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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 4 1618-1629
Copyright © 2004 by The Endocrine Society

Acute and Chronic Effects of Hormone Replacement Therapy on the Cardiovascular System in Healthy Postmenopausal Women

Lori D. Kirwan, Neil J. MacLusky, Heather M. Shapiro, Beth L. Abramson, Scott G. Thomas and Jack M. Goodman

Faculty of Physical Education and Health (L.D.K., S.G.T., J.M.G.), Department of Obstetrics and Gynecology (H.M.S.), Cardiac Prevention Centre and Women’s Cardiovascular Health, St. Michael’s Hospital (B.L.A.), University of Toronto, Toronto, Ontario M5S 2W6, Canada; and Department of Obstetrics and Gynecology, Columbia University Medical School (N.J.M.), New York, New York 10032

Address all correspondence and requests for reprints to: Dr. Jack M. Goodman, Ph.D., Faculty of Physical Education and Health, University of Toronto, 55 Harbord Street, Toronto, Ontario M5S 2W6, Canada. E-mail: jack.goodman{at}utoronto.ca.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Previous studies have shown that conjugated estrogens and continuous medroxyprogesterone increases heart disease risk in healthy women. Little is known about the effects of the natural ovarian hormones estradiol and progesterone on cardiovascular function at rest and exercise. The purpose of this study was to investigate the short- and longer-term effects of a cyclic format of hormone replacement therapy (HRT) (1 mg estradiol daily with cyclic micronized progesterone, 200 mg for 10 d/month) on cardiovascular function at rest and during exercise in healthy, postmenopausal women. A double-blind, cross-over study was conducted in 31 patients. Peak oxygen uptake and ventilatory threshold in addition to submaximal cardiac output were determined. Peripheral measures of resting and peak ischemic blood flows were also determined. Measurements were made at baseline, after 4 h of estrogen/placebo exposure, and subsequently after 1, 2, and 3 months. The sequence of data collection was repeated after 6-wk washout. Oral estradiol with cyclic micronized progesterone increases peak ischemic peripheral blood flow chronically but fails to improve exercise tolerance and peak oxygen uptake. Similarly, submaximal central cardiovascular function is unaffected by HRT. This suggests that estradiol has a beneficial effect on peripheral blood flow, but this benefit offers little advantage in terms of peak exercise performance after 3 months of HRT.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ESTROGEN REPLACEMENT THERAPY (ERT) and its role in the cardiovascular health of women remain a controversial and active area of investigation. Many earlier epidemiological studies in healthy women free of coronary artery disease (CAD) indicated that hormone replacement therapy (HRT) was associated with improved cardiovascular health (1, 2, 3, 4). Recently two large-scale randomized clinical trials in women with CAD (5, 6) indicate that continuous daily conjugated estrogens plus medroxyprogesterone may not confer any benefit and in fact may increase the risk of heart attack and stroke (7). The estrogen-alone arm of the study is still ongoing, suggesting that the same risk may not be as great for estrogen administered without continuous progestin. Continuous exposure to progestins down-regulates both estrogen and progesterone receptor synthesis and reduces estrogen and progestin sensitivity (reviewed in Ref. 8). In addition, there is biologic evidence that medroxyprogesterone acetate (MPA) has a detrimental effect on the beneficial effects of conjugated estrogens in vascular reactive studies (9, 10, 11), whereas micronized progesterone does not have comparable detrimental effects (12).

The conflicting results between the epidemiological data and these clinical trials may well reflect the considerable methodological differences that exist between the studies. Perhaps most important, there has not been uniformity in the hormonal preparations used for HRT. Different regimens of HRT have different effects on the cardiovascular system. Hodis et al. (13), in a random controlled trial, found that women taking unopposed oral 17ß-estradiol had significantly lower rates of progression of atherosclerosis than those not receiving any ERT. This is in opposition to the results of the three large clinical trials cited above that found negative effects using combined conjugated estrogens and medroxyprogesterone acetate. Conjugated estrogens are a mixture of powerful hormonally active substances originating in the urine of pregnant horses, containing at least 10 conjugated estrogens, some of which are not found naturally in women (14). In addition, Premarin also contains a number of equine androgens and progestins (15). Defining the biological effects of each of the components of this complex mixture has only recently begun to occur as the different components have been identified (16). Whereas the natural hormones, estradiol and progesterone, are now available in oral micronized form, there is a lack of information regarding the effects of oral estradiol and micronized progesterone on the cardiovascular system. Clarification of mechanisms is needed to guide practitioners and patients toward appropriate decisions, particularly because many women will still require HRT for the treatment of the symptoms of menopause.

