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Jacob Recanati Autonomic Dysfunction Center (N.H., I.T., I.M., Y.E., M.M.P., G.J.), Department of Medicine "C"; and Department of Obstetrics and Gynecology (J.I.-E.), Rambam Medical Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Address all correspondence and requests for reprints to: Giris Jacob, M.D., D.Sc., Director, Jacob Recanati Autonomic Dysfunction Center, and Department of Medicine "C", Rambam Medical Center, PO Box 9602, Haifa 31096, Israel. E-mail: . g_jacob{at}rambam.health.gov.il
Abstract
Gonadal hormones may affect homeostatic mechanisms regulating the cardiovascular system. We investigated this relationship at five different crucial hormonal time points along the menstrual cycle.
Eight eumenorrheic healthy subjects underwent a battery of autonomic tests, hemodynamics, and volume-regulatory hormone measurements. Fluid-regulatory hormones, plasma renin activity, and aldosterone increased along the luteal phase (P = 0.003 and 0.02, respectively), whereas rest supine-corrected hematocrit declined in the course of the menstrual cycle (P = 0.001). Plasma norepinephrine decreased from 1.4 ± 0.2 to 0.95 ± 0.1 nmol/liter (P < 0.02) [early follicular (EF) to late follicular]. Thereafter, concentrations gradually returned to EF levels. Lf to Hf domain ratio (spectral analysis of electrocardiogram) showed a difference from that of norepinephrine. The cardiovagal baroreflex sensitivity increased significantly along the luteal phase (P = 0.04). The dose of isoproterenol required to increase heart rate (HR) 15 beats per minute was 0.19 ± 0.04 µg during the EF time point, and it increased to 0.39 ± 0.06 µg during the late luteal time point (P = 0.05). However, blood pressure, HR, and their responses to orthostatic stress remained unchanged.
Fluctuations in the ovarian hormones along the menstrual cycle are associated with unchanged blood pressure and HR, despite the significant variations in the different homeostatic mechanisms regulating the cardiovascular system.
THE HIGH INCIDENCE of ischemic heart disease during menopause suggests a close association between ovarian hormone levels and the cardiovascular system (1, 2). In addition, there are several lines of evidence connecting symptoms and illnesses such as edema (3, 4), idiopathic orthostatic intolerance (5, 6), syncope (7), mood, and psychiatric illness (8) to the hormonal alterations along the menstrual cycle (9). Emerging data regarding variations in plasma volume (PV), cardiovascular homeostasis, and sympathetic regulation have increased interest in the effects of female gonadal hormone.
PV homeostatic variations during the menstrual cycle are assumed to be related, in part, to the increase in plasma renin activity (PRA) and aldosterone levels during the luteal phase (10, 11). However, there are conflicting data concerning these variations in other studies (12, 13).
The presence of ERs in the heart, vascular smooth muscle, and autonomic brain stem centers (e.g. nucleus tractus solitarius, ventrolateral medulla) (14) and hormone-mediated changes in adrenoreceptor density (15), cAMP levels (16), and nitric oxide synthase activity (17) suggest a possible involvement in the regulation of the cardiovascular system. Recently, Minson et al. (18) reported that in healthy eumenorrheic women, muscle sympathetic nerve activity and plasma norepinephrine were lower during the early follicular (EF) time point compared with the midluteal (ML) time point. However, other studies showed no differences in rest muscle sympathetic nerve activity (19) and plasma norepinephrine concentration (20).
A possible explanation for the confusing data is that ovarian hormone effects on the cardiovascular regulatory systems were examined in different experimental designs, mainly in the animal model, postmenopausal women, and only two time points along the human menstrual cycle. We postulate that the ovarian hormonal changes along the menstrual cycle are associated with significant neurohumoral alterations regulating the cardiovascular system. To our knowledge, this is the first investigation in humans that examines and correlates a broad spectrum of variables, including hemodynamic parameters, volume-regulatory hormones, PV shift, systemic autonomic control, baroreflex, and adrenoreceptor responsiveness during five distinct hormonal time points along one menstrual cycle in humans.
