. Standard of measurements, physiological interpretation and clinical use.
We enrolled 30 healthy postmenopausal women (mean time since the last menstrual period, 32 months [range, 12–83 months]) >50 years of age (mean [±]age, 53±2 years). No participant had received hormonal treatment before the study.
All patients had no evidence of coronary heart diseases, as confirmed by electrocardiography, echocardiography, and treadmill test. During the study, all women were asked to maintain their body weight, smoking habits, and alcohol and caffeine intake. Insulin resistance was assessed by homeostasis model assessment (HOMA) (
All tests were performed in the morning and after overnight fasting (for at least 12 hours). The potential risks of the study were clearly explained to each woman, and all participants gave informed consent. They study was approved by the ethical committee of our institution.
Study protocol
The study was a randomized, placebo trial. At baseline, all participants were studied at 8:00 a.m. in a quiet, comfortable room that was kept at 22°C to 24°C. A venous blood sample was immediately drawn for plasma metabolite measurement. Each participant rested in the supine position for at least 30 minutes before baseline Holter recording was started. Holter monitoring lasted 60 minutes.
Patients were then randomly assigned to treatment with tibolone, 2.5 mg/d (Livial; Organon, Rome, Italy) (n = 15) or placebo (sodium citrate) (n = 15). Each treatment lasted 4 months. At the end of treatment period, all patients were reevaluated.
Anthropometric measurements
Weight and height were measured by using a standard technique. Body mass index was calculated as body weight in kilograms divided by height in square meters. Waist circumference was measured at the midpoint between the lower rib margin and the iliac crest (normally the umbilical level), and hip circumference was measured at the trochanter level. Both circumferences were measured to the nearest 0.5 cm with a plastic tape measure; the ratio between the two measurements provided the waist-to-hip ratio.
Anthropometric measures are used because changes in body composition may significantly affect insulin resistance and cardiac autonomic nervous activity. We wanted to exclude the possibility that changes in heart rate variability may have resulted solely from changes in body composition or insulin resistance.
HOMA index
Insulin resistance was assessed by using the HOMA index (
). Homeostasis model assessment (HOMA) is a mathematical model that describes the degree of insulin resistance from a patient’s fasting plasma insulin and glucose concentrations (
). In brief, the computer program first calculates the interval tachogram. From section of tachogram that includes 512 interval values, simple statistics (mean and variance) are calculated. The computer program automatically calculates the autoregressive coefficients needed to define the power spectral density estimate and prints out the power and frequency of every spectral component.
Two major oscillatory components are usually detectable. One component, which varies synchronous with respiration, is described as high frequency (about 0.25 Hz), and the other component, which corresponds to the slow waves of arterial pressure, is described as low frequency (about 0.1 Hz). Each spectral component is presented as normalized units (nu) by dividing the component by the total power minus the direct current component, if present. Only components comprising >5% of total power were considered significant.
The low frequency/high frequency ratio is considered an index of balance between cardiac sympathetic and parasympathetic tone (
Task Force of the European Society of CardiologyNorth American Society of Paging and Electrophysiology Heart rate variability. Standard of measurements, physiological interpretation and clinical use.
Respiratory frequency over 2 minutes was also calculated before the test. Women with a respiratory rate less than 10 breaths/min (<0.15 Hz) were excluded.
Analytical techniques
Plasma glucose concentrations were determined by glucose oxidative methods (glucose autoanalyzer, Beckman Coulter, Inc., Fullerton, CA). Plasma LDL and HDL cholesterol and triglyceride levels were determined by routine laboratory methods. Plasma free fatty acid levels were determined according to the method of Dole et al. (
). To avoid in vitro lipolysis, plasma free fatty acid levels were determined in chilled plasma containing ethylenediamine tetraacetic acid and 0.275 mg/mL of paraoxon, a lipoprotein lipase inhibitor (
). Plasma insulin levels were determined by radioimmunoassay.
Statistical analyses
All results are expressed as the mean (±SD). Mean arterial blood pressure was calculated as diastolic blood pressure plus one third of the pulse pressure. Changes in plasma free fatty acid and triglyceride concentrations, HOMA index, and low frequency/high frequency ratio are used only to compare the changes (not the absolute values) of these variables. Because of the skewed distribution, total power, low frequency, high frequency were logarithmically transformed for statistical testing and back transformed for presentation in table and in figures.
Analysis of variance was used to analyze differences between the two study groups. Pearson’s simple correlation was used to analyze the association between variables. Partial correlations were used to examine the relation between two variables independently of covariates. P<.05 was considered statistically significant. All calculations were made on an IBM PC computer by using SPSS software, version 10.0 (SPSS, Inc., Chicago, IL).
