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Rapid Responses: Rapid Responses published:
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Rocks and hard places....
- Cobie Brinkman (12 February 2004)
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HRT is the worst treatment for symptoms
- Ellen C G Grant (13 February 2004)
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IS NATURE FOOLISH?
- BM Hegde (15 February 2004)
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HRT is not neuroprotective
- Matthew L Grove (17 February 2004)
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Is the menopause natural?
- Jonathan S Charlton (17 February 2004)
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Women's Health Initiative and Breast cancer
- Geoffrey D Madden (17 February 2004)
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endocrinologists debate this too!
- Jon Madura (18 February 2004)
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WHI study was ill-conceived
- Geoff Taylor (19 February 2004)
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Re: Is the menopause natural?
- Paula S. Derry (25 February 2004)
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HRT/osteoporosis clinical trials- ethical concerns
- Dr. Neil de Jesus Rangel. DM(Endocrinology) (5 March 2004)
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Cobie Brinkman, Lecturer in Neuroscience Australian National University, School of Psychology, Canberra, Australia 0200
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Is the editor a woman? I have found comment on the risk of HRT to vary with the sex of the commentator. As a professional woman using HRT it is worth three months not to have to worry about getting a major hot flush in the middle of an important meeting, I can assure the editor. As a neuroscientist, I am disappointed that an editor who is a member of such an important working party concentrates on what, for indivdiual women, amount to very small changes in risks of developing, or not, some forms of disease, and omits all together the strong suggestion from a considerable number of animal studies that at least estrogen has a neuroprotective function, and that this aspect of HRT has as yet not been properly been evaluated in human studies. While many people are skeptical, I find it hard to believe that in this respect, humans would turn out to be unique animals. What price to society not to investigate a potential reduction in CNS damage? I for one will continue to take at least estrogen. I'd rather run a small risk of having to lose a breast than lose myself. Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist 20 Coombe Ridings, Kingston-upon-Thames, Surrey, KT2 7JU, UK
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Klim McPherson (February 14, p 357)1 believes that current biological theory does not predict the effects of hormones on cancer and vascular disease well. Undoubtedly “we never know as much as we think we do” if we stubbornly refuse to accept long established biochemical facts. We have known since 1960s that progestogen/oestrogen oral contraceptives lowered plasma zinc and raised copper levels.2 In 1979 Marie Curie Research Foundation workers joined me in reporting that migraine patients with high serum copper/zinc ratios had impaired liver clearance rates 3 and increased adverse reactions to common foods and chemicals.4 The commonest cause of frequent severe headaches and migraine was hormone use. Evidence has been accumulating for more then 50 years of the importance of trace minerals in the regulation of immunity.5 Deficiencies of zinc, copper and magnesium impair the function of B vitamins and block essential fatty acid pathways. These are all excellent biochemical reasons for hormone use causing vascular and mental disease and cancers. Deficiencies of enzyme cofactors are usual in patients with symptoms at times of hormonal change. Primary dysmenorrhoea, pregnancy sickness, postpartum depression, premenstrual tension, menopausal symptoms and osteoporosis are warning signals of biochemical dysfunction, often caused by previous use of hormones. Although some women’s warning symptoms are temporarily suppressed, further exposures will increase underlying biochemical upsets and many women have severe withdrawal symptoms when they stop HRT. I completely disagree that HRT is justified for women with symptoms. Randomised studies still underestimate the real risks, and even produce spurious apparently decreased risks, such as for fractures and colon and endometrial cancers, because of the residual effects of previous almost universal use of contraceptive hormones or HRT before randomisation. The recorded average use in breast cancer studies is 2-3 years for HRT and contraceptive hormones. Any use of HRT is too long. As many herbal treatments are oestrogenic, they may also be potentially carcinogenic. Essential nutrient analysis is not generally available. No one can choose the best and safest symptomatic treatment if the most relevant facts are missing. No wonder the last half century has been disastrous for women’s health. 1 McPherson K. Where are we now with hormone replacement therapy? BMJ 2004;328: 357. 2 Halsted HJ, Hackly BM, Smith JC. Plasma zinc and copper in pregnancy and after oral contraception. Lancet 1968;2: 278-283. 3 Capel ID, Grant ECG, Dorrell HM, et al. Disturbed lever function in migraine patients. Headache 1979;19:270-272. 4 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance. J Nutr Environ Med 1998;8:105 -116. 5 Sherman AR. Immune dysfunction in iron, copper, and zinc deficiencies. In: Bodgen JD, Klevay LM, eds. Clinical Nutrition of the Essential Trace Elements and Minerals: The Guide for Health Professionals. Totawa, NJ: Humana Press Inc.,2000: 309-331. Competing interests: None declared |