Subjects and Methods
Subjects
Nine subjects were recruited through an advertisement at a university near Rambam Medical Center. All enrolled subjects met the following criteria: 1) eumenorrheic healthy women, 2) age between 21 and 40 yr, 3) no oral contraceptive use within the last 6 months, 4) body mass index within the normal range (18.5–24.9 kg/m2) , and 5) no history of alcohol, drug abuse, smoking, or any medications. All subjects received a full explanation of the study and read and signed the informed consent form that was approved by the local institutional review board. Their diet was free of caffeine-containing beverages 24 h before each study day.
Experimental design
All investigational procedures were performed after overnight fasting in a human physiological laboratory at Recanati Autonomic Dysfunction Center. Each subject was studied at five different time points along one menstrual cycle in controlled environment conditions in a quiet and partially darkened room with an ambient temperature of approximately 24 C. Detailed rationale of ovarian cycle timing and hormonal profiles are depicted in Table 1
. The measured parameters at each time point were: 1) ovarian steroids and gonadotropins; 2) blood pressure (BP) and heart rate (HR); 3) acute PV changes extrapolated from hematocrit (Hct) values; 4) plasma catecholamine, PRA, and aldosterone; 5) R-R variability analysis; 6) adrenoreceptor responsiveness; and 7) baroreflex sensitivity.
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Thereafter, a three-lead electrocardiogram and continuous beat-to-beat arterial tonometer (Colin, TX) were used to monitor HR and BP, and the data were displayed on a computer screen and on thermal array recorder (TA-6000, Gould, Valley View, OH). The subject rested for 30 min, and then an electrocardiogram was acquired for 6 min and digitized at a sample rate of 500 Hz for the assessment of R-R variability. Subsequently, the subject rested supine, and the responses to adrenergic agonists were determined to assess cardiovascular adrenoreceptor responsiveness. First, 
1-adrenoreceptor responsiveness was determined by recording beat-to-beat systolic BP in response to graded iv boluses of phenylephrine (25, 50, 100, 150, and 200 µg). Then, ß-adrenoreceptor responsiveness was assessed by the HR changes in response to incremental boluses of isoproterenol (0.0625, 0.125, 0.25, 0.75, and 1 µg). We used PHE15 (the dose of phenylephrine required to increase systolic BP by 15 mm Hg) and ISO15 (the dose of isoproterenol required to increase the HR by 15 beats per minute). The individual baroreflex slope (milliseconds per mm Hg) was extrapolated from the linear portion by plotting changes in systolic BP, induced by phenylephrine, against the corresponding changes in R-R intervals (21).
Analysis methods
Blood was collected for catecholamines as described previously (21). Assays were performed for each subject separately, at the end of her ovarian cycle. Concentrations of norepinephrine and epinephrine were measured by HPLC in a method modified from Goldstein et al. (22). Ovarian hormones, gonadotropins, aldosterone, and PRA were analyzed in the endocrinological laboratory at Rambam Medical Center.
Acute PV shift during quiet standing was estimated from quadruplicate microcapillary venous Hct measurements and corrected for trapped plasma (0.96) and whole body Hct (0.91) (0.96 x 0.91 = 0.87). Hct was measured after 10 min centrifugation at 11,500 rpm and read on a microcapillary tube reader. Acute dynamic percentage changes (
) in PV were calculated from Hct, where Hct1 is baseline and Hct2 is the tested. Dynamic PV (%) = 100 x (Hct1 - Hct2)/Hct2 x (1 - Hct1) (23). However, along the menstrual cycle, during the different baseline supine time points we considered only the corrected Hct (a possible measure of PV changes).
