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Rapid Responses: Rapid Responses published:
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WISDOM, starting age of HRT and vascular risks
- Ellen C G Grant (13 July 2007)
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HRT user - early menopause
- Nina Kathleen Edge (14 July 2007)
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Combined OCs and HRTs have similar effects, including increased risks of thrombosis and heart attacks.
- Ellen C G Grant (18 July 2007)
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Long Term HRT and its risks
- Maria Louise O Demesa (18 July 2007)
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Chronomics: Cardiovascular disease risk of hormonal replacement therapy related to decreased heart rate variability?
- Germaine Cornelissen, Frank L Greenway, Franz Halberg (29 July 2007)
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Hormone replacement therapy and information: in Italy a Consensus Conference to help woman decision
- Paola Mosconi, Roberto Satolli, Cinzia Colombo, Alessandro Liberati, Serena Donati, and Alfonso Mele (4 August 2007)
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Estrogen alone is unethical and is also unethical to include the women with potential risk factors to the cardiovascular events in the trial with the HRT drugs
- Neeru Gupta, Kishan Kumar Jani (24 August 2007)
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WISDOM Trial, Postmenopausal Hormone Replacement and Cardiovascular Events: Why it is still not wise to use equine estrogens
- Matthias Barton, Matthias R. Meyer, Indranil Bhattacharya, Elvira Haas (28 August 2007)
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Ellen C G Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU, UK
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WISDOM authors claim to enlighten about the increased risk of cardiovascular events and thromboembolism when hormone replacement therapy was started at a mean age of 63.1 However, of women randomized to take part, 55% had already used HRT for a median 5.3 years. Median use for current users was even longer at 9 years. Also 31% were younger than age 60. All this probably means that most women started HRT in their 50s. Furthermore, many women would have previously used progestogens and oestrogens for contraception. Women who had developed serious conditions or died due to past hormone use would not be willing or available for randomization to take more HRT. Only 2% of a possible 284,175 women screened or checked took the risk of more hormone exposures. WISDOM was stopped after only 11.9 months because of increases in major cardiovascular events and thromboembolism but the result does not represent the effect of the first year of exposure to HRT hormones for the majority of the women. While obviously more women die of vascular diseases and cancers as they become older, the increased risks caused by contraceptive or HRT hormones are due to the activation of thousands of genes. This affects women of all ages and is not related to the age of the menopause. 1. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women BMJ 2007; 0: bmj.39266.425069.ADv1 Competing interests: None declared |
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Nina Kathleen Edge, Designer in fashion industry 32 Beltie Road, Torphins, Aberdeenshire, AB31 4JT
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I read this paper with interest, I have read many other medical papers regarding HRT over the last 4 ½ years prompted by the release of the WHI. I agree with the statement within this paper “implications of results” – “the medical profession and the media must interpret and disseminate the results of WISDOM with caution and responsibility” The “critical window hypothesis” without established atherosclerosis, I believe, is plausible. Future findings from the American KEEPS study will provide valuable information that will support or dispute this theory. Dr Ellen Grant’s responses to HRT papers I have read before, the dosage and purpose of hormone use within the contraceptive pill and HRT are obviously quite different. The endogenous hormones Estrogen and Progesterone - there are others - are the hormones of life itself. It is logical for mankind to attempt to replicate these hormones, but their use has to be executed with care and intelligence Competing interests: None declared |
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Ellen C G Grant, Physicain and medical gynaecologist Kingston-upon-Thames, KT2 7JU, UK
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Biological scientists must know that the actions of hormones do not vary with the reasons for which they are given. It may be fashionable to believe that contraceptive pills are different from HRT pills but, in reality, the overall effects are the same including the increased risks of vascular diseases.1 All combined contraceptive and menopausal pills are designed to act predominantly like progesterone which is necessary to prevent endometrial hyperplasia and endometrial cancer due to oestrogen dominance.2 The biological power of combined pills is not obvious from the doses used as the potency of different progestogens can vary more than 12 times.3 This means that pill combinations with lower doses can be more powerful than pills containing higher doses. Similar or identical doses of norethisterone, norgestrel, levonorgestrel and medroxyprogesterone acetate have been used for both