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Original Studies |
Baker Medical Research Institute, Prahran, Victoria 3181, Australia
Address all correspondence and requests for reprints to: A/Prof. P. A. Komesaroff, Baker Medical Research Institute, P.O. Box 6492, Melbourne, Victoria 8008, Australia. E-mail: paul.komesaroff{at}baker.edu.au
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Abstract |
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Introduction |
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In recent studies in perimenopausal women we have shown that estrogen administration attenuates total body norepinephrine (NE) spillover and vascular responses to intraarterial NE and increases basal endothelial nitric oxide release (2, 3). Young women have been shown to have reduced hormonal responses to psychological stress compared with young men (4, 5, 6), although their cardiovascular responses to stress have been reported to be greater (7, 8). Some evidence exists from previous studies that estrogen blunts stress responses in postmenopausal women (9).
Psychological stress results in increases in adrenocortical hormones and catecholamines, both of which potentially influence cardiovascular reactivity. Further, mental stress may be related to risk factors for coronary artery disease (10, 11) or directly to cardiovascular events (12). Accordingly, one of the factors contributing to the apparent beneficial actions of estrogens on the cardiovascular system may include modulation of the stress response.
In this placebo-controlled study, we examined the effects of 8 weeks of estrogen supplementation on the hemodynamic and hormonal responses to 10 min of psychological stress in healthy perimenopausal women, chosen because of the clinical impression that stress responses are increased in this group. Plasma levels of cortisol (F), ACTH, epinephrine (EPI), and NE and total body and forearm NE spillover were measured at baseline, during stress, and at the end of stress.
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Subjects and Methods |
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Subjects were randomized to receive 8 weeks of either estrogen supplementation as estradiol valerate (Progynova, Schering, Alexandria, Australia; 2 mg daily; n = 7) or placebo (n = 5); sample sizes were chosen on the basis of previous studies (2, 3, 13) to achieve a power of 80% to detect a difference of 20% in the response variables with a type 1 error of 0.05. Hemodynamic studies and assessment of forearm vascular reactivity were performed on two separate occasions, 8 weeks apart. Subjects were unaware of the treatment they were receiving, and all measurements of hormone levels and NE kinetics were made by investigators who were blinded to the treatment regimen. On each study day, subjects underwent the following procedures.
Arterial cannulation
Subjects rested in the supine position throughout each study in a quiet temperature-controlled room maintained at 22 C. The brachial artery of the left arm was then cannulated with a 21-gauge, 5-cm catheter (Cook, Brisbane, Australia) under strict aseptic conditions after local anesthesia (1% lignocaine, Astra, Sydney, Australia) for intraarterial measurement of blood pressure (Spacelabs, Inc., Washington DC), and arterial blood sampling. Heart rate was continuously monitored by electrocardiography. After brachial cannulation, subjects rested for 30 min before commencement of the study.
Psychological stress test
The stress was administered as a standard mental arithmetic test as previously described (13). In brief, subjects were asked to perform a series of subtractions and additions, accompanied by a repetitive annoying background noise to induce difficulty in concentration.
Blood sampling
Simultaneous venous and arterial blood samples were taken at baseline and at 5 and 10 min after commencement of stress. An additional blood sample was taken at 25 min.
Measurements of F, ACTH, and estrogen levels
Assays for F and ACTH were carried out on the baseline, 5 min, and 10 min samples and for ACTH on the 25 min sample on both days. Baseline samples were also assayed for estradiol. ACTH was adsorbed from plasma onto porous Vycor glass and measured by specific RIA as previously described (14). The material was a gift of Dr. Rolf Gaillard, Association of Trade with America, Geneva, Switzerland. The interassay coefficient of variation was 7% (n = 4), and the sensitivity was 15 pg/mL. F was measured in unextracted plasma by specific RIA. The intraassay coefficient of variation was 8% (n = 32), and sensitivity was 10 nmol/L. Estradiol was also measured by RIA. The intraassay coefficient of variation was 9% (n = 32), and the sensitivity was 30 pmol/L.
Assay of endogenous and radiolabeled catecholamines
Blood samples were transferred immediately to ice-chilled tubes containing ethyleneglycol-bis-(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid and reduced glutathione and were centrifuged at 4 C. The plasma was stored at -70 C before assay (always within 2 months). Plasma concentrations of endogenous NE were determined by high performance liquid chromatography with electrochemical detection, as previously described (2). The intraassay coefficient of variation was 8%, the interassay coefficient of variation was 9% (n = 10), and the sensitivity of the assay was 12 pg/mL. Plasma [3H]NE was assayed by liquid scintillation counting.