Power spectral analyses of R-R intervals were calculated by Welch periodogram method for power spectral density calculation (MATLAB version 5.3.1, September 1999, Mathworks, Inc.). Band pass filter was used for respiration and noise reduction. A Hanning windowing in the time domain was adopted to attenuate spectral leakage (512 samples). Two subsets of the frequency domain were used: low frequency (0.04–0.14 Hz) and high frequency (0.15–0.4 Hz). Changes in sympathetic activity were evaluated by the calculation of the ratio of normalized low and high frequencies (Lfnu/Hfnu unitless ratio), which is an indirect marker of the balance between sympathetic and vagal cardiovascular control (24).
Statistical analysis
Results are expressed as mean ± SEM. Paired and unpaired two-sided t tests were used for comparisons between time points. One-way ANOVArm (repeated measurement) was used to assess the effect of the time points on the different variables. Two-way ANOVArm was used for the comparison between supine and upright posture. Nonlinear regression analysis [one-phase exponential decay, PV% = a·e-kt + plateau (maximal PV changes)] was used for the calculation of the constant K (constant of exponential decay) and area under the curve (AUC) as measures of the individual plasma shift rate during standing (see Fig. 2B). Linear regression analysis was used to assess correlations between the various parameters and for the determination of dose effect for each drug and the baroreflex slopes. Data were analyzed with Quattro Pro (version 7; Corel Corp. Ltd., Ottawa, Canada) and GraphPad Prism (version 3.0; GraphPad Software, Inc., San Diego, CA). The level selected for statistical significance was set at P less than 0.05.
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Subjects’ mean age, weight, height, and body mass index were 25 ± 0.8 yr (range, 22–29 yr), 56 ± 1.4 kg, 165 ± 3.5 cm, and 20.8 ± 0.7 kg/m2, respectively. Study results of one of the nine subjects were excluded due to an anovulatory menstrual cycle hormonal pattern. Gonadotropins and ovarian hormonal patterns along the menstrual cycle of the studied subjects were as predicted (Table 1
). As shown in Fig. 1, A and B, these changes were statistically significant during the different follicular and luteal phases.
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As depicted in Table 2, there were no significant changes in resting supine BP and HR during the different time points. Furthermore, changes in the above hemodynamic parameters that occurred after assumption of upright posture were not affected significantly by the menstrual phases.
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). The rise in corrected Hct at the late follicular (LF) time point was not statistically significant, whereas the major decrease in corrected Hct was observed during the ML and late luteal (LL) time points compared with EF. The maximal shift in PV (calculated from Hct changes) observed during 20 min of standing were not significant between the different studied menstrual time points. Moreover, exponential constant decay, a measure of plasma shifting rate, and the areas under the curves (AUCs), a measure of total PV shift, were similar at all time points (Table 2). Neurohumoral changes
Rest supine plasma norepinephrine concentration significantly decreased during the LF time point compared with EF (0.95 ± 0.1 vs. 1.4 ± 0.2 nmol/liter, respectively; P < 0.02). During the subsequent luteal phase, plasma norepinephrine concentrations returned gradually to EF levels (Fig. 3A). Twenty minutes of standing caused similar significant increments in plasma norepinephrine at each time point as shown in Fig. 3A (two-way ANOVArm, P = 0.001). On the other hand, rest supine and upright plasma epinephrine concentrations did not change significantly in the course of the menstrual cycle (Table 2).
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, B and C (P values for LF vs. EF and ML vs. EF for PRA and aldosterone were 0.015 and 0.01, 0.06 and 0.05, respectively; paired t test). It is noteworthy that there was a significant positive correlation between rest supine and upright posture PRA levels and plasma aldosterone concentrations along the menstrual cycle (r = 0.4; P < 0.001). Also, PRA and aldosterone are increased in parallel with high P and estrogen plasma levels (Table 3).
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Baseline time domain analysis of R-R intervals are depicted in Table 2. The significant fluctuations in the Lfnu/Hfnu ratio that occur during the different phases of the menstrual cycle are illustrated in Fig. 4. The maximal central sympathetic activity controlling HR was detected during the early luteal (EL) time point (compared with LF; P = 0.05). These changes were not significantly correlated to the changes in plasma norepinephrine concentrations along the menstrual cycle (r = 0.12; P = 0.45).
