- Email: [email protected]
Hormones for coronary disease
CORRESPONDENCE
complete ban illustrates the difficulty of implementing such legislation domestically, especially on a universal level. A framework convention cannot go further than the political will of the negotiators at a given time. This process will continue to unfold and mature after the adoption of the Convention. The text has also been criticised for showing some caution in the area of liability. It is not typical for framework conventions to contain liability provisions due to the highly controversial nature of the subject. In such a context, it should be noted that the inclusion of an article on liability constitutes a major accomplishment in the negotiations, and reflects countries’ commitment to holding tobacco companies accountable for the harm they cause. Both Ambassador Seixas Correa (Chair of the Intergovernmental Negotiating Body) and Gro Harlem Brundtland strongly believe that the current text is a firm basis from which the negotiations can bring in a maximum number of signatory countries and thereby have a major effect on public health in the future. Derek Yach World Health Organization, Geneva, Switzerland (e-mail: [email protected]) 1
Kapp C. WHO chief endorses diluted antitobacco text. Lancet 2003; 361: 315.
Hormones for coronary disease Sir—Although oestrogen therapy alone does not seem to prevent reinfarction, as shown by the ESPRIT (Estrogen in the Prevention of ReInfarction Trial) team (Dec 21/28, p 2001),1 it could be harmless from a cardiovascular standpoint if administered with aspirin. Oestrogen may worsen hypercoaguable states, partly as a result of a decrease in concentrations of folate, with secondary hyperhomocysteinaemia, and modifications of factor VII, fibrinogen, and fibrinolysis. Despite the proven benefits of aspirin prophylaxis,2 in the Women’s Health Initiative3 only 20% of women, whose average age was 65 years, were given aspirin, even though 36% of them had hypertension. Aspirin may have negated the cardiovascular risks of oestrogen (and progesterone), which triggered the initial jump in cardiac events soon after starting hormone replacement therapy (HRT). True, one may contend that the ESPRIT study simply corroborates the conclusion of the Heart and Estrogen/ Progestin Replacement Study4—that postmyocardial infarction mortality is
612
not reduced by HRT—however, 22% of patients taking HRT in the earlier study did not receive aspirin. Since aspirin significantly reduces ischaemic heart disease,5 perhaps providing aspirin with oestrogen should become the norm when prescribing oestrogen. Jeffrey M Bloom 1334 Marsh Street, San Luis Obispo, CA 93401, USA (e-mail: [email protected]) 1
The ESPRIT team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002; 360: 2001–08 2 Hansson L, Zanchetti A, Carruthers SG, et al, for the HOT Study Group. Effects of intensive blood-pressure lowering and lowdose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755–62. 3 Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33. 4 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: 605–13. 5 The Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of lowintensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233–41.
Sir—The negative results of the ESPRIT study1 were to be expected, because oestrogens are thrombogenic and myocardial infarction is caused by coronary artery thrombosis. Commentator Jacques Rossouw2 suggests that “research should focus more on avoiding risk than finding benefit”. What does this mean? Should women who survive the vasoactive and thrombogenic adverse effects of oral contraceptives then be screened when they are menopausal to see if they might survive hormone replacement therapy (HRT)? Exogenous oestrogens are thrombogenic because of how they act, whether administered by oral or transdermal routes. Use of HRT can suppress symptoms of biochemical upsets caused by oral contraceptives. Combinations of oestrogens and progestagens produce obvious vascular side-effects.3 The pattern and nature of side-effects change when the dose of oestrogen is increased with a constant dose of progestagen. Jane Galbraith’s review4 of the Royal College of General Practitioners’ Oral Contraception Study shows that vascular conditions, including myocardial infarctions,
increased with use of oral contraceptives. Other studies of oral contraceptives have found an increased risk of pelvic disorders leading to more hysterectomies. Oestrogens and progestagens may also have teratogenic, carcinogenic, and immunosuppressive effects, and may also impair essential nutrient balance and liver and pancreatic function.3 There is a reluctance to accept that hormones, which are too dangerous to be taken in long-term randomised trials,5 are also too dangerous for general use. It is puzzling why the Women’s Health Initiative oestrogen only randomised trial is continuing. As I have suggested previously,3 menopausal symptoms can be managed with the same non-drug methods that have been used to prevent headaches, migraine, and hypertension in patients attending migraine clinics. By contrast, use of oestrogen may increase the risk of several cancers and other diseases. Surely it is sensible to prevent hormone-induced vascular diseases by no longer using hormones as oral contraceptives or as HRT? Ellen C G Grant 20 Coombe Ridings, Kingston-upon-Thames, Surrey, KT2 7JU, UK (e-mail: [email protected]) 1