Postmenopausal status is associated with an increased risk for cardiovascular events, in part because of detrimental changes in plasma lipoproteins and endothelial function. Estrogen has genomic, as well as rapid nongenomic, effects that alter vasodilation, coagulation, inflammation, and the vascular injury response, some of which may have potentially beneficial or adverse cardiovascular consequences (17, 18). Estrogen has positive effects on flow-mediated vasodilation and peripheral vascular function, and these changes could contribute to reducing the likelihood of cardiovascular disease and the incidence of cardiovascular events in many postmenopausal women (19, 20, 21, 22, 23, 24). Despite these known effects, the impact of these changes on the stressed cardiovascular system (as during exercise) is unknown.

Peak aerobic power may be defined as peak rate of oxygen delivery during graded exercise to exhaustion and is the standard measure of cardiovascular fitness. The determinants of peak oxygen consumption (VO2peak) include factors that limit oxygen delivery (cardiac output, arterial oxygen content, local blood flow) as well as oxygen use at the muscle level (oxygen extraction and metabolism). It has been repeatedly demonstrated that an increase in O2 delivery can increase VO2peak (25, 26, 27), suggestive of an O2 supply limitation. Our laboratory and others have demonstrated that VO2peak is closely related to peak vascular conductance (G) and peak flow-mediated vasodilation in both health and disease in men (28, 29, 30 30A ); however, there have been no studies published to date examining this relationship in postmenopausal women and more specifically, whether HRT mediates this relationship. Metabolic exercise testing can be a sensitive probe for examining the capacity of the cardiovascular system, and it is unknown whether HRT can enhance oxygen delivery or intake or influence the limiting factors of exercise. Given the relationship between peak flow-mediated vasodilation and VO2peak, one would expect that if oxygen supply is increased (via increased flow to muscle), then increased VO2peak would occur.

Although two studies using conjugated estrogens have found no effect of female sex hormones on exercise tolerance in healthy women (31, 32), neither study explored the specific components of exercise tolerance including central (cardiac output) and peripheral (peripheral blood flow and oxygen extraction) function. In addition, the time course of therapy (i.e. acute vs. chronic exposure) may manifest time-dependent effects on cardiovascular control, and to date this has not been studied. Moreover, it is possible that the effects of the natural female sex steroids (estradiol and progesterone) might be different from those of conjugated and synthetic steroids. Knowledge of these issues would be helpful in interpreting the results of metabolic exercise testing with women receiving HRT and determining the physiological effects of HRT on central and peripheral cardiovascular function. Accordingly, the purpose of this study was to investigate the short- and longer-term effects of 1 mg estradiol and cyclic micronized progesterone (MP; 200 mg) on cardiovascular function at rest and during exercise in healthy, postmenopausal women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study design

A randomized, double-blind, placebo-controlled, cross-over trial was conducted, as illustrated in Fig. 1Go. After screening, subjects were randomized into either initial HRT or placebo groups. Physiological assessments (described below) were made sequentially beginning at baseline (B1), after acute exposure (4 h), and after chronic exposure to HRT (4, 8, and 12 wk). After a 6-wk washout period, subjects crossed treatments and repeated at baseline (B2) and over time as above.



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  		FIG. 1. Study design. After prescreening the subjects were randomized into either HRT or placebo. Before any treatment was taken, the subjects were tested at B1. After taking the first pill of either 1 mg estradiol or placebo, the subjects were tested 4 h later. The subjects continued on assigned treatment and were tested at 1, 2, and 3 months at which time they stopped taking the medication and washed out for 6 wk. The subjects then crossed over to the alternate treatment and continued on the same testing schedule as in the first phase.