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Incremental iv boluses of isoproterenol produced a greater tachycardia in the follicular phase compared with the luteal phase (P = 0.05). The ISO15, which is inversely related to cardiac ß1-adrenoreceptor sensitivity (21), was 0.19 ± 0.04 µg at EF and 0.39 ± 0.06 µg at LL (Fig. 5A). P (but not estrogen) plasma levels significantly correlate with ISO15 (Table 3). However, the BP increasing effect of phenylephrine (PHE15) did not change significantly during the menstrual phases: 115 ± 32, 120 ± 20, 123 ± 15, 141 ± 23, and 175 ± 35 µg for EF, LF, EL, ML, and LL, respectively. Cardiovagal baroreflex, extrapolated from individual linear regression (r coefficients, 0.85–0.95), changed significantly along the menstrual cycle (P < 0.04). As illustrated in Fig. 5B, the main increment in baroreflex sensitivity was observed at ML and LL, compared with LF time points (P = 0.01 and 0.045, respectively). It is noteworthy that there was no correlation between PHE15, ISO15, and baroreflex sensitivity.
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. Discussion
This is the first study that explores the complex relationship between the female reproductive hormones and the cardiovascular system during five distinct time points along one menstrual cycle. Ovarian hormone alterations along the menstrual cycle are associated with corresponding significant changes in multiple neurohumoral homeostatic mechanisms regulating the cardiovascular system, without changes in BP and HR. It is noteworthy that measured plasma ovarian steroids in our subjects, during the five studied time points, were similar to the predicted hormonal patterns on the basis of previously published data (9). Thus, the rationale behind the selection of the studied time points is the uniqueness of the effect of each of their corresponding hormonal profiles on hemodynamic homeostasis.
Fluid-regulatory hormones
The decrease in baseline corrected Hct along the luteal phase, which is beyond the initial increment (possible compensatory erythropoiesis), suggests a PV increment as was observed in a study that compared only two menstrual time points (11). Indeed, fluid-regulating hormones, PRA and aldosterone, are increased in parallel with high P and estrogen plasma levels (as shown in Table 3). Therefore, our findings are consistent with the assumption that P is one of the main modulators of PRA and aldosterone levels during pregnancy (25) and during ovarian cycle (13). Although the increase in fluid-regulatory hormones may be compensatory to the natriuretic property of P (26) and the vasodilatory effect of estrogen (mediated by nitric oxide) (17), a definite explanation for fluid retention has yet to be investigated. Foot circumference increment observed in a previous study (4) during the LL phase could suggest an augmentation in PV shift. However, our findings disagree with this hypothesis, because of the similar rate and quantitative PV shift into the interstitium along the various time points.
Norepinephrine and neuronal control
Lfnu/Hfnu ratio is a partial surrogate dimension of the central sympathetic activity, whereas norepinephrine plasma concentration is an integrated measure of sympathetic nerve activity affected by central firing rate, as well as by neuronal uptake (
90%), target cell uptake, and extraneuronal metabolism (27). Therefore, the lack of correlation between the two discrete parameters (r = 0.12; P = 0.45) is anticipated. To clarify this dissociation, simultaneously measuring muscle sympathetic nerve activity and norepinephrine kinetics is required. Notwithstanding, the significant variations in both parameters along the menstrual cycle are of great interest and value.
During the follicular phase, both norepinephrine plasma concentration and Lfnu/Hfnu ratio were higher at the EF compared with the LF time point. Similarly, in menopausal women (low hormonal status), it was reported that estrogen supplementation caused a significant decline in systemic norepinephrine spillover and in sympathetic tone (28), with an increased vagal tone (29). Subsequently, during the luteal phase, although the central sympathetic control declined, norepinephrine further increased. Contrary to our results regarding R-R domain ratio, only one study reported that along the menstrual cycle the Lf /Hf ratio remains unchanged (30). Although no data are available on a detailed characteristic pattern with time, previous investigations at only two time points detected higher plasma norepinephrine concentrations during the luteal phase compared with the follicular phase (13, 18, 31).