2
3
4
5
The ESPRIT team. Oestrogen therapy for prevention of reinfarction in postmenopausal women. Lancet 2002; 360: 2001–08. Rossouw JR. Hormones for coronary disease—full circle. Lancet 2002; 360: 1996–97. Grant ECG. The Pill, hormone replacement therapy, vascular and mood over-reactivity and mineral imbalance. J Nutr Environ Med 1998: 8: 105–16. Galbraith JI. A methodological review of the Royal College of General Practitioners’ Oral Contraception Study. J Nutr Environ Med 1998; 8: 187–94. Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet 2002: 360: 942–44.
Sir—We agree with Jacques Roussouw, in his Commentary1 on the ESPRIT study,2 that there is a need for further research into sex differences in coronary risk. However, he does not discuss alternative hypotheses to the oestrogen-protection hypothesis that dominated thinking in the 1990s. Women have fewer coronary heart disease events such as acute myocardial infarction, especially during young adult years, than do men.3,4 One explanation for this difference might be that men undergo a decrease in HDL cholesterol concentration at puberty, whereas women do not. Since this decrease in protective HDL cholesterol can be due to the increase in androgens at puberty, male androgens might contribute to
THE LANCET • Vol 361 • February 15, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
complete ban illustrates the difficulty of implementing such legislation domestically, especially on a universal level. A framework convention cannot go further than the political will of the negotiators at a given time. This process will continue to unfold and mature after the adoption of the Convention. The text has also been criticised for showing some caution in the area of liability. It is not typical for framework conventions to contain liability provisions due to the highly controversial nature of the subject. In such a context, it should be noted that the inclusion of an article on liability constitutes a major accomplishment in the negotiations, and reflects countries’ commitment to holding tobacco companies accountable for the harm they cause. Both Ambassador Seixas Correa (Chair of the Intergovernmental Negotiating Body) and Gro Harlem Brundtland strongly believe that the current text is a firm basis from which the negotiations can bring in a maximum number of signatory countries and thereby have a major effect on public health in the future. Derek Yach World Health Organization, Geneva, Switzerland (e-mail: [email protected]) 1
Kapp C. WHO chief endorses diluted antitobacco text. Lancet 2003; 361: 315.
Hormones for coronary disease Sir—Although oestrogen therapy alone does not seem to prevent reinfarction, as shown by the ESPRIT (Estrogen in the Prevention of ReInfarction Trial) team (Dec 21/28, p 2001),1 it could be harmless from a cardiovascular standpoint if administered with aspirin. Oestrogen may worsen hypercoaguable states, partly as a result of a decrease in concentrations of folate, with secondary hyperhomocysteinaemia, and modifications of factor VII, fibrinogen, and fibrinolysis. Despite the proven benefits of aspirin prophylaxis,2 in the Women’s Health Initiative3 only 20% of women, whose average age was 65 years, were given aspirin, even though 36% of them had hypertension. Aspirin may have negated the cardiovascular risks of oestrogen (and progesterone), which triggered the initial jump in cardiac events soon after starting hormone replacement therapy (HRT). True, one may contend that the ESPRIT study simply corroborates the conclusion of the Heart and Estrogen/ Progestin Replacement Study4—that postmyocardial infarction mortality is
612
not reduced by HRT—however, 22% of patients taking HRT in the earlier study did not receive aspirin. Since aspirin significantly reduces ischaemic heart disease,5 perhaps providing aspirin with oestrogen should become the norm when prescribing oestrogen. Jeffrey M Bloom 1334 Marsh Street, San Luis Obispo, CA 93401, USA (e-mail: [email protected]) 1
The ESPRIT team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002; 360: 2001–08 2 Hansson L, Zanchetti A, Carruthers SG, et al, for the HOT Study Group. Effects of intensive blood-pressure lowering and lowdose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755–62. 3 Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33. 4 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: 605–13. 5 The Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of lowintensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233–41.
