Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Links to HRT information on MCA website
- Jane Viner, SW8 5NQ (12 July 2002)
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Stopping Hormone replacement therapy
- Ellen C G Grant (14 July 2002)
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HRT and The Breast
- J Michael Dixon (15 July 2002)
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Lets try not to be smug
- Peter R Bradley (17 July 2002)
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BEFORE AND AFTER 9th of JULY
- Tayfun Bagis, Adnan Gokcel, Serkan Erkanli, Esra Kilicdag, Ebru Tarim (17 July 2002)
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Increase in breast cancer was not statistically significant
- Adam Jacobs (19 July 2002)
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Jane Viner, MCA Internet Editor Medicines Control Agency, SW8 5NQ
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The MCA has produced guidance about the HRT study for health professionals and patients.The URLs are as follows: www.mca.gov.uk/ourwork/monitorsafequalmed/safetymessages/hrtrisks.pdf www.mca.gov.uk/ourwork/monitorsafequalmed/safetymessages/hrt.pdf
Jane Viner MCA Internet Editor |
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Ellen C G Grant, physician and medical gynaecologist KT2 7JU
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Stopping Hormone Replacement Therapy. EDITOR - Millions of women in the USA are now stopping taking HRT. Randomised double blind controlled trials have been discontinued prematurely because they have confirmed the well known facts that taking oestrogen and progesterone-like hormones increases the risk of invasive breast cancer, coronary heart disease, stroke and pulmonary emboli.1 Overall risks may be greater than those estimated as these trials do not take into account any carcinogenic and thrombotic effects of previous oestrogen and progestogen exposures in the form of oral contraceptives. Alternative and safer treatments for osteoporosis and menopausal symptoms should now be used. The media have been telling worried women to see their doctors. What are the likely problems with stopping HRT? Premenopausal or perimenopausal women may have a risk of pregnancy and should use a non-hormonal method of contraception. As steroid hormones are potentially addictive, symptoms such as withdrawal headaches, mood changes and increases in flushing are likely.2 Nutritional deficiencies, especially of zinc, magnesium and copper increase reactions to foods and chemicals.3 Smoking and alcohol should be avoided. Sensible supplements are elemental zinc 30 mgs and magnesium 100 – 300 mgs daily. Copper one mg twice weekly is adequate unless superoxide dismutase blood levels are low when copper is given on alternative days with zinc for three weeks. An adequate vitamin B complex and omega-3 and omega-6 essential fatty acid supplements are often needed. Irregular and heavy withdrawal bleeding may require further investigation because of the residual risks of either endometrial hyperplasia or cancer. The good news is that falls in hormone taking match fall in breast cancer incidences.4 Deborah Grady and colleagues comment that other trials of antiatherosclerotic interventions, including diet, niacin, and statin use, benefits observed during the first years of treatment persisted or increased over time, even in the absence of continued treatment.5 This is in contrast to the resulys of their HERS II HRT study, which found a first year increase in coronary artery disease and no cardiovascular benefit during a 6.8 year follow-up. It may now be irresponsible to prescribe HRT. Ellen C G Grant 1 Fletcher S W, Colditz G A. Failure of estrogen plus progestin therapy for prevention. JAMA 2002;288:336-8. 2 White M, Grant ECG. Addiction to oestrogen and progesterone. J Nutr Environ Med 1998;8:117-120. 3 Grant ECG. The Pill, hormone replacement therapy, vascular and mood over -reactivity, and mineral imbalance. J Nutr Environ Med 1998;8:105-116. 4 Grant ECG, Antony HM, Myhill S et al. Breast cancer and hormone exposure. Lancet 1996;348:682. 5 Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcome during 6.8 years od hormone therapy. Heart and Estrogen/Progestin replacement study follow-up (HERS II). JAMA 2002;288:49-57. |
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J Michael Dixon, Consultant Surgeon and Senior Lecturer Edinburgh Breast Unit, Western General Hospital, Edinburgh EH4 2XU
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Editor, HRT and the breast The next few weeks will be very difficult for primary care doctors and women with menopausal symptoms following the publication of the randomised study in JAMA which was stopped early because of an increased risk of breast cancer in women taking continuous combined conjugated oestrogen and medroxyprogesterone acetate (1). The results are predictable based on findings from earlier studies not only in relation to breast cancer risk, but related to the increased rate of cardiovascular events, pulmonary embolism and stroke reported in the HERS study (2-4). Both the randomised trial and an editorial (5) are available on www.jama.com. This recent publication provides new and definitive data and confirms that the concerns expressed in my BMJ leader (6) about combined continuous HRT preparations were correct. Yours sincerely, Mr J Michael Dixon,
