Recent studies suggest that older men and older women of similar age exhibit different cardiovascular adaptations to endurance exercise training and that these differences may be related to estrogen deficiencies in the women (30,32). In older men peak oxygen consumption was shown to increase via improvements in both peak cardiac output and peak arteriovenous oxygen difference. In contrast, improvements in peak oxygen consumption in the women resulted solely from an increase in arteriovenous oxygen difference. Since no alterations in peak cardiac output accompanied the increase in peak oxygen consumption seen in the women, the authors hypothesized that older women are unable to demonstrate central adaptations to exercise training. The fact that the women subjects were all past menopause and not taking estrogen supplements also led to speculation that the lack of an increase in maximal cardiac output and maximal stroke volume may be a consequence of sex hormone deficiency.
The aforementioned studies represent the only published work to date concerning the effects of menopause on the cardiovascular hemodynamics of women during peak exercise. Neither study explored the possible influence of estrogen replacement therapy or controlled for such confounding factors as differences in blood volume, hematocrit, or hemoglobin concentration, all of which can significantly affect such cardiovascular variables as oxygen consumption, stroke volume, and central venous pressure. Furthermore, there is ample evidence from animal research suggesting that estrogen may indeed influence cardiovascular hemodynamics, both at rest and during exercise(17,28,29). The purpose of the present study, therefore, was to test the hypothesis that supplemental estrogen enhances cardiovascular hemodynamics at peak exercise in endurance trained postmenopausal women.
Subjects. Parameters for subject recruitment and subsequent stratification were set forth as follows: All subjects were required to have experienced complete cessation of menses for at least 3 but not more than 10 yr. Additionally, they were all required to show unequivocal evidence of having engaged in endurance exercise in the form of walking, running, cycling, or exercising on a mechanical ergometer for at least 1 yr. Throughout their training history, these subjects had to have averaged three or more exercise bouts per week for 30 or more minutes per bout at an intensity level of at least 11 on the Borg scale.
Subjects classified as estrogen users were required to have undergone a regimental ingestion of estrogen or estrogen with low-dose progesterone for one or more years. Subjects not taking supplemental estrogen had to show evidence of a plasma estradiol concentration consistent with postmenopausal status; therefore, a plasma estradiol level of less than 20 pg·mL-1 was required for all subjects not taking hormone therapy. In accordance with the above criteria, postmenopausal female subjects were recruited into one of two groups: those exercising and taking estrogen replacement (ER) and those exercising and not taking estrogen replacement(NOER).
After approval for the study was obtained by the university human subjects review board and checked for compliance with guidelines for the use of human subjects set forth by The American College of Sports Medicine, recruitment began with the posting of flyers throughout the university community where the research was performed. Recruitment strategies also included a mass mailing of flyers to local physicians, local businesses, and university offices; telephone contact and follow-up mailings to road race directors in central and southeast Texas; and follow-up phone calls to potential subjects who were referred by those already recruited. Although every effort was made to recruit women of minority status, none volunteered to serve as subjects. From a total of 26 volunteers screened, 22 women met the specified inclusion criteria and served as subjects: 12 in the ER group and 10 in the NOER group.
Medical history, exercise data, and physical exam. Before the collection of physiologic data, subjects completed an orientation visit to the laboratory to acquaint them with the testing equipment and protocols. At this time, they were given a written description and an explantation of all of the tests to be performed. After being fully informed regarding the nature of the study and the risks involved, all subjects signed an informed consent which met the guidelines set forth by both the university human subjects review board and the American College of Sports Medicine. Next, they completed a health history and physical activity questionnaire designed to ascertain, in detail, their medical history along with the modality, frequency, intensity, and duration of their exercise regimen. The principle investigator of the study was present during the completion of the questionnaire to ensure that all information concerning physical activity and medical history was recorded accurately. During this visit, subjects also underwent a physical examination by a cardiologist. Those who showed evidence of medical contraindications to exercise as outlined by the American College of Sports Medicine, were taking medication for hypertension or other maladies known to affect cardiac performance and structure, or had a resting systolic blood pressure greater than 160 and/or a diastolic blood pressure greater than 96 were excluded from the study. Also excluded were those with any type of chronic disease or ailments that might influence physiological responses to either estrogen or exercise and those who smoked. Furthermore, resting echocardiograms were performed on all subjects. With the exception of two instances of mild and hemodynamically insignificant mitral valve prolapse, indices of ventricular function in all subjects were found to be normal. Three subject volunteers were excluded from participation because of elevated blood pressure and one subject dropped out of the study because of a family emergency.
