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ORIGINAL RESEARCH |
From the Departments of Psychology, Medicine, Obstetrics and Gynecology, and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Address reprint requests to: Patricia Straneva, Department of Psychiatry, University of North Carolina at Chapel Hill, CB #7175, Chapel Hill, NC 27514-7175 E-mail: stranepa{at}med.unc.edu
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Abstract |
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Methods: Twenty-three smokers and 23 nonsmokers taking different OC formulations (ie, containing higher or lower androgenic progesterones) were tested for cardiovascular reactivity during mathematic, speech preparation, speech, and cold pressor stress.
Results: During mental stress, smokers, regardless of OC formulation, had lower systolic blood pressure (BP) (eg, 10.2 versus 15.1 mmHg, P < .05), heart rate (eg, 7.5 versus 15.0 beats per minute, P < .01), and cardiac index reactivity (eg, 0.08 versus 0.48 L/minute/M2, P < .01) but greater vascular resistance index responses (eg, 115.6 versus -51.9 dyne-sec • cm-5 • M2, P < .05). Women who took higher androgen OCs, regardless of smoking status, showed greater vascular resistance index increases during speech stress than those who took lower androgen OCs (215.8 versus 9.4 dyne-sec • cm-5 • M2, P < .05). Smokers who took more androgenic OCs had greater systolic BP responses to speech preparation compared with nonsmokers who took the same OCs (12.1 versus 6.1 mmHg, P < .05), and smokers who took lower androgen OCs (12.1 versus 4.4 mmHg, P < .05). Least-squares means examination found that smokers who took higher androgen OCs had greater vascular resistance index increases to all mental stressors than nonsmokers who took lower androgen OCs.
Conclusion: Higher androgen OCs might be linked to greater vascular and BP increases during stress, especially in smokers. Given that increased vascular resistance and BP contribute to cardiovascular mortality, those results suggest that androgenic profiles of synthetic progesterones might be an important consideration in OC choice.
Combining smoking and oral contraceptives (OCs) has long been associated with increased cardiovascular mortality. However, most evidence is based on OC formulations no longer in use. In addition to the late 1970s introduction of low-dose estrogen OCs (second-generation OCs), the recent development of 19-nortestosterone derivative progesterones has made possible a family of third-generation, low-dose OC formulations. The newer progesterones have lower androgenic profiles, which might be associated with attenuated increases in cardiovascular risk.1 Androgens have been implicated in the pathogenesis of cardiovascular disease, in part by increasing coronary artery and skeletal muscle vasoconstriction.2 Increased vascular resistance might be a relevant risk factor for cardiovascular disease because it is a primary determinant of left ventricular mass, which is an independent predictor of cardiovascular mortality.3 Although a handful of studies suggested that higher androgen OCs might be associated with increased blood pressure (BP),4,5 none has examined BP effects of OC type specifically in smokers, or examined mechanisms (eg, increased vascular resistance) underlying the BP effects.
Thus, this study investigated the interaction of smoking status and OC formulations (second- versus third-generation) on cardiovascular reactivity to a variety of standardized stressors. Individual differences in cardiovascular reactivity to stress have been implicated in the pathogenesis of hypertension.6 We hypothesized, based on the evidence for the vasoconstrictive actions of androgens,2 combined with nicotine’s sympathomimetic activity, that smokers who took second-generation OCs would show the greatest vascular resistance and blood pressure increases during stress.
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Materials and Methods |
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Groups did not differ in age, height, family history of hypertension, weekly energy expenditure, or duration of OC use (Table 1
). For smokers, there was no difference in number of cigarettes smoked per day or number of years smoking. Third-generation smokers were heavier than all other groups. Smokers consumed a minimum of ten cigarettes per day for at least 2 years. Nonsmokers had never smoked or had successfully quit for a minimum of 5 years. Regular use of OCs for a minimum of 1 year before testing was required, with OC package inserts used to confirm OC formulation. Testing was during the third week of active pills, when progesterone content was at maximum levels.