 
Subject recruitment

Subjects were postmenopausal women recruited from physician referral and the community through local newspaper advertisements. Postmenopausal status was defined by amenorrhea for at least 1 yr and confirmed by serum estradiol and FSH levels as described below. Entrance into the study occurred after two prescreening visits to confirm eligibility. The Human Research and Ethics Committee at the University of Toronto approved the study protocol, and written informed consent was obtained from all subjects.

Prescreening visit 1

Initially a gynecologist determined overall general health and performed a gynecological exam, transvaginal ultrasound, mammogram, and review of bone mineral density. Inclusion criteria included no suspicion of malignancy; no uterine myomas greater than 4 cm; no endometrial pathology; endometrial thickness (<6 mm); and normal mammograms with low risk of breast cancer based on their family history, no history of cardiac disease, hypertension, or pulmonary disease states. Exclusion criteria included diagnosed diabetes mellitus, use of any cardiac medications, or any orthopedic conditions likely to interfere with exercise testing.

Prescreening visit 2

To confirm a postmenopausal state, venous blood sampling was performed for subsequent determination of serum estradiol and FSH concentration. Those failing to meet these standards (FSH > 40 IU/liter; estradiol < 80 pmol/liter) were excluded from the study. Subjects also underwent a preexercise testing laboratory orientation.

Randomization and initial assessment

After the prescreening procedures, a total of 33 subjects ranging in age from 47 to 66 yr were randomized into initial HRT or placebo groups. Both groups performed baseline testing free of medication. After the baseline assessment, subjects were given their package of pills for the first arm of the study and were instructed to take one pill 4 h before the first assessment (4-h test), which was booked within 1 wk of the baseline test. The placebo and treatment pills were visually identical and contained either 1 mg 17ß-estradiol or placebo. After the 4-h test, the subjects were told to continue taking their assigned medication daily. Subjects who had not had a hysterectomy were required to take additional pills containing either 200 mg MP or placebo for a period of 10 d. Once finished, they would continue with the estradiol or placebo for the rest of the month and present for the second assessment (1 month). This procedure ensured a minimal progesterone effect during testing because this medication phase was positioned at the maximal time period before each assessment (approximately 3 wk). The procedure was repeated during the second phase (cross-over) of the study (see Fig. 1Go).

Subjects who had not had a hysterectomy (n = 27) were told before the medication started that there would be a possibility of menstruation, and it was stressed that any side effects should not be communicated to those conducting the assessments. Subjects had access to the gynecologist throughout the study to discuss this or any other side effects.

Measurements

During each assessment time point (Fig. 1Go), the following procedures were performed: health histories, anthropometric measures, blood work, measures of resting and peak peripheral blood flow, a graded metabolic exercise test to symptom-limited peak, and a stage II exercise test for cardiac output and stroke volume determination.

Anthropometry

Adiposity measures included measurement of body mass index, waist circumference (33) (measured in the standing position at the lateral level of the 12th rib), and hip circumference (measured over the widest girth of the hip). The sum of skinfolds (millimeters, John Bull, British Indicators) were obtained from three sites including the suprailiac, triceps, and subscapular regions with percent body fat estimations made from standard equations (34).

Assays

Blood was taken in the seated position from the antecubital vein at the beginning of each visit. Visits were scheduled at the same time of day for each visit. Serum estradiol, total testosterone, and serum progesterone were measured in duplicate by competitive immunoassay (Vitros Immunodiagnostic Products, Ortho-Clinical Diagnostics, Amersham, UK). SHBG was measured using a chemiluminescent immunometric assay (Immulite 2000, Diagnostics Products Corp., Los Angeles, CA). Serum was stored at –20 C, and all samples were run in the same assays to eliminate contributions from interassay assay variance. The intraassay coefficients of variation were 6.1% for estradiol, 7.9% for progesterone, 4.9% for testosterone, and 7% for SHBG. Assay sensitivities were 10 pmol/liter for estradiol, 0.25 nmol/liter for progesterone, less than 0.03 nmol/liter for testosterone, and 0.02 nmol/liter for SHBG. Free androgen index was calculated using the ratio of total testosterone to the concentration of SHBG (35).