Assessment of body composition. Although hydrostatic weighing at residual volume had been slated as a part of the research protocol, the inability of five of the first seven subjects to endure the procedure necessitated the use of an alternative measure of body composition. Therefore, percent body fat and lean body mass were calculated from body density estimated from the sum of seven skinfolds (12). All assessments were performed by the same experienced investigator. Body surface area was estimated from subject weight using a formula by Biering, cited and validated by Martin et al. (20). This particular estimation of body surface area demonstrated a smaller mean difference from criterion measures in older individuals than that of the often-used estimation of DuBois and DuBois (20).
Assessment of blood volume and plasma estradiol. Evans blue dye, a substance which attaches to plasma albumin and utilizes the indicator dilution principle of compartmental volume assessment, was used to measure plasma volume. The assessment protocol was modified from that outlined previously by Foldager and Bloomqvist (6). Plasma volume calculated from the Evans blue protocol was then converted to total blood volume using standard hematocrit correction factors. Plasma estradiol was measured using supply kits (Diagnostics Products Corporation, Los Angeles, CA) that use contemporary radioimmunoassay techniques.
Assessment of peak oxygen consumption and peak cardiac output. A symptom limited graded exercise test using a progressive incremental workload protocol on a motor driven treadmill (Quinton model Q65, Seattle, WA) was conducted under the direct supervision of a cardiologist, who evaluated all test results. Any subject who demonstrated hemodynamic or ECG criteria for heart disease during the test was excluded from the study. None of the subjects demonstrated such criteria. Blood pressure and a 12-lead electrocardiogram (Quinton model Q-3040) were monitored at rest, throughout the test at each stage of the protocol, and at least 4 min after volitional test termination. Respiratory gas exchange (˙VO2 and˙VCO2) was measured continuously and averaged over 15-s intervals via open-circuit spirometry, using an automated metabolic cart calibrated with gas mixtures of known composition (Medical Graphics CPX/D, St. Paul, MN.). An incremental staging treadmill protocol was used to assess peak oxygen consumption (˙VO2peak) and peak cardiac output (˙Qpeak). The protocol began at a workload of 3 METs and continued to volitional termination. The first six stages were 4 min in length, with the workload increasing by one MET each stage. ˙VO2, ˙VCO2, and cardiac output were measured during each stage. After completing the fourth stage, the workload for subsequent stages was determined by the subject's heart rate. If the heart rate was greater than or equal to 85% of the age-predicted maximum heart rate, the work rate for subsequent stages was increased by 1 MET each stage. If, after stage 4, the heart rate was less than 85% of the age-predicted maximum, the work rate for subsequent stages was increased by two METs each stage. The protocol was continued until the subjects indicated they could no longer proceed.
A CO2 re-breathing paradigm first described by DeFares(5) and later refined by Da Silva et al.(4) was used to assess cardiac output at the end of each stage of the exercise protocol. A gas mixture of 4% CO2 and 96% O2 was pumped into a 5-L rubber bag attached to a pneumatically controlled bidirectional valve. During the last 30 s of each stage, the subject's respiration was switched into the re-breathing bag using the pneumatic valve. The subject then inhaled and exhaled into the bag for 12 s at a rate of 40 breaths per minute. Compliance with the prescribed breathing rate was aided with the use of a metronome. At the end of the 12 s re-breathing maneuver, the subject's respiration was switched back to room air with the pneumatic controller. The data from the first breath after breathing was switched into the bag was discarded and cardiac output for each stage was automatically calculated by the CPX/D unit based on the exponential rise in CO2 after each breath of the maneuver (4). This calculation incorporates arterial CO2 concentrations calculated from end tidal CO2 partial pressures and a CO2 dissociation curve and concurrent ˙VCO2 measurements collected from expired gases. The cardiac output is then calculated using the Fick principle. Using a method developed by Makrides et al. (18), peak cardiac output for each subject was calculated using the regression of cardiac output on oxygen uptake at each stage of submaximal exercise and extrapolating the cardiac output value to ˙VO2peak. The reliability of this technique in our laboratory has previously demonstrated an intraclass correlation coefficient of 0.90. To establish the reliability of the peak oxygen consumption and cardiac output assessments in the study subjects, the same protocol and data collection paradigm was repeated on a subsequent visit to the laboratory. Discrepancies larger than 15% necessitated a third assessment; otherwise, the mean values for the two assessments were used as data.