Assessment of total body NE clearance and spillover
Total body NE clearance and spillover to plasma were measured by a radiotracer method, as previously described (2). This method involves the continuous iv infusion of a tracer dose of tritiated NE (Levo-7 [3H]NE, New England Nuclear, Boston, MA; 0.7 µCi/min; SA, 12–20 Ci/mmol) to a steady state concentration in plasma. The total NE spillover to plasma, and the total plasma NE clearance rate can then be calculated as follows: total body NE clearance = [3H]NE infusion rate (dpm/min)/plasma [3H]NE concentration, and total body NE spillover = [3H]NE infusion rate/plasma NE specific activity (dpm/pg), where dpm is the disintegrations per min of [3H]NE.
Assessment of forearm NE spillover
Forearm spillover rates were calculated according to the Fick principle, with adjustment for NE uptake across the forearm, using the fractional extraction of [3H]NE, as previously described (13): fractional extraction of [3H]NE across the forearm = [(arterial [3H]NE) - (venous [3H]NE)]/(arterial [3H]NE), and forearm NE spillover = [(NEv - NEa) + (Nea x NEex)] x FPF, where NEa and NEv are the NE concentrations in the arterial and venous effluent plasma, NEex is the fractional extraction of [3H]NE in a single passage through the forearm, and FPF is the forearm plasma flow (milliliters per min).
Calculations and statistical analysis
Results are expressed as the mean ± SEM. Stress response curves were compared by two-way repeated measures ANOVA; where data were not normally distributed, analysis was undertaken using Friedman’s repeat measures ANOVA on ranks with post-hoc analysis conducted using Dunnett’s method. Other data were compared by Student’s t test after application of a modified Levene procedure to assess homogeneity of variance. Where the sample variance ratio was greater than 4, a log transformation was performed before the application of this test. Where multiple comparisons were made, an appropriate Bonferroni correction factor was applied. Statistical testing was carried out using the SigmaStat software program. The null hypothesis was rejected at P < 0.05.
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Results |
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The mean age of the subjects receiving estrogen was 48 ± 2 yr, and that of those receiving placebo was 50 ± 2 yr. Mean weights were 49.8 ± 2.2 and 63.6 ± 2.2 kg, respectively. Although all women were actively experiencing menopausal symptoms and all showed FSH levels clearly in the menopausal range, estradiol levels varied between 25–140 pmol/L, indicating some variability in hormonal status at baseline.
Effect of estrogen supplementation on basal estradiol, FSH, F,
ACTH, EPI, and NE levels and blood pressure (Table 1
)
No significant change was detected in basal ACTH, F, EPI, or NE levels with either E or placebo. Estradiol levels increased in subjects receiving estrogen (P < 0.008), but there was no change in subjects receiving placebo.
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Estrogen significantly attenuated the increases in both systolic
and diastolic pressures induced by mental stress (P <
0.001; see Fig. 1). However, there was no
effect on the increases in heart rate or forearm blood flow (data not
shown).
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Mean responses to mental stress before and after E and before and
after placebo are shown for ACTH and F in Fig. 2. After estrogen supplementation, the F
responses were markedly attenuated, as measured by two-way ANOVA with
repeated measures (P = 0.02); areas under the curves
and changes from baseline were also reduced according to t
test (P < 0.05). ACTH responses were reduced according
to Friedman repeated measures ANOVA on ranks (P <
0.05) and as measured by areas under the curves (P =
0.04). There was no change in either the ACTH or F response after
placebo.
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Mean arterial EPI and NE responses to mental stress before and
after E and before and after placebo are shown in Fig. 3. NE responses were attenuated according
to two-way repeated measures ANOVA (P = 0.03), and EPI
responses were reduced according to repeated measures ANOVA on ranks
(P < 0.05). No significant differences were detected
after treatment with placebo.
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Mean responses of total body and forearm NE spillover to mental
stress before and after E and before and after placebo are shown in
Fig. 4. As previously reported (2), basal
total body NE spillover was reduced after E treatment, and the levels
remained reduced throughout the stress. Total NE spillover was reduced
after E treatment according to two-way repeated measures ANOVA
(P = 0.04); however, there was no effect on forearm NE
spillover, and no significant differences were detected after
placebo.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We have previously shown that in perimenopausal women, estrogen supplementation enhances basal nitric oxide release (3) and attenuates both total body NE spillover and NE-induced vasoconstriction (2). As in the present study, these changes were associated with a reduction in resting blood pressure. The attenuation of stress-induced increases in both systolic and diastolic blood pressure in this study further highlights the hemodynamic effects of estrogen supplementation.