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Impedance cardiography was used to permit noninvasive monitoring of stroke volume and heart rate. The Minnesota Impedance Cardiograph (Model 304B, Surcom, Minneapolis, MN) was used in conjunction with tetrapolar band electrode configuration to record impedance, dZ/dt, and Zo signals. Impedance and electrocardiogram signals were processed online and subsequently manually edited for accuracy by the interactive Cardiac Output Program software (Bio-Impedance Technology Inc., Chapel Hill, NC), developed and validated in our laboratory.9 For each minute of interest, a 30-second continuous sample of waveforms (taken concurrently with BP) was processed to generate an ensemble-averaged cardiac cycle. From each cardiac cycle, stroke volume was determined with the Kubicek et al10 equation, heart rate was determined by the mean interbeat interval, and pre-ejection period was measured as the time interval between the onset of the QRS complex and the upstroke of the impedance cardiograph. Cardiac output and total peripheral resistance were calculated using standard formulas.9
Participants refrained from over-the-counter medications for 24 hours before testing, refrained from caffeine the day of testing, and consumed a light meal before visiting the laboratory. Smokers were asked to refrain from smoking for 1 hour before testing. All testing was on a work or school day and equal numbers of subjects per group were tested in the morning and afternoon.
A 10-minute seated baseline period preceded stressors, with cardiovascular measures taken at minutes 1, 3, 6, 8, and 10. Stressors were presented in order, a 5-minute recovery period after each, with bonus money contingent upon performance during mental stressors. First, a tape-recorded mathematics task required participants to add each number presented (from 1 to 9) to the immediately preceding number, stating the answer aloud. Task duration was 9.5 minutes, with progressively shorter interdigit intervals. Cardiovascular measures were taken at minutes 1:36, 4:00, 6:15 and 7:45.
Next, participants were presented with a hypothetical situation involving an interpersonal disagreement. Each had 2 minutes for speech preparation and 3 minutes for speech delivery, during which they spoke into a tape recorder and described what their actions and emotional responses would be in the situation. Cardiovascular measures were taken at minute 2 of speech preparation and at minutes 1 and 3 of speech delivery. Finally, subjects remained quiet and motionless during the forehead cold pressor while the experimenter held a plastic bag filled with ice and water on their foreheads for 2 minutes. Cardiovascular measures were taken at minutes 1 and 2.
A post-task questionnaire was administered immediately after each stressor to assess anger, tension, confusion, fatigue, perceptions of inadequacy, feelings of helplessness, ability to concentrate, satisfaction with performance, task fairness, and amount of effort exerted during the tasks.
Serum lipid and lipoproteins were analyzed in duplicate at the University of North Carolina Hospital Laboratories. Triglycerides and total cholesterol were determined enzymatically, high density lipoprotein (HDL) was determined by the dextran sulfate precipitation method, and low density lipoprotein (LDL) was arithmetically derived using the Friedewald equation.11 The intra-assay coefficient of variation for each of the lipids assayed was total cholesterol 3.0%, HDL 4.9%, and triglycerides 5.0%.
To examine whether smoking or OC type was associated with differences in mood or personality that might influence cardiovascular reactivity, we administered the Beck Depression Inventory,12 Spielberger Trait Anxiety Inventory,8 Feelings About Yourself (measuring self-esteem and perceived control over the world),13,14 Anger Expression Scale,15 Interpersonal Support Evaluation List,16 Perceived Stress Scale,17 and Cooke-Medley Hostility Scale.18 Those questionnaires were administered because hostility, depression, and social support might influence BP reactivity.