Calculation of hemodynamic indices. Using a mercury filled sphygmomanometer, systolic and diastolic blood pressures were taken from the brachial artery of each subject during maximum exertion on the treadmill. The peak mean arterial pressure (MAPpeak) can be satisfactorily approximated as: (SBPpeak + (2 × DBPpeak))/3, where SBPpeak = peak systolic blood pressure and DBPpeak = peak diastolic blood pressure (1). Total peripheral resistance to blood flow (TPRpeak) can then be estimated as(MAPpeak/˙Qpeak) (16), and multiplied by a factor of 80 to convert units of mm Hg·L-1·min-1 to dynes·s·cm-5(3). Peak left ventricular stroke work (LVSWpeak) can be estimated by the equation: LVSWpeak = SVpeak × MAPpeak × 0.0136, where LVSWpeak = left ventricular stroke work measured in gram·meters, SVpeak = calculated peak stroke volume measured in mL, and MAPpeak = estimated peak mean arterial pressure measured in mm Hg (11). The peak index of oxygen consumption by the left ventricular myocardium, termed the rate-pressure product, can be estimated using the equation: RPPpeak =(HRpeak × SBPpeak)/100, where RPPpeak is a unitless index of peak left ventricular myocardial oxygen consumption, HRpeak = peak heart rate, and SBPpeak = peak systolic blood pressure.
Calculations such as those described above appear with considerable frequency in the literature(14,18,19,31); however, it should be noted that the resultant values constitute indirect assessments and should therefore be interpreted with caution.
Since body size can affect cardiovascular function, data were analyzed in both raw form and indexed to body surface area. All data were analyzed using Student t-tests with the significance level for all statistical comparisons set at α = 0.05.
Subject characteristics. There were no significant differences in age, height, weight, body fat percentage, body surface area, and years past menopause between the two subject categories. These demographics are depicted in Table 1. There were also no significant differences between the two groups with respect to frequency, duration, and intensity of exercise. The length of time the subjects had engaged in activity (measured as number of years exercising) was also not significantly different. Values for the training parameters of the two exercise groups are depicted inTable 2.
Estrogen and blood volume measurements. The average estrogen dosage and duration of administration was 0.91 ± 0.2 mg for 5.8± 2.5 yr for the ER group. It is important to note that within the ER group, there were no significant differences in any of the dependent measures with regard to whether the subjects were taking a progestin along with their estrogen (P < 0.05). As expected, the actual plasma estradiol levels in the group not taking hormone replacement were quite small, demonstrating a value of 5.5 pg·mL-1, while the group taking estrogen showed substantially higher values. Neither blood volume or blood volume index was significantly different between the two groups. The blood volume results, along with hematocrit, hemoglobin, and the estradiol values for the two groups, are depicted in Table 3.
Hemodynamic data from the exercise tests. Each subject underwent two symptom-limited graded exercise tests within a week, each of which yielded a measure of ˙VO2peak and ˙Qpeak. None of the differences between the two measurements for either variable exceeded 15%, and intraclass correlation coefficients between tests for ˙VO2peak and˙Qpeak, were 0.77 and 0.91, respectively. Consequently, the results of the two tests were averaged to form data points.