Graded exercise testing

After a 1-min warm-up at zero load, graded exercise testing was performed on an electrically braked cycle ergometer (Ergoline Ergometrics 800S), with work rate increasing 15 W/min. An automated sphygmomanometer was used to record blood pressure each minute (Tango, Sun Tech Medical Instruments). Respiratory gas exchange was measured continuously and averaged over 20-sec intervals by open-circuit spirometry, using an automated metabolic cart (Sensormedics, 2900) calibrated with gas mixtures of known composition. Measures of VO2peak, minute ventilation, ventilatory threshold (VT), peak work rate, and peak heart rate were obtained. The VT was determined using the break point in the ventilatory equivalent for oxygen plotted against oxygen uptake (VO2) without a corresponding change in the ventilatory equivalent for carbon dioxide plotted against VO2 (VECO2 vs. VCO2). Confirmation of VT was provided by additional criteria (VCO2 vs. VO2, minute ventilation vs. VO2), and the VT was determined by taking the value of agreement between at least two of three graphs. If no agreement was observed among any of the graphs, then the value of the break point using the VCO2 vs. VO2 relationship alone (V-slope) was used (36, 37, 38).

Cardiac output

Cardiac output (Q) was determined using the equilibrium CO2 rebreathing technique (39, 40) during exercise at three workloads corresponding to 30, 45, and 60 W or 40, 50, and 60% of peak work rate achieved during the graded exercise testing. Stroke volume (SV; milliliters) was determined from the quotient of Q and heart rate recorded at each measurement. Measures of total peripheral resistance and the mixed arteriovenous oxygen difference (avO2 diff) were also calculated for each work rate (see Table 4Go).


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  		TABLE 4. Submaximal response to exercise: comparison between HRT and N-HRT

 
Skeletal muscle blood flow

Resting and peak flow-mediated vasodilatory capacity (milliliters per 100 ml per minute) were measured by venous occlusion strain-gauge plethysmography (Vasculab SPG16, Medasonics, Mountain View, CA), using a technique described in detail previously by our group (28, 42). Briefly, lower leg blood flow measurements were conducted at constant room temperature (22–24 C), with the subject in a supine position with the calf slightly elevated above heart level, and maintained in that position with a foot rest. The calf was isolated using pneumatic cuffs with one distal cuff placed at the ankle and used to isolate the calf blood flow from the foot by inflating to supraarterial systolic pressure (200 mm Hg). A second proximal collecting cuff was placed above the knee and used to occlude venous return. An indium-gallium strain gauge was selected to fit the calf and was positioned so that it encircled the calf at its widest part with slight tension (about 10 g). The subject was encouraged to relax, and the gauge was then electronically calibrated (43). Baseline resting measures were made by inflating the distal exclusion pneumatic cuff around the ankle to suprasystolic levels and rapidly inflating the proximal collecting venous occlusion cuff to a preset level above venous pressure (55 mg) for a 10-sec period followed by a 10-sec rest and then reinflated to continue the cycle until stable measurements have been made. Resting and ischemic measures of blood flow were performed in triplicate, obtained in succession. Concurrent measurements of heart rate (beats/per minute), mean arterial pressure (MAP), and systolic and diastolic blood pressure were obtained from the middle finger on a beat-to-beat basis (Finapres, Ohmeda, Englewood, CO), with all data transferred to digital format. Data from the slope of the time-leg volume curve was used to determine blood flow (BF) and G was calculated as the quotient of BF and MAP, reported as milliliters per 100ml per minute. All calculations were done using custom software.

To produce a maximal flow-mediated peripheral vasodilation, a 3-min resting occlusion period, followed by ischemic exercise to fatigue was performed (hence, ischemic blood flow). The proximal occlusion cuff was inflated to suprasystolic pressure (200–220 mm Hg) for 3 min to occlude blood flow to the calf. The distal occlusion cuff was kept inflated to 200 mm Hg during this period. Plantar flexion exercise was then performed against a resistance provided by a calf ergometer until plantar flexion failure (inability to produce full excursion) or verbalized pain. Immediately after fatigue, the inflation-deflation cycle and data recording were initiated as described above. Test-retest reliability for blood flow measures was examined in a group of healthy postmenopausal women (n = 8) tested in our lab and statistically assessed using intraclass correlation and found to yield an alpha of 0.91 (F = 22.88) for peak BF and 0.90 (F = 18.35) for resting BF.