For each cardiovascular measure, data were analyzed as mean reactivity scores (average task level minus average baseline level). There were group differences in body mass index, so stroke volume, cardiac output, and total peripheral resistance were indexed for body surface area, yielding stroke volume index, cardiac index, and vascular resistance index. All analyses were conducted using SAS (SAS Institute, Cary, NC) procedures. The first analysis involved examining group differences in baseline cardiovascular, psychosocial, and lipid measures using a 2 (smoking status) x 2 (OC formulation) analysis of variance. Stressors elicited different hemo-dynamic profiles (ie, myocardial versus vascular resistance increases19), so responses were analyzed separately by task using a 2 (smoking status) x 2 (OC formulation) analysis of variance. For significant interactions, examination of least-squares means comparisons was used to investigate the source of the effect. Least-squares means are generated by SAS general linear model procedures and are the predicted means, assuming a balanced design and setting all covariates to their mean levels.
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Results |
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). Smokers, regardless of OC group, had significantly lower heart rate reactivity during mathematics and speech [main effect of smoking Fs (1,42) = 7.5 & 13.3] and lower cardiac index reactivity during mathematics and speech preparation [main effect of smoking Fs (1,42) = 13.76 and 6.57, respectively] (Table 2). Smokers also had lesser decreases in pre-ejection period, indicating less myocardial contractility, during the mathematics task [main effect of smoking Fs (1,42) = 17.12]. Smokers showed significantly greater vascular tone during mental stressors evidenced by greater increases in vascular resistance index during the mathematics and speech preparation compared with nonsmokers [main effect of smoking status Fs (1,42) = 5.62 and 5.06, respectively].
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Women who took third-generation OCs, regardless of smoking status, had significantly smaller increases in vascular resistance index during the speech stressor (9.4 versus 215.8 dyne-sec • cm-5 • M2, P < .05) and, although nonsignificant, similar patterns were observed during mathematics and speech preparation (59.3 versus 124.7; 8.6 versus 55.0, dyne-sec • cm-5 • M2 respectively).
There was a significant interaction between smoking and OC formulation, effecting systolic BP in speech preparation [F(1,42) = 12.45, P < .01]. Least-squares means comparisons showed that smokers using second-generation OCs had greater systolic BP responses during speech preparation than nonsmokers using second-generation OCs (12.1 versus 6.1 mmHg, P < .05) and smokers using third-generation OCs (12.1 versus 4.4 mmHg, P < .05).
Analyses of vascular resistance index did not show significant interactions, based upon our a priori hypotheses of greater vascular resistance in smokers who took second-generation OCs. However, to explore the hemo-dynamic basis of the significant smoking x OC interactions for BP, we examined least-squares means comparisons of vascular resistance index reactivity. Smokers taking second-generation OCs had significantly greater increases in vascular resistance index compared with nonsmokers taking third-generation OCs during all mental stressors (Figure 1). The largest difference in vascular tone during mental stress was consistently between smokers who took second-generation OCs and had large vasoconstrictive responses, and nonsmokers who took third-generation OCs and tended to show vasodilatory responses, whereas the other two groups showed intermediate vascular responses.
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Although there were no differences in performance during mathematics, smokers, regardless of OC formulation used, were more angry [F (1, 40) = 6.53, P < .05] that they had exerted greater effort [F (1, 41) = 5.80, P < .05], and were less satisfied with their performances [F (1,44) = 5.68, P < .05] compared with nonsmokers. During speech, smokers reported more tension [F (1, 42) = 6.38, P < .05], frustration [F (1, 40) = 11.81, P < .01], confusion [F (1,41) = 5.77, P < .05], fatigue [F (1,44) = 4.67, P < .05], inadequacy [F (1,43) = 20.86, P < .01], less satisfaction with performance [F (1, 43) = 12.33, P < .05], less calm [F (1,43) = 8.27, P < .01], found the task more difficult [F (1, 40) = 6.54, P < .05], and felt the cold pressor task was more unfair [F (1,44) = 11.76, P < .01] than nonsmokers. There were no significant task-related mood effects involving OC type.