References 1. 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: 321-333. 2. Simon JA, Hsia J, Cauley JA et al. Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-progestin Replacement Study (HERS). Circulation 2001; 103: 638-642. 3. Grady D, Herrington D, Bittner V et al for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen-progestin Replacement Study Follow-up (HERS II). JAMA 2002; 288: 49-57. 4. Grady D, Wenger NK, Herrington D Et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000; 132: 689-696. 5. Fletcher SW, Colditz GA. Failure of estrogen plus progesting therapy for prevention. JAMA 2002; 288: 336-8. 6. Dixon JM. Hormone replacement therapy and the breast. BMJ 2001; 323: 1381-1382. |
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Peter R Bradley, GP, Brisbane Springwood, Qld 4127, Australia
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No doubt there will be many oponents of HRT who will be saying big "I told you so's" re this subject. I would just like to register the following thoughts; Most, if not all of us have only promoted this management, many reluctantly, because much of the evidence coming out, until this study showed that the positives outweighed the negatives. For a while there it seemed like not a month went by when some study was not being announced as showing yet another benefit. Think of dementia, skin cancers, cataracts, and so on, and this in addition to the already recognised ones of BMD, bowel cancer, mood, sleep, loss of libido, vaginal dryness, concentration, etc. And I for one, have witnessed myself, favourable effects on blood pressure, lipid profiles and arthritis. This being so, and having the best possible morbidity prevention for our patients as a priority, one felt one must offer this opportunity to slow nature's clock, at least. I for one, am still not convinced we were wrong - yet, as to why, - read on if you will. Logic says we cannot stop the clock, or turn it back, we can just slow it down. So if, as it seems to be, the menopause is a state of chronic hormonal deficiency, with an acceleration of the degenerative effects of aging, which is what the big picture suggests, then the fact that the average age of women entering this study was 63 years, must surely be a concern. That is, with many, the horse had bolted already, ground had been lost which could not be reclaimed, especially in the CVS, so we can hardly be surprised that we did not see significant cardiovascular improvements. By the same token, if as we know is the case, most breast cancers in this group are oestrogen sensitive/dependent, then one assumes they will grow a bit faster in the treated group, therefore being picked up earlier, (and presumably with less time to metastasise), and therefore one would expect to see an initial preponderance turning up in this group, but this would also seem to explain the more favourable outcomes previously described. That is - picked up sooner = better outcome? Also bear in mind the favourable stats for those with past cancers who were trialled on HRT - they also did better we were told. And what about the recent huge study recently reported on the O/C pill, showing no significant adverse increase in breast cancer in long term users? There is something illogical in all this and if oestrogen causes breast cancer, then it goes about it in a very funny way, especially in the light of its relative rarity in pre-perimenopausal and menopausal women. We have not heard the last of this, and I feel it is a pity the study was aborted prematurely. It will make it very hard for this doubt to now be addressed by other studies. The favourable figures in the untreated group re the thrombo-embolic data also bear consideration. It is common knowledge the elderly, - females in particular - bleed more easily than younger people. Any anaesthetist will confirm that, and it is this group most in danger from severe GI bleeds from NSAIDs is it not? That being so, I suggest that the number of thrombo-embolic/DVT cases in the treated group may partly at least be the result of the perverse effect of the untreated having a lower than normal coagulability. I look forward to more impartial analysis of this study in the near future. Hopefully there are other studies pending which will not be abandoned early. We must not throw the baby out with the bathwater too quickly. - Sorry, an oldie but a goodie. |
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Tayfun Bagis, Asistant Prof. Baskent University 01120, Adnan Gokcel, Serkan Erkanli, Esra Kilicdag, Ebru Tarim