Subject compliance

Compliance was confirmed via pill counts at each testing time point and cross-referenced to serum hormone blood values.

Data analysis

The data were entered and analyzed using commercial statistical software (SPSS; Statistical Package for the Social Sciences; version 11, SPSS Inc., Chicago, IL). This cross-over design was analyzed using a two-stage process (44, 45). First, the data were examined for first-order carryover effects. This was done using paired t tests examining for differences between B1 and B2 (see Fig. 1Go) in the group who received treatment in the first phase. Second, period effects were examined using paired t tests examining for differences between B1 and B2 in the group who received placebo first. The Bonferroni correction was applied for multiple comparisons. If there was no first-order carryover or period treatment interaction, the data were pooled (periods one and two) and then analyzed for HRT effects over time using standard procedures for a repeated-measures ANOVA (46). This analysis was performed using the first within-subjects factor-treatment with two levels (treatment and placebo) and the second within-subjects factor-time with five levels (baseline, 4 h, 1 month, 2 months, and 3 months). Data were considered statistically significant at P = 0.05 and are reported as means (±SEM).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Subject characteristics

Of the 33 subjects recruited for the study, two women (6%) at baseline dropped out. One dropped out due to side effects of HRT and one was excluded due to inability to comply to exercise testing, leaving a total of 31 women (mean age = 55 ± 0.7 yr) who completed the study. Four women entered the study having had a hysterectomy and would therefore not be required to take progesterone/placebo. Sixteen women were randomly assigned to the placebo group in period one and treatment in period two (sequence one), whereas 15 women received treatment in period one and placebo in period two (sequence two). There were no significant differences in baseline characteristics such as body mass, height, percent body fat, and lean body mass before placebo and before treatment. Baseline characteristics are shown in Table 1Go. The average time since the last menstrual period in years was 4.37 (±0.78), ranging from 1 to 16 yr. Pill counts confirmed compliance (100%) and were confirmed against hormone levels (see below).


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  		TABLE 1. Subject characteristics over time comparing subjects while on HRT and not on HRT (N-HRT)

 
Carry-over and period effects

There were no carry-over or period effects found in any of the variables of interest for this study such as resting blood flow, peak BF, VO2peak, submaximal stroke volumes, submaximal cardiac output, and serum estradiol and SHBG (all P < 0.05). The results will now present the data analyzed using standard repeated measures design due to no carry-over or period effects found.

Endocrine data

Serum estradiol levels increased significantly over time in the group taking treatment and are displayed in Table 1Go. Estradiol rose from 44.3 pmol/liter (±3.0) at baseline to 224.6 (±24.22) pmol/liter 4 h after the first pill was taken to 417.93 (±53.82) pmol/liter after 3 months of treatment, which is within the range of estradiol in the midfollicular phase of the menstrual cycle. Progesterone levels did not increase in the treatment group, confirming our efforts to minimize its blood concentration during the assessments (positioned at least 3 wk away from the progesterone cycle). Total testosterone did not change in treatment or placebo groups; however, free androgen index decreased significantly in the treatment group (P < 0.001), reflective of the significant changes found in SHBG. SHBG increased significantly in the treatment group (P < 0.001) but did not change in the placebo group (P = 0.3) (Table 1Go).

Peak exercise data

Short- and long-term treatment with estrogen failed to alter peak exercise responses. No differences were found in peak measures of VO2 (relative or absolute), total exercise time, heart rate, MAP, respiratory equivalent ratio, or workload after acute estrogen (4 h) or chronic estrogen (at 1, 2, and 3 months). These data are summarized in Table 2Go.


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  		TABLE 2. Peak exercise response over time comparing subjects while on HRT and not on (N-HRT)

 
Resting and peak lower leg blood flow

Estrogen treatment did not change resting BF, and the treatment/time interaction was insignificant (P = 0.604). Similarly, resting MAP and G was not affected by either acute or chronic (1, 2, or 3 months) estrogen therapy. However, peak BF (Fig. 2Go) was significantly increased by estrogen therapy over time, as was peak vascular conductance, both demonstrating a significant estrogen/time interaction (P = 0.006, P = 0.002, respectively). A complete data set is displayed in Table 3Go. No correlation between change in actual serum estradiol levels and change in peak BF values over the 3-month period (r = 0.263; P = 0.168) was found.



