LETTERS TO THE EDITOR
Reply
Helena Teede, MBBSa and
Barry McGrath, MDa
a Department of Medicine, Monash Medical Centre, 246 Clayton Road, Melbourne, Australia 3168
The hypothesis generated by Hellstrom in his letter proposes that estrogen negates the vasoconstrictive and prothrombotic changes induced by cardiovascular risk factors (CVRFs), including smoking. The concept that CVRFs act by altering the vasoconstrictive/vasodilative balance toward vasoconstriction, with increased spasm of resistance vessels, and that estrogen may reverse this balance, is plausible. However, we suggest that estrogen shifts the balance between fibrinolytic and coagulation systems toward a prothrombotic state.
Smoking impairs endothelial function, alters lipid oxidation and increases intima medial thickness (IMT) and atherosclerosis. Alternatively, estrogen reduces the impact of CVRFs, including smoking, by improvement in lipid profiles, lipoprotein oxidation, endothelial function, and reduction in coronary intimal plaque and proliferation of vascular smooth muscle. We have previously demonstrated that estrogen also negates age-related deterioration in arterial structure (IMT) and function (1), an effect more marked in high risk smokers (2). For Hellstrom’s hypothesis to hold true, the benefits of estrogen directly on the vessel wall would be mediated through a reduction in spasm of the resistance vessels, which is possible. Yet this does not address the obstructive effects of atherosclerotic plaque, nor the important influence of large artery biomechanical properties (compliance).
The suggestion that the cardiovascular effects of estrogen therapy are mediated through antithrombotic effects is more difficult to justify, however. To date, the only controlled interventional trial based on cardiovascular outcomes is the large, well-designed, secondary prevention Heart and Estrogen-progestin Replacement Study (HERS) (3). Despite a wealth of previous data suggesting individual mechanisms of cardioprotection with HRT, no net clinical benefit was observed. Rather, an early increase in both arterial vascular and venous thrombotic events was associated with HRT, potentially mediated by the prothrombotic effect of combined HRT. In keeping with this, in a recent controlled trial of combined oral HRT, we demonstrated coagulation activation with generation of both thrombin and fibrin (4). Although concomitant secondary activation of fibrinolysis was observed, a shift toward a prothrombotic state was suggested. The majority of studies on coagulation have also noted adverse procoagulant effects of HRT. We cannot agree that estrogen reduces the effects of smoking by antithrombotic mechanisms, and we suggest instead that the prothrombotic effects of estrogen may serve to neutralize the beneficial vessel wall effects.
The results of HERS perhaps also serve to emphasise another vital point. Although estrogen improves individual circulation characteristics, including arterial compliance and IMT, when studied in isolation, its effects are diverse and complex, and we believe it is inappropriate to extrapolate from the study of isolated mechanisms of estrogen action to the clinical implications of HRT use. We would agree with the cautionary note expressed in the accompanying editorial by O’Grady that observational data should not be overinterpreted or used alone to dictate clinical management which should be based on definitive clinical trials. After the HERS results, it is unlikely that other controlled trials in high risk women will be initiated. However, a better understanding of the mechanisms of estrogen action may assist in identifying alternative interventions, including new selective estrogen modulating agents, with beneficial actions on the vessel wall, without prothrombotic effects.
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References
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1. Teede HJ, Liang YL, Shiel LM, et al. Hormone replacement therapy in postmenopausal women protects against smoking-induced changes in vascular structure and function. J Am Coll Cardiol. 1999;34:131–137[Abstract/Free Full Text]
2. McGrath BPLiang Yu-Lu Teede HJ, et al. Age-related deterioration in arterial structure and function in postmenopausal women: the impact of hormone replacement therapy. Atheroscler Thromb Vasc Biol. 1998;18:1149–1156[Abstract/Free Full Text]
3. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605–613[Abstract/Free Full Text]
4. Peverill R, Teede H, McGrath BP, et al. Hormone replacement therapy increases coagulation activity, fibrinolytic potential and fibrinolysis (abstr). Arteriosch Thromb Vasc Biol. In press.
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