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BM Hegde, Retired Vice Chancellor Mangalore-575 004, India
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Dear Editor, If the hormones are that important for the welfare of women why does Nature, unless we presume nature to be foolish, stop hormone supply after menopause? Our presumption that we are wiser than Nature, using our reductionist science, has been proven wrong time and again. Even in this instance another vital information comes to fore. Hormones have improved the fat profile of women but have worsened their cardiovascular risk! We are still groping in the dark in the realm of risk factors. In the holistic concept of illness and wellness there are, probably, as many asset factors as there are risk factors. It is the balance that keeps man well or ill purely by CHANCE, the very thing that our statistical methods are trying to avoid! The greatest discovery of the twenty-first century is the discovery of man's ignorance. Science rarely could answer the question "why" although it could explain "how". Science only makes models, mostly mathematical constructs. Any complicated question, when looked at from a new angle, only becomes more complicated. That is where we are with HRT today. With all our advances we can not predict as to why a young man at thirty dies suddenly after a myocardial infarct while an elderly octogenarian goes on with his stable angina, many a time with all three vessels badly obstructed, for decades? The fat theory is based on very shaky foundation, but is a good commercial proposition, anyway. Reductionism might not be able to unravel the life course in biology. The infradian rhythm of the menstrual cycle has the influence even from the gravitational pull of the Moon! Time evolution, in a dynamic system, depends on the total initial state of the organism and might not change for the better by altering one or two initial parameters. In that context Tucker’s estimate, quoted in the article, might not be reliable either. Long term drug therapy of many chronic illnesses is beset with similar problems, if one were to critically analyze drug therapy of raised sugar, cholesterol and, even, blood pressure, while all of them could be helpful to allay symptoms. One always argues that hypertension is a silent killer and needs long term therapy in apparently healthy individuals. In my long experience of four decades of managing hypertensives (experience is not measurable scientifically) I am yet to encounter an absolutely asymptomatic significant hypertensive, unless he/she is an alcoholic or a heavy smoker. In the latter event the minor symptoms get masked and the physician has to be over cautious. I also felt that there is never a situation where the blood pressure gets elevated without any reason. Most, if not all, “so called” idiopathic hypertensives have enough and more emotional and psychological problems if one goes deep into their make up. The relevance of this to menopausal symptoms, which are made out to be disabling, is significant. While menopause is a problem for the literate working women and the knowledgeable class, it is rarely felt by the illiterate village women that we get to see in our setting in government hospitals. The incidence in five-star, hi-tech, private hospitals in India could be comparable to the west, though. Menopausal symptoms have a lot to do with the woman's background, her psyche, her knowledge of health matters, her access to unfiltered information in the internet and, her awareness of the advertisement blitz about the HRT's potential to prevent almost all killer diseases. For the ignorant it is bliss and not an event in life at all as there are more important things to worry about, most of all not knowing where the next meal comes from! This article beautifully sums up the truth about the unpredictability of hitherto unknown risks of long term drug therapy in modern medicine. We have been predicting the unpredictable. Whereas drugs, by and large, are good for symptom relief, consequently a boon to the ill, they could pose serious risks in the long run unbeknownst to medical science. There are many imponderables in the game of wellness and illness management. Longitudinal observational studies are as good, if not better than, the cross sectional controlled studies. The latter have their inherent defect in that two human beings can never be identical to compare. We can not know their genotype and their consciousness, which together with the phenotype, make the whole man! As of now most of our theories of future events could only be guesstimates, if there is a word like that. Wrote Hippocrates: "Cure rarely, comfort mostly, but console always." Very prophetic indeed!Thanking you, yours ever, bmhegde Competing interests: None declared |
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Matthew L Grove, Consultant Rheumatologist NTGH, NE29 8NH
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Finally, a BMJ editorial that addresses the thorny HRT issue with an balance - far better than the damage-controlling effort published by Ryman after WHI first broke. To Cobie Brinkman - I'm sure you've seen the results of the WHIMS study (a subgroup analysis from WHI, I'm afraid, but a prespecified and biologically relevant one) (1). An extra 23 cases of dementia per 10,000 women treated with HRT doesn't sound neuroprotective. Do you have any other data from large scale prospective RCTs (or other high quality sources) to indicate neuroprotective benefit? (1) JAMA 2003; 298; 2651-2662 Competing interests: None declared |