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  		FIG. 2. Peak ischemic blood flow: HRT vs. non-HRT (N-HRT). Comparison of peak ischemic blood flow values in subjects during HRT phase and N-HRT phase over time. *, Significant time·treatment interaction (P = 0.002).

 

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  		TABLE 3. Resting and exercise peak ischemic lower-leg blood flow and vascular conductance over time comparing subjects while on HRT and not on HRT (N-HRT)

 
Submaximal cardiac output and stroke volume

Data for cardiac output, MAP, stroke volume, and total peripheral resistance were obtained at three absolute submaximal work rates (30, 45, and 60 W) and are presented in Fig. 3Go. Oxygen consumption, arteriovenous oxygen difference, and heart rate at these submaximal work rates are presented in Table 4Go. There were no effects of HRT on any of these variables across time. HRT did not influence submaximal cardiovascular response to exercise acutely (4 h) or chronically (1, 2, and 3 months).




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  		FIG. 3. Submaximal response to exercise: comparison between HRT and non-HRT (N-HRT).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study is the first to examine effects of acute and chronic ERT on the central and peripheral cardiovascular response to exercise, with measures obtained serially over a time course (4 h and 1, 2, and 3 months) in healthy postmenopausal women. Whereas acute exposure to oral estrogen failed to increase peak flow-mediated vasodilatation, chronic estrogen therapy (1–3 months) significantly increased peak BF. Despite this persistent effect, the increased peak BF was not accompanied by any increase in exercise tolerance. In addition, we could not detect any estrogen-mediated effect on the submaximal cardiac output and stroke volume response to exercise.

Peak exercise

We were unable to detect any change in peak exercise variables secondary to estrogen use. In fact, previous studies examining HRT on exercise tolerance and peak capacity are equivocal. Redberg et al. (47) found that the use of HRT was associated with higher VO2peak in a cohort of 248 healthy postmenopausal women. The use of HRT was independently predictive of exercise capacity controlling for age, even though self-reported physical activity levels were higher in the non-HRT group. However, this study was not a randomized trial and is subject to healthy user bias that is common in HRT users who usually exercise more, smoke less, have better nutrition, have higher education, consume less alcohol, and have higher socioeconomic status (48, 49). Our data are in agreement with Lee et al. (31), who report no effect of 1 month of 0.625 mg conjugated estrogen on the response to a treadmill test. This was a randomized, single-blind, cross-over trial that measured resting and exercise hemodynamics as well as left ventricular dimensions in 16 women (mean age 56 ± 8 yr). No effect was found on peak heart rate, blood pressure, rate pressure product, or any of the echocardiographic measures (end systolic or diastolic diameters). In a study using a higher of dose of estradiol than the present study (2 mg/d vs. 1 mg/d), Snabes et al. (50) examined the effects of ERT on peak oxygen intake during treadmill exercise in a slightly older group of postmenopausal women (mean age = 59 yr) using a randomized, double-blind, cross-over design and also found no effect of ERT on peak VO2, blood pressure or heart rate response. Our data are similar that reported by Snabes et al., confirming that 1 mg of estradiol per day for 3 months has no effect on exercise capacity in postmenopausal women.

Submaximal cardiac output and stroke volume

In the present study, acute and chronic treatment did not affect submaximal cardiac hemodynamics (VO2, Q, heart rate, SV, avO2 diff, blood pressure, or total peripheral resistance) across a wide exercise intensity range (40–60% maximum oxygen intake). A cross-sectional analysis by McCole et al. (51) of postmenopausal women (age 63 ± 5 yr) failed to observe any ERT effect on cardiovascular hemodynamics (40–100% maximum oxygen output), including measures of VO2, Q, heart rate, SV, avO2 diff, blood pressure, or total peripheral resistance. The absolute values for SVs at 40–60% reported by McCole et al. are higher than ours at similar work rates (78 ml vs. 70 ml, workload 2; 78 ml vs. 77 ml, WL 3). This may be explained by the higher level of physical activity reported by the subjects in McCole’s study and slight variations in the exercise protocol. We observed a rise in SV throughout increasing exercise intensities (30, 45, and 60 W). Previous studies in postmenopausal women report that SV increases with exercise and then either plateaus or declines after workloads corresponding to about 60% VO2peak (51, 52). The highest workload used in this study equalled approximately 62% of peak, and, therefore, we cannot address the issue of a possible decline at high workloads in this population. The present study demonstrates that SV at the lower workloads is not influenced by HRT in sedentary women. Whereas this remains a poorly understood aspect of exercise hemodynamics, the present data confirm that HRT does not modulate the cardiac response to submaximal exercise in postmenopausal women.