contraception and HRT. Synthetic ethinyl estradiol in contraceptive pills is more powerful than natural estradiol or mares’conjugated urinary oestrogens in HRT. Therefore microgram doses of synthetic oestrogen are used for contraception and milligram doses of “natural” oestrogens are used for HRT pills but both will have, more or less, the same effect. In 3 studies the relative risk of thrombosis for oral contraceptive users was 4.0, 4.1, and 6.0 respectively.4-6 In another 3 studies, the relative risk of thrombosis for current HRT users was 2.1, 3.5, and 3.6. The risks were double at 6.7- 6.9 for the first 1-12 months of use.7-9 The increased risk of myocardial infarction with oral contraceptives for current versus past or never users was 4.65 in a World Health Organisation study in 1997. The odds risk ratio for acute myocardial infarction was 31 for hormone users over age 35 who did not smoke. The risk increased massively to 400 for oral contraceptive users older than age 35 who also smoked.10 Although the risk of thrombosis is higher for new users in their first year, the risk also increases with longer term use. Therefore, it is important to know the results for trial volunteers from the first time they started to take hormones. It is unsatisfactory for randomised HRT trials to give results from the date women were first randomised as many would be continuing and many would be stopping long-term hormone use but still have some residual effects. Relatively few women would be starting first ever use. Such confusions underestimate the harmful effects of taking hormones and have even led to spurious claims of benefit, including prevention of heart attacks. Thousands of genes are up or down regulated by both exogenous and endogenous progesterone and oestrogen including many affecting blood vessel development, vasoactive amine levels and clotting mechanisms. For decades there has been considerable scientific and epidemiological evidence of increases in thrombosis and heart attacks in young hormone users long before the age of the menopause. 1 Grant ECG. Hormones, thrombosis and heart attacks. J Nutr Environ Med 1998;8:159-167. 2 Grant ECG. Hormone balance of oral contraceptives. J Obstet Gynaecol Br Commonwealth. 1967; 2 :75-9. 3 Dickey R P. Managing contraceptive pill patients. 1995 Essential Medical Information Systems Inc, Durant, OK, 74702-1607, USA. pp 130-131. 4 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception (1995). Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346: 582-8. 5 Bloemenkamp KWM, Rosendaal FR, Helerhorst FM, et al. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing third-generation progestagen. Lancet 1995; 346: 1593±6. 6 Spitzer WO, Spitzer WO, Lewis MA, Heinemann LAJ, et al. On behalf of the Transnational Research Group on Oral Contraceptives and the Health of Young Women. Third generation of oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996; 312: 83±8. 7 Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977±80. 8 Jick H, Derby LE, Myers MW, et al. Risk of hospital admission for idiopathic thromboembolism among users of postmenopausal oestrogens. Lancet 1966; 348: 981±3. 9 Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1966; 348: 983±7. 10 WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international case control study. Lancet 1997; 349: 1202±9. Competing interests: None declared |
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Maria Louise O Demesa, Resident Physician Philippines 1700
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I appreciate the author for writing a very intersting article. It is very beneficial especially to the postmenopausal women who are eager to undergo HRT and are concerned about its long term effects. However, the sample population of post hysterectomy women needs only oestrogen therapy as cited by a study saying that therapy after hysterectomy is undertaken in the majority of cases with oestrogen alone, with no need for progestogen addition (Rees 2005).T his is further supported by an article which stated after hysterectomy and bilateral salpingo-oophorectomy, women need oestrogens, sometimes in the higher dose than for more mild symptoms (J.STUDD ). I would like also to suggest a further and deeper study of the risk of breast cancer which alarms most women. In a recent study on Womens Health (Fairlie) women aged 50 who take oestrogen only HRT for five years, about 33.5 in every 1000 will get breast cancer and those taking combined HRT the number of cases that would be diagnosed by after 15 years would be 38 cases in a 1000 after 5 years. The article, however is very informative. Competing interests: None declared |
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Germaine Cornelissen, Professor University of Minnesota, MMC 8609, 420 Delaware Street SE, Minneapolis, MN 55455, Frank L Greenway, Franz Halberg