The present study and a recently published investigation (18) detect nonsignificant changes in cardiovagal baroreflex gain when comparing only two time points, EF vs. ML. However, detailed observation of the menstrual cycle time course demonstrates a significant increase in the cardiovagal baroreflex sensitivity during the luteal phase. Moreover, animal model investigations show that gonadal hormones may affect directly the modulation of the central autonomic nervous system (32, 33).
Adrenoreceptor responsiveness
We found a 2-fold increase in cardiac ß1-adrenoreceptor responsiveness during the EF compared with the LL time point. However, although no data are available in the literature on cardiovascular ß1-adrenoreceptors during the menstrual cycle, myometrial ß1-adrenoreceptors are found to be up-regulated during the mid-follicular phase in a study conducted in humans (34). We found that systemic cardiovascular 1-adrenoreceptor responsiveness was not affected by the different hormonal profiles along the menstrual cycle. This observation lies in conflict with previous studies that reported an increment in local forearm 1-adrenoreceptor sensitivity at the ML time point (high estrogen and P) and after estrogen supplementation (28, 35). These differences between the systemic and local 1-adrenoreceptor responsiveness rely on changes in adrenoreceptor sensitivity, as well as on variations occurring in the cardiovagal baroreflex sensitivity (36). Increased sensitivity during the luteal phase can counterbalance the rise in BP caused by phenylephrine and mask eventual adrenoreceptor hypersensitivity.
Study limitations
1) As is evident, it is not possible to test the physiologic effects of a hypothetical high, pure P time point in the setting of low estrogen levels during the normal menstrual cycle. 2) The method employed to estimate PV is well validated for the estimation of acute PV changes (23, 37); however, it was not established for chronic variations in human PV. Thus, we restricted our assumption about PV changes along the menstrual cycle by using only Hct values. 3) Our conclusion regarding acute PV shift was only in healthy subjects in the absence of ankle edema. 4) Baroreflex activity was investigated by the alterations in the response to high BP achieved by phenylephrine (cardiovagal baroreflex), without examining the sympathetic baroreflex. (5) The cyclic changes of the measured parameters in this complex investigation could have been better demonstrated by repeating the same measurements along a subsequent menstrual cycle.
Conclusion
Despite the complex alterations in the hemodynamic homeostatic mechanisms, our results, like other reported data, show that the menstrual cycle phases do not affect rest supine BP and HR (13, 18, 20). PRA, aldosterone, plasma norepinephrine, and possible PV increments in the high hormonal milieu at the luteal phase are counterbalanced by a decrease in ß1-adrenoreceptor sensitivity and an increase in cardiovagal baroreflex activity. Therefore, these opposite influences of the gonadal hormones may explain in part why BP, HR, and orthostatic stress responses remain unchanged throughout the menstrual cycle. The data emerging from the five studied time points of the menstrual cycle emphasize the complexity of the relationship between ovarian steroids and various hemodynamic regulatory systems. Furthermore, these results could enlighten physiological and clinopathological conditions, e.g. cyclic edema, orthostatic intolerance, and premenstrual syndrome. Further investigations are required to explore the possible biomechanisms underlying our findings.
Acknowledgments
We kindly thank Avital Greenberg, M.Sc., for performing catecholamine assays and Rivka Arnon, B.A, from the Endocrinology laboratory.
Footnotes
This work was supported by a grant from the "Ya’el" research fund (Biosense Israel).
Abbreviations: ANOVArm, ANOVA repeated measurement; AUC, area under the curve; BP, blood pressure; EF, early follicular; EL, early luteal; Hct, hematocrit; Hfnu, normalized high frequency; HR, heart rate; ISO15, isoproterenol dose required to increase HR 15 beats per minute; LF, late follicular; Lfnu, normalized low frequency; LL, late luteal; ML, midluteal; P, progesterone; PHE, phenylephrine; PRA, plasma renin activity; PV, plasma volume.
Received September 14, 2001.
Accepted January 5, 2002.
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