As can be seen in Table 4, the relative measures of˙VO2peak for the two groups were extraordinarily similar, and there were no significant differences in peak heart rate. Although ˙Qpeak is almost 1 L·min-1 greater in the ER group, the difference did not reach statistical significance until body habitus was accounted for(˙QIpeak). Similarly, peak stroke index was significantly higher in the ER group. As would be expected given the oxygen consumption and cardiac output variables, peak arteriovenous oxygen difference was higher in the NOER group. The indices of pressure, resistance, and myocardial work at peak exercise were all substantially lower in the ER group. However; because of a large within group variation, only TPRpeak demonstrated statistical significance. Regardless, the 14% differences in TPRpeak between the ER and NOER groups is noteworthy and alludes to the mechanism that may have facilitated the higher ˙QIpeak seen in the ER subject group(Table 5).
Magnitude of the difference found in cardiac output. The difference in ˙QIpeak (1.1 L·min-1·(m2)-1) between the two subject groups, both of which are exercised trained, is comparable to changes actually induced by training in women whose ages were similar to those of our subjects (22). Likewise, when compared in absolute terms, the 0.9 L·min-1 difference in ˙Qpeak seen between the two trained groups in the present study is almost identical to the magnitude of training-induced elevations reported in other studies with similar subject populations. For example, Kilbom and Astrand (15) found that in 55-yr-old women, 7 wk of exercise performed three times per week for 30 min at 70% of maximum oxygen consumption was associated with a 1.0 L·min-1 increase in peak cardiac output. This is only 0.1 L·min-1 more than the difference between two exercising groups in the present study. Therefore, based on the results of the present study, it is reasonable to hypothesize that the magnitude of the difference in peak cardiac output between two groups of similarly active women, one group taking estrogen, the other not, might be comparable with differences between trained and untrained women as reported in other studies.
Differences in hemodynamic parameters. Further delineation of hemodynamic parameters related to oxygen transport and oxygen consumption offers additional insight into possible estrogen mediated adaptations seen during peak exercise between the two subject groups. The slightly smaller mean arterial pressures at peak exercise (MAPpeak) seen in the ER groups was disproportionately small when compared with the associated discrepancy in TPRpeak, which was over 100 dynes·s·cm-5 less than that of the NOER group. Since blood flow (˙Qpeak) is determined by the pressure in the system (MAPpeak) divided by the total resistance(TPRpeak), it can be hypothesized that an estrogen mediated reduction in TPRpeak played a significant role in facilitating the slightly larger ˙QIpeak seen in the ER group. The feasibility of this type of estrogen related alteration in peripheral resistance is well founded in the literature. Bourne (2), for example, found that after 6 wk of treatment with transdermal estrogen, postmenopausal women exhibited a 50% reduction in uterine artery pulsatility index, indicating a substantial reduction in impedance to blood flow. Evidence for this phenomenon outside the reproductive system is provided by Gangar et al. (7), who discovered a significant negative correlation (r = -0.7) between pulsatility index measured in the carotid artery and time since the onset of estrogen therapy. These authors concluded that estrogen has a generalized vasodilatory effect on the arterial system. The results of a study by Martin et al.(19), which indicated blood flow conductance in the calf to be 21% higher in estrogen treated women versus untreated women, lend even more credence to our hypothesis, implying that this effect may indeed be operational in the peripheral vasculature. Furthermore, the difference in TPRpeak between the ER and NOER women in our study did not, in all likelihood, result from differences in blood viscosity because there was no difference in hematocrit between the two groups. Since significant differences in the length of the vasculature between these two groups is also unlikely, difference in vessel radius is, from a mathematical standpoint, the only other determinant of systemic resistance that could account for the differences in TPR. Other human and animal model studies(25,33), and conclusions in review papers(27) also support our postulate.
Possible mechanisms of hemodynamic differences. Although still speculative, there is mounting evidence that the mechanism for the aforementioned phenomenon may be related to sympathetic receptor activity and/or the function of calcium channels. According to Gisclard et al.(9), estrogen may inhibit the adrenergic contractile response in arterial smooth muscle via depression of α-receptor function, ultimately retarding vasoconstriction in peripheral arteries, which, in turn, may lower peripheral resistance. Williams et al.(34) reported similar findings concerningα-receptor function and suggested that the estrogen-mediated attenuation of peripheral vascular constriction may be dose dependent.