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After a median 11.9-month follow-up instead of the planned 10 years of treatment, the WISDOM study was ended, concluding that hormone replacement therapy (HRT) increases cardiovascular and thromboembolic risk in women aged 50-69 years at randomization (1). Three studies were conducted at the Pennington Center of the University of Louisiana in Baton Rouge that used 24-hour ambulatory blood pressure monitoring. Study participants included Caucasian and African American women, some of whom were on HRT. Their age ranged from 40 to 59 years (mean ± SD: 48.2 ± 6.3 years). Women on HRT were invariably found to have decreased heart rate variability (HRV), gauged by the 24-hour standard deviation of heart rate, measured automatically by ABPM around the clock (P<0.01 from binomial test, corrected for a decreasing trend in HRV as a function of age). Decreased HRV is a predictor of vascular disease risk not only in patients suffering from coronary artery disease, valvular disease or congestive heart failure (2, 3), but also in apparently healthy people (4). Should the decreased HRV underlie the observed increased cardiovascular disease risk associated with HRT, an easily assessable marker would be available to identify women who may be at risk from HRT and women who may benefit from it without undue increased cardiovascular disease risk. 1. Vickers MR, MacLennan AH, Lawton B, Ford D, Martin J, Meredith SK, DeStavola BL, Rose S, Dowell A, Wilkes HC, Darbyshire JH, Meade TW. Main morbidities recorded in the women’s international study of long duration oestrogen after menopause (WISDOM): a randomized controlled trial of hormone replacement therapy in postmenopausal women. BMJ 11 Jul 2007. doi: 10.1136/bmj.39266.425069.AD . 2. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ, ATRAMI Investigators. Baroreflex sensitivity and heart rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998; 351: 478-84. 3. Task Force of the European Society of ardiology, the North American Society of Pacing Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Circulation 1996; 93: 1043-65. 4. Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation 1994; 90: 878-83. Germaine Cornélissen1, Frank L Greenway2, Franz Halberg1
Competing interests: None declared |
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Paola Mosconi, Head of Laboratory for medical research and consumer involvement Mario Negri Institute, Via La Masa 19, 20156 Milano Italy, Roberto Satolli, Cinzia Colombo, Alessandro Liberati, Serena Donati, and Alfonso Mele
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Sir, further results on benefits and risks of hormone replacement therapy (HRT) are welcome in order to diffuse evidence based messages to menopausal women. In fact, previous publications on HRT have generated - in Italy as well as in other countries - a fan of often conflicting positions, interpretations and recommendations produced from institutions or scientific societies. Also associations of citizens/patients promoting woman health have produced information material, whose messages are often at variance with available evidence. Therefore, women today still receives contrasting information on HRT benefits and risks from the medical community, media and consumer associations. This puzzled information lead to uncertainty and confusion making difficult to achieve informed decision. In this context a full understanding of the information needs is crucial. To helps in this directions PartecipaSalute (1) and the Istituto Superiore di Sanità, the technical and scientific body of the Italian National Health Service, planned a national Consensus Conference entitled “Which information for the woman in menopause on the HRT”, it will be held on 16-17 May 2008 in Torino. The Consensus Conference will be the results a preparatory work involving two working groups that, with an explicit methodology, will address: a) the scientific controversy, b) the information conveyed by journalists and by consumers’ associations. It is also expected that the conclusion of the Consensus Conference will be implemented and a before-after study will monitor how the information on HRT risk and benefit balance will be improved as consequence of the Consensus Conference. This project is supported by Compagnia San Paolo- Torino, a charity foundation, and no found from pharmaceutical companies will be accepted. (1) Mosconi P, et al. PartecipaSalute, an Italian project to involve lay people, patients’ associations and scientific-medical representatives on the health debate. Health Expectations 2007, 10: 194-204 Competing interests: None declared |
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Neeru Gupta, Assistant Director General Indian Council of Medical Research, Ansari Nagar, New Delhi-110029, Kishan Kumar Jani
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There are ethical considerations for use of estrogen alone in the trial especially in women in the age group (50-69 years) who are already high-risk group for adverse effect of estrogen e.g. cancers, thomboembolism, etc1,2. We do not like to prescribe oral contraceptives in women more than 35 years of age. To judge the effect on breast cancer or any other cancer a minimum follow-up period of five years is required. After a median 11.9-month follow-up instead of the planned 10 years of treatment, the WISDOM study was ended3. I also want to draw attention to the following lines in the article3: Cardiovascular events- The 11 cardiovascular events recorded were all in women randomised to hormone replacement therapy (nine to combined therapy and two to oestrogen therapy). All but two of these women were over 64 years of age at trial entry and had one or more cardiovascular risk factors (three had a history of myocardial infarction or angina, two had diabetes, four smoked, and eight had a body mass index 25)3. These are not excluded in the study4. Such high risk women should not have been enrolled, it is unethical. According to a study published in New England Journal of Medicine, neither estrogen alone nor estrogen plus medroxyprogesterone acetate affected the progression of coronary atherosclerosis in women with established disease and the results suggested that such women should not use estrogen replacement with an expectation of cardiovascular benefits5. Very low dose hormones in pulsatile manner with diurnal rhythm mimicking the natural hormonal cycle may be ideal, who knows.....??!! References: 1. Ejeby K, Högland A, Eggens I, Engfeldt P. [Are hormones dangerous? Physicians as well as patients need more information about postmenopausal hormone therapy] [Article in Swedish] Lakartidningen. 