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In the last decade, menopause and related conditions became one of the most popular issues in gynecologic practice. There are several reasons for this popularity. One of them is increased number of women who have reached the postmenopausal period and the other is the accumulation of data on the positive effects of estrogens on the conditions affecting women’s mortality, morbidity and overall well being. Preventive care for osteoporosis, cardiovascular disease and perhaps for dementia, besides relief of menopausal symptoms and improvement of quality of life were the main rationale behind hormone replacement therapy (HRT). Although previously we had enough data to reassure women that the benefits of HRT outweigh the risks, we could not encourage women for using preparations for long term.(1) Women stopped using their medications due to breakthrough bleeding, fear of cancer and also due to misinformation obtained from unprofessional sources such as the media, friends, relatives or physicians who are not familiar with HRT. That is why continuance rates are higher in clinical trials with respect to the general population. Surprisingly, it was demonstrated in a study that only 50% of female gynecologists who reached menopause are on HRT. Dr. Rossouw, one of the authors of WHI study, in his lecture in 1999 (2) provided us with a lot of information to appreciate overall risks and benefits of HRT. He gave an example of simple approach to sensitivity analysis for HRT. The calculation takes into account the sum of the national mortality data for each HRT-associated outcome (CHD, stroke, venous thromboembolism, breast cancer, uterine cancer, hip fracture) and then recalculates the sum by adjusting each outcome by the relative risk for current HRT users according to most optimistic and less optimistic scenarios. Conclusion of this example was that if the risk reduction ratio for CHD were assumed to be less than 20%, there would be no overall benefit. He stated that under the severe bias scenario, which assumes no benefit for CHD, 61,592 more women according to 1992 US vital statistics would die compared to the population who did not take HRT. With all the data above we are now faced with the results of WHI study. How can we interpret the results of WHI study? First of all, the results have showed that the less optimistic scenarios on HRT prior to WHI were better than the results of WHI study. Another result is the fact that we cannot manage our patients based on observational studies per se. Subsequent to these results we are faced with many questions that should be answered. Is it possible to enhance women’s quality of life by prescribing them a medication and tell them that this particular medication has some risks outweighing the benefits? It is possible to expect more favourable outcomes with medications other than Prempro, but how can we advise the patients that these other medications are safe? HRT regimens can be used for short-term indications (for example only for 3 years) and the doses can be titrated in an individualized manner, but how can we counsel the patients on the risks of CHD for the first year? We know that hot flashes and bone responses are dose dependent(3). What can we do if we do not have sufficient response to the lower doses? Moreover is a 3-year treatment period consistent with the rationale behind HRT? Answers to these questions still await the results of new and ongoing studies. Nevertheless, we think that it will not be easy to encourage postmenopausal women to participate in these kinds of studies after the results of WHI. It is very difficult to understand why the designers of WHI study conducted this prevention trial on women with a mean age of 63.2 years. We believe this point needs to be clarified. In countries without preventive health care programs, menopause is a very important period that offers a chance for evaluating women under risk. However, after this study, we think that the number of women referring to menopause clinics will drop sharply. This again is the tragic result of WHI study. WHI study told everyone “The emperor has nothing on at all” We do not know whether he is really naked or not, but what we know is that we will be facing great obstacles in using HRT. REFERENCES: 1- Ettinger B, Li DK, Klein R. Continuation of postmenopausal hormone replacement therapy: comparison of cyclic versus continuous combined schedules. Menopause. 1996;3:185-189. 2- Rossouw JE. What we still need to learn about hormone replacement therapy? In Infertility and Reproductive Medicine Clinics of North America. Volume 10 Number 2 W.B Saunders Company. Page 189-209 3- Ettinger B, Genant HK, Steiger P, Madvig P. Low-dosage micronized 17- beta estradiol prevents bone loss in postmenopausal women. Am J Obstet Gynecol 1992;166:479-488. |
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Adam Jacobs, Director Dianthus Medical Limited, London SW19 3TZ
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I am not at all surprised that the reporting of the women's health initiative trial of HRT [1] in the popular media neglected to mention that the increase in breast cancer was not statistically significant. However, I am a little disappointed that the news item in the BMJ also overlooked this important detail [2]. References 1. 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: 321-333 2. Hopkins Tanne J. Hormone trial for disease prevention stopped early. BMJ 2002; 325: 61 |
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