There is also evidence that estrogen may reduce peripheral resistance by acting as a calcium channel blocker. Jiang et al. (13) recently found that estrogen administration attenuated the endothelin-1 mediated contractile response of rabbit coronary arteries regardless of whether the endothelium was present. The authors concluded that since activation of calcium channels is thought to be central to the mechanism of endothelin-1 contraction, estrogen may exert calcium antagonist properties. Although it has been postulated that plasma endothelin, in and of itself, may be modulated by estrogen (26), evidence for the premise remains obscure. It should be noted that all the aforementioned studies dealt with vascular responses measured at rest or in vitro; therefore, additional work is needed to determine whether these postulated mechanisms function, as we suggest, during peak exercise. It is, however, reasonable to hypothesize that since a-receptor and calcium channel function are related(10) and both have been shown to be involved in estrogen-mediated maintenance of vascular caliber, estrogen may play a role in attenuating the amount of peripheral resistance accompanying peak exercise, thereby facilitating a slight increase in peak cardiac output. This hypothesis is illustrated in Figure 1 using a cardiovascular function curve model.
Peak heart rates were similar between the ER and NOER groups, implying that the slightly larger ˙QIpeak seen in the ER group may have been facilitated by a larger stroke volume. Indeed, calculated peak stroke volume index was shown to be significantly greater in the ER group. The hypothesis that estrogen may play a regulatory role in stroke volume has not been well investigated; however, two relatively recent studies do support the possibility. Giraud et al. (8) found that exogenous estrogen administration in ovariectomized ewes was associated with a 16% increase in resting stroke volume. Likewise, Veille et al.(33) determined that pharmacologically-induced elevations in endogenous estrogen facilitated a stroke volume enhancement of 10 mL. However, the authors of both studies measured stroke volume only at rest, and no studies could be found in which stroke volume at peak exercise was compared between estrogen-treated versus untreated subjects. Although Spina et al. (30) found no training-induced elevations in maximal stroke volume in postmenopausal women not on estrogen supplements, no comparisons were made with estrogen-treated counterparts, and possible blood volume changes were not accounted for. The results of the present study would seem to indicate that exogenous estrogen may, indeed, contribute to a larger peak stroke volume. Since blood volume index was almost identical within the subject groups, it would seem that it is independent of estrogen status and not influential in determining peak stroke volume. Whether the differences noted between the two trained groups in peak stroke volume resulted from a reduction in afterload mediated by a smaller TPR, an estrogen-induced elevation in the inotropic state of the myocardium, enhancements of left ventricular diastolic function, or a combination of the above remains unclear. There is, however, evidence to suggest that, at rest, estrogen loss may contribute to a decline in both peak ventricular filling rate and myocardial contractility (24), implying reductions in both systolic and diastolic function. There is also evidence that estrogen replacement may reverse some of these decrements(23). However, in the present study, TPR was shown to be substantially smaller in the exercise group taking estrogen; therefore, it likely that the larger stroke volume seen in the ER subjects was, at least to some extent, facilitated by a reduction in afterload associated with a reduction in vascular resistance.
The small difference in ˙QIpeak between the ER and NOER groups is also reflected in the peak values for calculated arteriovenous oxygen difference. As seen in Table 4, the value for the NOER group is significantly higher than those seen in any of the other subject groups. Since there were no significant differences among the groups in blood oxygen carrying capacity, as evidenced by homogeneity of hematocrit and hemoglobin concentrations, and it is unlikely that estrogen has significant influences on arterial oxygen saturation, it can be hypothesized that the greater arteriovenous oxygen difference seen in the NOER group is attributable to alterations in physiology related to oxygen extraction by the tissues. In older individuals, these potential alterations include increased muscle involvement or enhancements in capillary density, mitochondrial density, or enzymatic function (21). It is unlikely that alterations in the amount of muscle involved or a larger capillary density are responsible because both would increase the total cross-sectional area of the vasculature, which, from a hemodynamic perspective, would decrease TPRpeak. Since peak TPRpeak was greater in the NOER group, the larger arteriovenous oxygen difference would most likely be attributable to adaptive differences in cellular mechanisms of oxygen extraction and utilization; however, no information concerning the effects of estrogen on the cellular mechanisms of oxygen transport or extraction could be found to support or refute these speculations.