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Discussion |
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That pattern of reactivity during mental stress in smokers was consistent with another recent report,7 but extends that study by including OC users. One possibility for the response pattern in smokers relates to the evidence that long-term smoking elevates catecholamines, which might lead to down-regulation of peripheral ß-adrenergic receptors in smokers.21 The lower myocardial but increased vascular resistance reactivity to stress in the present cohort of smokers was consistent with ß-adrenoceptor down-regulation.
Another possibility for the cardiovascular reactivity pattern in smokers relates to the antiestrogenic effects of smoking. For example, premenopausal women smokers have reduced levels of urinary estrogens,22 and reduced formation of active estrogenic metabolites,23 and post-menopausal smokers given oral estrogen have lower circulating levels of estradiol (E2) than nonsmokers.24 This antiestrogenic mechanism of smoking might be especially relevant to the response patterns of smokers in the present study because Doppler-derived measures of arterial blood flow, before and after estrogen replacement therapy, showed that estrogen increased stroke volume and decreased resistance to blood flow.25 If smoking has antiestrogenic actions, and estrogen is an inotropic and vasodilatory agent, then this may explain the lower cardiac index but elevated vascular resistance index in smokers who take OCs compared with non-smokers who take OCs. Future studies examining relationships between E2 levels, ß-adrenoceptor responsivity and stress reactivity are warranted.
We also observed effects involving OC formulation, regardless of smoking status. All women who took third-generation OCs showed a pattern of lesser vaso-constriction to mental stress than those who took second-generation OCs, a pattern that was significant during speech stress. Increased vascular resistance during stress was documented in several groups at risk for hypertension and has been shown to predict left ventricular mass.26 Reduced vascular resistance reactivity might be an important cardiovascular benefit of lower androgen OCs. Those results are consistent with reports suggesting that, in contrast to second-generation OCs, newer OC formulations are not associated with increases in BP.27 To the best of our knowledge, we are the first to specifically examine potential cardiovascular benefits of lower androgen OCs in smokers and non-smokers, and our results suggested beneficial reductions in vascular tone for both groups; however, third-generation OCs might not be indicated for all women. For example, an increased risk for thromboembolic complications of third-generation OCs was reported,28 whereas a more recent study suggested that newer OCs might be linked to increased risk for thromboembolic complications in only a subgroup of women, those with genetic markers for venous thrombosis.29 Ultimately, the choice of OC formulation must take into account genetic and family histories, and current lifestyle practices.
Consistent with our a priori hypotheses regarding greater vascular tone and BP reactivity in smokers who took second-generation OCs, these smokers showed significantly greater increases in vascular resistance reactivity compared with nonsmokers who took third-generation OCs, whereas the other groups displayed intermediate vascular reactivity. Smokers who took second-generation OCs also had significantly greater increases in systolic BP during speech preparation than nonsmokers who took the same OC formulation and smokers who took third-generation OCs. Although speculative, the greater vascular tone during all mental stressors and greater BP reactivity during speech preparation in smokers who took second-generation OCs might show androgenic OCs have a greater effect on smokers because of their vasoconstrictive properties,2 and because smokers have reduced ability to vasodilate due to down-regulation of peripheral, vasodilatory ß-adrenoceptors.21 That interpretation must be tempered by the small samples in our study and the fact that the BP effects were in only one of three mental stressors, raising the possibility that BP effects were due to chance alone.
Our study, although consistent with other reports suggesting that third-generation OCs impart lesser cardiovascular risk, has its limitations. One limitation was the possibility of selection bias because participants were not randomly assigned to OC groups. There were no differences related to OC formulation in personality or demographic measures, nor were there any differences noted regarding reasons for using OCs (eg, cycle regulation, birth control). Another limitation was that the results of this study might only apply to whites because minorities were underrepresented. Results were based on a relatively small sample, especially for exploring interactions of smoking status and OC formulation, and should be considered preliminary.
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Footnotes |
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Received December 22, 1998. Received in revised form July 6, 1999. Accepted July 22, 1999.
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References |
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