1997 ; 94(12):1080-3. 2. Ito K. Hormone replacement therapy and cancers: the biological roles of estrogen and progestin in tumorigenesis are different between the endometrium and breast. Tohoku J Exp Med. 2007; 212(1):1-12. 3. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women BMJ 2007; 335: 239; doi:10.1136/bmj.39266.425069.AD. 4. Vickers MR, Martin J, Meade TW and the WISDOM Study Team. The women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial. BMC Women's Health 2007;7:2. www.biomedcentral.com/1472-6874/7/2[CrossRef][Medline] 5. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, Waters D. Effects of estrogen replacement on the progression of coronary- artery atherosclerosis. N Engl J Med. 2000;343(8):522-9. . Competing interests: None declared |
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Matthias Barton, Attending Physician University Hospital Zurich, Dept. of Medicine, 8091 Zurich, Switzerland, Matthias R. Meyer, Indranil Bhattacharya, Elvira Haas
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The authors of the WISDOM study report an increased risk of cardiovascular events and thromboembolism using equine estrogens and medroxyprogesterone acetate (MPA) (1), essentially confirming the previous results of HERS and WHI (2). The results of the WISDOM trial not surprising at all, and similar to the HERS and WHI investigators and based on their findings the WISDOM authors draw conclusions regarding “hormone replacement” therapy in general. (1,2). We previously indicated that a mix of hormones derived from horse urine are not suitable and do not represent a “replacement” of natural human estrogens such as 17-beta estradiol (2) because equine hormones also contain androgens and several sex steroids of yet unknown vascular activity (3). Regulation of estrogen targets, the classical estrogen receptors alpha and beta (and the novel membrane estrogen receptor GPR30, which is highly expressed in structurally intact human arteries (4)), is sensitive to natural estrogens (4). Despite the fact that high estrogen levels in premenopausal women and in postmenopausal women receiving hormone therapy are associated with reduced inflammation and improved stability of atherosclerotic plaques (5,6), the role of estrogen receptors during atherogenesis is still unclear (6). Interestingly, in a 7.4 year follow-up analysis of the Women’s Health Initiative Manson et al. recently reported a reduction in coronary calcium in young surgically postmenopausal treated with unopposed equine estrogens (7), indicating that even equine estrogens – in the absence of MPA - can reduce coronary calcification if treatment is started early after menopause (7). However, therapeutic success of any hormone treatment in postmenopausal will be depending on the presence of concomitant risk factors such as hypertension, obesity, hypercholesterolemia, and aging (6). Surprisingly, beneficial effects of natural 17-beta estradiol on vascular reactivity are still present in younger postmenopausal women even in the presence of angiographically documented coronary atherosclerosis (8). However, these beneficial effects diminish with age and are essentially abrogated in women aged 70 years and older (8). This indicates that changes in the vascular wall related to aging may be much more important than previously appreciated, and that even natural hormones such as 17-beta estradiol might lose their ability to improve vascular homeostasis with advanced aging. 1. Vickers MR, MacLennan AH, Lawton B, Ford D, Martin J, Meredith SK, DeStavola BL, Rose S, Dowell A, Wilkes HC, Darbyshire JH, Meade TW; WISDOM group. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ. 2007; 335: 239- 2. Pines A, Sturdee DW, Maclennan AH, Schneider HP, Burger H, Fenton A. The heart of the WHI study: time for hormone therapy policies to be revised. Climacteric. 2007;10:267-269. 3. Barton M, Dubey RK. Postmenopausal hormone-replacement therapy. N Engl J Med. 2002;346:63-65. 4. Haas E, Meyer MR, Schurr U, et al. Differential effects of 17beta -estradiol on function and expression of estrogen receptor alpha, estrogen receptor beta, and GPR30 in arteries and veins of patients with atherosclerosis. Hypertension. 2007;49:1358-1363. 5. Burke AP, Farb A, Malcom G, Virmani R. Effect of menopause on plaque morphologic characteristics in coronary atherosclerosis. Am Heart J. 2001;141:S58-S62. 6. Barton M, Meyer MR, Haas E. Hormone replacement therapy and atherosclerosis in postmenopausal women: does aging limit therapeutic benefits? Arterioscler Thromb Vasc Biol. 2007;27: 1669-1672 7. Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356: 2591-2602 8. Sherwood A, Bower JK, McFetridge-Durdle J, Blumenthal JA, Newby LK, Hinderliter AL.Age moderates the short-term effects of transdermal 17- beta-estradiol on endothelium-dependent vascular function in postmenopausal women. Arterioscler Thromb Vasc Biol. 2007; 27: 1782-1787 Competing interests: None declared |
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