Resting and peak lower leg blood flow

The available studies examining the effects of estrogen on peripheral blood flow are inconclusive. Variability in the type, dose, route of administration, and presence of progestogen make interpretation and comparison of studies problematic. In addition, the acute vs. chronic effects of ERT may be mediated by different mechanisms (nongenomic vs. genomic). Moreover, the responses may be different in healthy women, compared with those with established CAD. Overall, there is substantial evidence that chronic estrogen improves endothelial function via the nitric oxide pathway (53).

Acute estrogen effects

In the present study, the acute oral intake of estrogen did not induce any change in resting or peak BF. It is well known that intraarterial infusion of 17ß-estradiol increases endothelium-dependent vasodilation in both healthy postmenopausal women and women with CAD (22, 24, 54, 55, 56, 57). The effects of orally consumed estrogen on BF are less clear. One group found a modest increase in resting BF (3.9 ± 0.5 vs. 2.4 ± 0.4 ml/100 ml·min) after acute sublingual 17ß-estradiol (1 mg) consumption (58). Our study confirms no effect of acute oral doses of estradiol.

Chronic estrogen effects

There are a limited number of studies that have examined the chronic effects of estrogen therapy on BF. A recent large cohort study (n = 1634) of older postmenopausal women found no differences in brachial flow-mediated vasodilator responses between women with CAD regardless of HRT status (21). However, there was a significant association between HRT use and flow-mediated vasodilator response (P = 0.01) in healthy women in a study by Herrington et al. (58A ), suggestive of differing effects between healthy women and those with CAD. Increased BF with HRT has been reported by other investigators examining Doppler-derived microvascular hyperemic BF (59). Similar findings can be found in women with mild hypercholesterolemia without evidence of CAD, who demonstrated increased flow-mediated dilatation of the brachial artery after transdermal estradiol (0.1 mg) administration for 14 wk (60). Similar findings were reported by Gilligan et al. (24), who used transdermal 17ß-estradiol (Estraderm 0.1 mg/d) for 3 wk and observed increased hyperemic blood flows but unchanged resting BF, using strain-gauge plethysmography. Our findings of an increased calf flow-mediated dilatation are in agreement with these findings and those of Lieberman et al. (19), who compared 1- and 2-mg doses of estradiol on flow-mediated vasodilation in a cross-over trial. Interestingly, they found a larger increase in vasodilation with the lower dose (1 mg vs. 2 mg), yet we found no correlation between change in actual serum estradiol levels and change in peak ischemic blood flow values over the 3-month period (r = 0.263; P = 0.168).

There are potentially different effects when comparing different estrogens, different progestogens, and different combinations of the two. First, conjugated estrogens (Premarin) like the ones used in the three recent large-scale randomized clinical trials examining the role of HRT and cardiovascular disease risk and mortality rates in women with CAD (5, 6) and without (7) contains at least 10 estrogens that are the sulfate esters of the ring B saturated estrogens: estrone, 17ß-estradiol, 17{alpha}-estradiol, and the ring B unsaturated estrogens: equilin, 17ß-dihydroequilin, 17{alpha}-dihydroequilin, equilenin, 17ß-dihydroequilenin, 17{alpha}-dihydroequilenin, and {delta}-8-estrone (14). Bioassays and estrogen receptor binding studies indicate that all 10 estrogens are biologically active, and furthermore, individual components, such as equilin sulfate, {delta}-8-estrone sulfate, 17ß-dihydroequilin sulfate, and estrone sulfate, have potent estrogenic effects (14). Advances in technology have revealed the presence of not only estrogens but also androgens and progestins in Premarin (15). The multiple components likely have different biological effects, and they are not fully understood (16). This mixing pot of chemicals may act differently than naturally occurring estradiol. This remains a strength of the present study because our choice of estradiol (and the impact on cardiovascular function) is directly relevant to postmenopausal women and premenopausal women.