Results
Table 1 shows clinical and laboratory characteristics of the study patients. At baseline, anthropometric, metabolic, and cardiovascular variables were similar in the placebo and tibolone groups. At the end of study, anthropometric, metabolic and cardiovascular variables remained unchanged in the placebo group. In contrast, patients who received tibolone had significant decreases in plasma levels of LDL cholesterol, triglyceride, and free fatty acid in the HOMA index but no change in plasma HDL cholesterol levels (Table 1).
TABLE 1Anthropometric and metabolic indices after placebo and tibolone administration.
Note: Results are the mean (±SD). All metabolites were stained during fasting. HDL = high-density lipoprotein; HOMA = homeostasis model assessment; LDL = low-density lipoprotein.
Manzella. Effect of tibolone on heart rate. Fertil Steril 2002.
Tibolone administration was associated with a significant increase in RR interval, total power, and high frequency and a decrease in low frequency and the low frequency/high frequency ratio (Table 2). Because differences between plasma free fatty acid levels and low frequency/high frequency ratio differed significantly after treatment with tibolone, delta (δ) changes in those variables were calculated to compare them more appropriately. In the tibolone group, δ changes in plasma free fatty acid levels correlated with δ changes in the low frequency/high frequency index (r=0.72; p<0.01). This correlation persisted even after adjustment for age, δ change in body mass index, δ change in HOMA index, and δ change in LDL cholesterol levels (Fig. 1).
TABLE 2Heart rate variability parameters after placebo and tibolone administration.
FIGURE 1Partial correlation between δ decrease in plasma free fatty acid (FFA) concentration and δ decrease in low frequency/high frequency (LF/HF) ratio in women who received tibolone (n = 15).
Our study demonstrates that long-term administration of tibolone decreases plasma levels of free fatty acid and has a positive effect on cardiac autonomic nervous activity in postmenopausal women.
Estrogen replacement therapy may decrease cardiovascular mortality in postmenopausal women in part by decreasing plasma levels of total cholesterol and LDL cholesterol and increasing plasma HDL cholesterol levels (
The Writing Group for the PEPI Trial Effect of estrogen/progestin regiment on heart disease risk factors in postmenopausal women the Postmenopausal Estrogen/progestin Interventions (PEPI) trial.
). This effect may be useful to prevent cardiovascular mortality in postmenopausal women. The decrease in plasma levels of triglyceride and free fatty acid provides a further pathophysiologic mechanism that may explain the relationship between menopause and cardiac mortality, since plasma free fatty acid levels negatively affect the sympathetic nervous system.
The relationship between plasma free fatty acid levels and the autonomic nervous system was suggested by Bulow et al. (
), who used lipid emulsion plus heparin to increase blood pressure and total peripheral resistance in pigs. Although the mechanism of this effect was not elucidated, these investigators had previously shown that local perfusion of adipose tissue with free fatty acid causes vasoconstriction (
) reported that infusion of lipid emulsion plus heparin reduced vein distensibility in healthy volunteers and increased responsiveness to phenylephrine. The latter observation suggested a direct pressor effect of fatty acids on vascular beds.
) reported that portal free fatty acid infusion also has significant pressor effects that may be mediated by increased sympathetic tone. It has also been demonstrated that elevated plasma free fatty acid levels may stimulate cardiac sympathetic nervous system in healthy persons (
To our knowledge, our study is the first to show that tibolone administration is associated with a decrease in plasma free fatty acid levels and beneficial modulation of cardiac autonomic activity in terms of the low frequency/high frequency ratio. We also show that positive modulation of cardiac autonomic nervous system is not influenced by degree of insulin resistance or distribution of body fat. The association between plasma free fatty acid levels and low frequency/high frequency ratio remained after adjustment for such confounding factors as age, body mass index, waist-to-hip ratio, and HOMA index.
A possible limitation of our study is the short duration of treatment and small sample. Larger studies of longer-term administration of tibolone are needed to confirm and extend our findings.
In conclusion, prolonged administration of tibolone was associated with a significant decrease in plasma triglyceride and free fatty acid levels and with rebalance of cardiac autonomic nervous activity in postmenopausal women. Our results are especially relevant in light of the data showing that postmenopausal women experience a significant increase in cardiac sympathetic activity (
). Epidemiologic studies should consider plasma free fatty acid levels as an important variable that affect the cardiac mortality risk in postmenopausal women.(