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Jonathan S Charlton, GP HA2 6HL
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I would only take issue with one, early, point and that is is the menopause a natural event in humans? As far as I can ascertain the only other mammal that goes through a menopause is the elephant whose natural life expectancy is 60, they have no natural predators and they only die when their teeth wear out and they effectively starve to death. From skeletal examinations our pre-civilisation anscestors (defined as before framing about 10 000 years ago) had a life expectancy of 30 for women and 35 for men so most of us are well past those ages and are alive largely because we don't have to hunt and don't have to run away from larger faster animals with big teeth and claws. It may well be therefore that the human menopause is not a natural event and is a result of our surviving well beyond our natural life span. It does not however make the menopause any more tolerable and the real issue is can we find an HRT which is effect neutral or even beneficial to our ladies Jonathan Competing interests: None declared |
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Geoffrey D Madden, General Practitioner Beenleigh, Queensland
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Klim McPherson's editorial is a timely summary of a sensible position on HRT. It does, however, perpetuate the myth that the Women's Health Initiative study published in JAMA (2002:288:321-33) shows that combined HRT increases the risk of breast cancer. That study shows no such thing, although it may have if it was able to continue. Competing interests: None declared |
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Jon Madura, n/a retired NJ-USA
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THis is a bit off the trail here but as a male on testosterone injections, I often come up for review by the hormone specialists. This past year - there were three endocrinologists involved debating stopping to see if my body would self-correct. Two said try while the other said NO. In the end the natural levels dropped causing the need for even more via injection. In my case we are battling -4.2 steroid induced osteoporosis, caused by over zealous doctors trying to solve my severe spinal pain concerns. Competing interests: None declared |
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Geoff Taylor, General Practitioner Busselton
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The great tragedy of the WHI study on HRT is that it is now highly unlikely that any further proper study will now be conducted. The WHI study missed the whole point of HRT which is to pharmacologically delay the menopause, and (in terms of cardiac risk) prevent the development of atherosclerotic disease. This is very different from taking women who are 10-20 years post-menopause, and then treating them. The majority of the women in the WHI study were overweight and a large percentage obese, hence suffering the metabolic syndrome and predisposed to heart disease. We have known for many years that oestrogens promote thrombosis. With pre-existing arterial disease this effect comes to the fore. If the study had been properly designed and followed women from the Menopause, I suspect the results would have been very different. It was good after all to see that HRT improved lipid profiles. It is heartening to me to at last see an article that states that heart disease was only increased in the first year of treatment (The Kaplan Meyer Graphs clearly showed this, and support the concept that those with pre-existing heart disease were the only ones with increased risk). It is also good to see it stated that HRT may only be promoting the growth of Breast cancer in women who were going to get it anyway, rather than be "causing" breast cancer. It seems to me that present studies cannot differentiate between cause and promotion of breast cancer. This is not just semantics - the medico-legal implications are huge for those of us at the coal face of practice. Competing interests: None declared |
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Paula S. Derry, Independent Practice, Health Psychology Baltimore, MD 21212
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It is true that most mammals do not have a menopause. Most mammals also do not have language or computers, an adolescent growth spurt, or (except for primates) menstruation. Humans are both similar to and different from other mammals. Life history theory (e.g., Bogin, 1999) has suggested that the human life course is unique in the lengthening of life stages found in other mammals and in adding new life stages. Menopause in humans is unusual in being universal and under genetic control. Pavelka and Fedigan (1991) suggest that menopause is unique even when humans are compared with other primates, who sometimes do have a period during old age during which they do not reproduce: These primates are typically very old (rather than, as humans are, still relatively healthy and nowhere near the end of the known life span); the phenomenon is not universal as it is in humans; and the primates do not deplete ovarian follicles. The data on life expectancy in human prehistory based on skeletal remains is methodologically controversial. Bogin, B. (1999). Patterns of Human Growth. Cambridge:Cambridge University Press. Pavelka, M., & Fedigan, L. (1991). Menopause: A comparative life history perspective. Yearbook of Physical Anthropology, 34, 13-38. Competing interests: None declared |
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Dr. Neil de Jesus Rangel. DM(Endocrinology), Consultant Endocrinologist Goa 403106.