Progestogens have repeatedly shown differing effects on the beneficial effects of estrogen in both animal and human studies. In monkeys, coronary vasospasm in response to pathophysiological stimulation without injury showed that progesterone plus estradiol protected but medroxyprogesterone plus estradiol failed to protect, allowing vasospasm (10). These authors conclude that medroxyprogesterone in contrast to progesterone increases the risk of coronary vasospasm. Similarly in humans, medroxyprogesterone has been shown to have detrimental effects on the beneficial effects of estradiol (9) and conjugated estrogens (62), whereas MP has been found to have no detrimental effects (60). These negative effects of medroxyprogesterone may explain the negative results of the Women’s Health Initiative. Our data clearly indicate that 1 mg estradiol and cyclic MP increases peripheral blood flow chronically (after 3 months) in healthy postmenopausal women.

The changes in blood flow are similar to those reported by our group previously after an exercise training intervention in patients with coronary heart disease, which lead to significant changes in peak flow-mediated blood flows (increasing from approximately 29 ml/100 ml·min to 45 ml/100 ml·min (63). They are also comparable with changes observed recently in older women undergoing cardiac rehabilitation (64). In the latter study, postmenopausal women with coronary heart disease demonstrated a significant increase in peak BF regardless of HRT status. In either case, peak BF increased from approximately 35 ml/100 ml·min to 47 ml/100 ml·min. Whereas the exercise training intervention failed to increase Q, it did increase VO2peak. However, HRT failed to modulate the changes in either case, suggesting it played no role in the observed changes for either BF or cardiovascular efficiency. It is worth mentioning that improvements in flow-mediated blood flow has been reported for both oral (reported here) and iv (60) consumption of estrogen, and the failure to improve VO2peak in the present study is supported by the earlier work of Green et al. (65), who failed to observe any differences in VO2peak between users and nonusers. There are no other data currently available on estrogen and VO2peak to compare with, and, as such, interpretation of the clinical application to these findings is limited. It does suggest that results from clinical exercise testing are not likely influenced by estrogen use in postmenopausal women.

Our group (28) and others (29, 30) have demonstrated that vasodilatory capacity is correlated to exercise capacity. However, we did not find any correlation between changes in VO2peak and changes in peak BF values (r = 0.269; P = 0.151) in this study. Unlike training-mediated increases in vascular reserve, the increase in vasodilatory capacity with estrogen treatment may be nonspecific to skeletal muscle and generalized to the entire vascular bed. Consequently, without a corresponding increase in blood volume (which we did not measure), one could not expect an increased muscle perfusion, and exercise performance (or submaximal SV) would not be expected to change. The stable measures of total peripheral resistance despite a constant Q and an increase in vascular reserve offers indirect evidence that a generalized vasodilatory effect may have occurred concomitant with an increase in blood volume, as has been shown by others (66).

Clinical implications

Our data confirm that 3 months chronic oral estradiol with cyclic MP increases peak peripheral BF chronically but does not improve exercise tolerance and peak exercise capacity. Similarly, submaximal central cardiovascular function is unaffected by HRT. This suggests that estradiol and progesterone have a beneficial effect on peak calf BF, but this benefit offers little advantage in peak oxygen uptake after 3 months of HRT. More research is needed to investigate longer-term effects of HRT on exercise capacity and cardiovascular performance.


   Footnotes
 
This work was supported by the Heart and Stroke Foundation of Ontario Grant NA3367.

Abbreviations: avO2 diff, Arteriovenous oxygen difference; BF, blood flow; CAD, coronary artery disease; ERT, estrogen replacement therapy; G, vascular conductance; HRT, hormone replacement therapy; MAP, mean arterial pressure; MP, micronized progesterone; Q, cardiac output; SV, stroke volume; VCO2, ventilatory equivalent for carbon dioxide; VO2, oxygen uptake; VO2peak, peak oxygen consumption; VT, ventilatory threshold.

Received February 25, 2003.

Accepted January 8, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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