Sir—The negative results of the ESPRIT study1 were to be expected, because oestrogens are thrombogenic and myocardial infarction is caused by coronary artery thrombosis. Commentator Jacques Rossouw2 suggests that “research should focus more on avoiding risk than finding benefit”. What does this mean? Should women who survive the vasoactive and thrombogenic adverse effects of oral contraceptives then be screened when they are menopausal to see if they might survive hormone replacement therapy (HRT)? Exogenous oestrogens are thrombogenic because of how they act, whether administered by oral or transdermal routes. Use of HRT can suppress symptoms of biochemical upsets caused by oral contraceptives. Combinations of oestrogens and progestagens produce obvious vascular side-effects.3 The pattern and nature of side-effects change when the dose of oestrogen is increased with a constant dose of progestagen. Jane Galbraith’s review4 of the Royal College of General Practitioners’ Oral Contraception Study shows that vascular conditions, including myocardial infarctions,
increased with use of oral contraceptives. Other studies of oral contraceptives have found an increased risk of pelvic disorders leading to more hysterectomies. Oestrogens and progestagens may also have teratogenic, carcinogenic, and immunosuppressive effects, and may also impair essential nutrient balance and liver and pancreatic function.3 There is a reluctance to accept that hormones, which are too dangerous to be taken in long-term randomised trials,5 are also too dangerous for general use. It is puzzling why the Women’s Health Initiative oestrogen only randomised trial is continuing. As I have suggested previously,3 menopausal symptoms can be managed with the same non-drug methods that have been used to prevent headaches, migraine, and hypertension in patients attending migraine clinics. By contrast, use of oestrogen may increase the risk of several cancers and other diseases. Surely it is sensible to prevent hormone-induced vascular diseases by no longer using hormones as oral contraceptives or as HRT? Ellen C G Grant 20 Coombe Ridings, Kingston-upon-Thames, Surrey, KT2 7JU, UK (e-mail: [email protected]) 1
2
3
4
5
The ESPRIT team. Oestrogen therapy for prevention of reinfarction in postmenopausal women. Lancet 2002; 360: 2001–08. Rossouw JR. Hormones for coronary disease—full circle. Lancet 2002; 360: 1996–97. Grant ECG. The Pill, hormone replacement therapy, vascular and mood over-reactivity and mineral imbalance. J Nutr Environ Med 1998: 8: 105–16. Galbraith JI. A methodological review of the Royal College of General Practitioners’ Oral Contraception Study. J Nutr Environ Med 1998; 8: 187–94. Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet 2002: 360: 942–44.
Sir—We agree with Jacques Roussouw, in his Commentary1 on the ESPRIT study,2 that there is a need for further research into sex differences in coronary risk. However, he does not discuss alternative hypotheses to the oestrogen-protection hypothesis that dominated thinking in the 1990s. Women have fewer coronary heart disease events such as acute myocardial infarction, especially during young adult years, than do men.3,4 One explanation for this difference might be that men undergo a decrease in HDL cholesterol concentration at puberty, whereas women do not. Since this decrease in protective HDL cholesterol can be due to the increase in androgens at puberty, male androgens might contribute to
THE LANCET • Vol 361 • February 15, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.