Clinical significance of the findings. Since peak oxygen consumptions were almost identical between the ER and NOER groups, it might appear that the larger peak arteriovenous oxygen difference seen in the NOER subjects is a “compensatory” mechanism for the adverse effects of estrogen loss on ˙QIpeak. On the other hand, this phenomenon may simply be a natural, nondetrimental change in adaptation physiology that accompanies menopause. In any case, the clinical or biological significance of these findings cannot, to even a small extent, be conclusively determined based on the results of the present study. However, if supplemental estrogen facilitates a reduction in peripheral vascular resistance and a corresponding improvement in blood flow at peak exercise, it can be speculated that for a given oxygen consumption, the peak workload of the heart might also be reduced. In addition, if the total work or quantity of oxygen consumed by the heart during maximum stress is, in fact, reduced by the administration of exogenous estrogen, it could further be hypothesized that estrogen supplementation might prove beneficial for postmenopausal women who are predisposed to or suffering from cardiovascular diseases such as aortic stenosis or chronic hypertension in which left ventricular work is increased to a pathological extent. To investigate this possibility using the present data, two estimations of myocardial workload were analyzed: left ventricular stroke work and rate-pressure product. As can be seen inTable 5, both stroke work and rate-pressure product at peak exercise were less in the ER group; however, the differences did not reach statistical significance. Nevertheless, these results are comparable with those of Scheuer et al. (29), who found that stroke work in isolated perfused hearts of gonadectomized female rats given estrogen supplements was slightly less than in hearts of gonadectomized counterparts not given estrogen. Other than Scheuer's work, no studies concerning the influences of estrogen on left ventricular work could be found, underscoring the need for further investigation in this area.
Summary and directions for future research. Our data suggest that at peak exercise, an estrogen-mitigated reduction in total peripheral resistance may contribute to a higher peak stroke volume, which, in turn, facilitates a slightly higher peak cardiac output in exercise-trained postmenopausal women taking estrogen versus similarly trained women not taking estrogen. Our findings are graphically summarized in Figure 2. It is our opinion that future work in this area should first be devoted to testing our hypothesis with longitudinal training studies and with more detailed types of instrumentation. If our findings and hypothesis are confirmed, efforts should be undertaken to determine what mechanisms are responsible for the lower vascular resistance and the concomitant increase in stroke volume at peak exercise between postmenopausal exercising women taking hormones versus those not taking hormones and, likewise, what mechanisms facilitate the higher peak arteriovenous oxygen difference in exercise-trained postmenopausal women not taking hormones versus those who are taking hormones.
This research was supported and funded by the American College of Sports Medicine Foundation Grant RF95141.
Address for correspondence: John S. Green, Ed.D., Ph.D., FACSM, Mailstop 4243, Department of Health and Kinesiology, Texas A&M University, College Station, TX 77843. E-mail: email@example.com.
Figure 2-Fick illustration of the training adaptations seen at peak exercise in postmenopausal women taking estrogen compared with similar trained women not taking estrogen. ˙VO2 = oxygen consumption, HR = heart rate, SV = stroke volume, [Hb] = hemoglobin concentration, SaO2 = oxygen saturation of arterial blood, S˙VO2 = oxygen saturation of mixed venous blood, ˙Q= cardiac output, P = systemic pressure, V = blood viscosity, L = vasculature length, r = vasculature radius, and A˙VO2-Diff = arteriovenous oxygen difference; ↑ indicates increase; ↓ indicates decrease; ← indicates no change
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Keywords:©1998The American College of Sports Medicine
MENOPAUSE; PEAK OXYGEN CONSUMPTION; CARDIAC OUTPUT; ESTROGEN REPLACEMENT THERAPY