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The results of the WHI has led to serious rethinking on HRT, and must I say, a lot of chaos and confusion. Post-WHI, very objective and specific guidelines are needed; especially those that patients can follow and make an informed choice. Like radiation, there seems to be no such thing as a safe dose or a safe duration for HRT(and probably SERMS). In this context, can the regulatory agencies justify continuing with the estrogen only arm of the study. My feeling is that the results may be the same as the discontinued arm. Could someone tell us how many women have chosen to drop out. Who would take responsibiliy for the harm that may be done if the outcome were the same. Same with the RUTH trial. Will it go the WHI way? Can its continuation be justified in view of the surprising results of the WHI? The status of tibolone hangs in the balance and it would be fair to women to stop using it as well; considering the findings of the Million Women Study. I have always been concerned about the risk of venous thromboembolism(VTE) in HRT users as well as in SERMS which should be considered HRT equivalent until proven otherwise. I have always suspected that methodologies in trials may grossly under-report the true incidence of VTE and what are reported are the more obvious serious cases. VTE are indeed the most serious direct complication of HRT/SERMS.All women need to know this and then decide on using a SERM. Its good to know that the regulatory agencies in the UK had the conviction to block the use of raloxifene for breast/endometrial cancer prophylaxis, for lack of robust data. The drug companies, it seems, will not learn from the WHI! SERMS can't be prescribed for osteoporosis since there's no robust data on hip fractures which one's more importantly bothered about.Why should a woman be risked an episode of VTE also. That leaves just the bisphosphonates where good data is available for vertebral and hip fractures.The very future of SERMS seems doubtful. No conscientious doctor would ever prescribe them for women's health. One last comment: the regulatory agencies seriously need to reconsider the very continuation of any placebo-controlled SERM trials in osteoporosis/woman's health/CHD prevention. Not only are they risky to women in terms of VTE; the placebo arms seriously harm the health of women at risk of fracturing. A significant number have vertebral fractures/radiological evidence of fractures and leaving them "untreated" constitutes a wilful neglect of a patients' health. Calcium and vitamin D(which are nutritional supplements) for the placebo arms aren't enough(I repeat, not enough) considering the availability of superior therapies(bisphosphonates). "Not treating" women at risk of fracturing/or those with fractures in a placebo arm is a serious form of medical negligence by investigators. Such trials can never be justified at this stage of our scientific knowledge. I have heard the usual story that you'd need several tens of 1000's of women to do a head on comparison/ "these women would not have been even taking calcium-vitamin D if they weren't in the trial";but my argument is that should unsuspecting/poor women be made to pay a heavy price for such a pathetic(commercial) justification. Serious ethical concerns on the placebo group, were raised in an editorial at the time of publication of the raloxifene trial results. I write this in public interest and wish that you publish this in its entirety. I hope that regulatory agencies may closely scrutinize all ongoing trials in the best inerest of women.The comment that companies hide data is extremely serious. All those who have suffered should go to the courts. The WHI is a serious wakeup call for all gynaecologists ,endocrinologists and enforcement/regulatory agencies; if not the drug companies who I must say, can buy just about anyone and get them to write those :Dear Doctor letters - don't worry the trial drug is safe..... Competing interests: Worked earlier till September 2003 in a SERM osteoporosis trial. |
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