Our results are consistent with those of previous studies, which have suggested that cardiovascular, glucocorticoid, and catecholamine responses to stress vary between males and females. The cardiovascular responses of young women to psychological stress appear to be greater than those of young men (5) and to be enhanced after E administration (15). Women have been shown to have a reduced EPI response to mental stress compared with men (7), and female college students have smaller F, EPI, and NE responses to examination stress and other behavioral stressors than do male students (4, 5, 6), although in these studies urinary catecholamine excretion, but not plasma levels or spillover, were measured, making the results difficult to interpret. Attention has been drawn to the possible role of sex steroids in modulating social, psychological, and metabolic variables (4, 5, 7, 9). Cardiovascular responses to stress are increased after menopause (16), and studies conducted on women during the menstrual cycle have shown variations in the stress response (17). For example, in one study in normal women the luteal phase was associated with greater stroke volume responses and lower vascular tone than those during the follicular phase (8); in another, women in the luteal phase reacted significantly more to a cold pressor test, but not to mental arithmetic (18); and in another, the responses of systolic blood pressure and pulse rate to normal environmental stressors in cycling young women were greater in the luteal phase (19). Further, in an experimental study in intact ewes we have shown that both glucocorticoid and catecholamine responses to stress vary during the estrous cycle (20).
In studies in young women it is difficult to distinguish between the effects of estrogens and those of progesterone. One previous study (9) addressed the question of the effect of estrogen administration on hormonal responses to stress in menopausal women. After 6 weeks of transdermal estrogen treatment, the maximum percent changes in ACTH, F, NE, and androstenedione failed to reach significance, suggesting a blunting of these responses. In this study EPI responses were not reported, and catecholamine spillover studies to assess the relative balance between NE release and clearance were not conducted. Another study, in young men, showed that E administration blunts the EPI and NE responses to mental stress (21). In a further experimental study in sheep we have shown that estrogen administration after ovariectomy attenuates the F and ACTH responses to audiovisual and hypoglycemic stress (20). These results support those of the present study, which suggest that estrogens may play a role in limiting the responses to psychological stress.
Both adrenocortical hormones and catecholamines can influence vascular reactivity, which is of importance in determining cardiovascular risk. Further, mental stress during daily life has been shown to more than double the acute risk of myocardial ischemia (10); adolescents who have a greater cardiovascular response to mental stress compared to a control population have a greater risk of subsequently developing essential hypertension (11); and in patients with coronary artery disease, mental stress-induced myocardial ischemia is associated with significant increases in risks of fatal and nonfatal cardiac events (12). Accordingly, the effects we have demonstrated may contribute to the apparent protective effects of E with respect to cardiovascular risk. As the acute symptoms of menopause commonly include increased anxiety and irritability, it is also possible that a reduction in the stress response accounts for part of the beneficial effect of E on menopausal symptoms. It should be noted, however, that in the current study E was given for an 8-week period only. It is uncertain whether the effects we have observed would persist over a longer period of estrogen use and whether they would be modified by other clinical approaches to hormonal therapy, such as the concomitant use of a progestin.
Although the mechanisms of the effects of E on glucocorticoid levels are not yet fully defined, it appears probable that it acts via ACTH, and thus the pituitary or hypothalamus, rather than directly on the adrenal gland. This is consistent with evidence obtained from women with hypothalamic amenorrhea, in whom a blunted response to CRH administration and increased F levels were observed (22). These effects could in part be explained by a direct action of estrogen on CRH gene expression; it is also likely that they are modulated at least in part by changes in glucocorticoid receptor (GR) number and/or function. In rats, it has been shown that estradiol abolishes the autologous down-regulation of GR seen in the hippocampus and hypothalamus (23). Further, there is evidence of gender-specific differences in the gene expression of hippocampal and hypothalamic GR and of an effect of exogenous E on GR messenger ribonucleic acid levels (24).
The mechanisms by which estrogens affect catecholamine levels are also
uncertain. The bulk of circulating EPI appears to originate from the
adrenal medulla, and that of NE from sympathetic neurons, although
under conditions of stress, adrenal secretion of the latter increases,
predominantly under neuronal control (25). Accordingly, both direct
effects of E on the adrenal gland and effects on the central or
peripheral nervous system are possible. Neurological pathways seem more
likely (26, 27), although several different actions may be involved; it
is established that estrogens increase the affinity of
1-adrenergic receptors (28), and they may also affect
ß-receptor number and affinity (29); there is evidence that E
modulates catecholamine synthesis in neural tissue (30), and increased
urinary catecholamine secretion after E administration suggests that an
effect on clearance is also possible (31). Whatever the mechanisms of
action of estrogens on both glucocorticoid and catecholamine pathways,
a complex relationship among hormonal effects, amelioration of
symptoms, and stress responses is likely.
In conclusion, this study has shown that E supplementation in perimenopausal women in standard doses attenuates the pressor, glucocorticoid, and catecholamine responses to stress. These effects could explain part of the apparent beneficial actions of E both on acute symptoms of menopause and on long term cardiovascular risk.
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Acknowledgments |
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Footnotes |
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Received October 28, 1998.
Revised September 23, 1998.
Accepted November 2, 1998.
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