Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Primary Care? Oral Sex Hormone Therapy HT is Not Physiological Sex Hormone Replacement SHR, Which Requires both Systemic Androgen and Estradiol/Progesterone.
- Neil D Burman (24 January 2005)
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HRT, strokes and vasodilatation
- Ellen C G Grant (28 January 2005)
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HRT and risk of stroke meta-analysis: does the inclusion of WHI overemphasize the risk?
- David A Hanley (11 February 2005)
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Cerebral Microcirculation Biophysical Semeiotic Evaluation and Personalized Stroke Prevention, according to Single Patient Based Medicine.
- Sergio Stagnaro (11 February 2005)
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Hazards of hormone replacment therapy
- Michelle C Bird (11 February 2005)
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Reduced DHEA May Cause Thrombosis: HRT reduces DHEA
- James M. Howard (13 February 2005)
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HRT causes thrombosis: HRT reduces DHEA by causing zinc deficiency
- Ellen C G Grant (14 February 2005)
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The Origin Of DHEA - You Guessed it !
- Dr. Herbert H. Nehrlich (14 February 2005)
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Re: HRT causes thrombosis: HRT reduces DHEA by causing zinc deficiency
- James M. Howard (15 February 2005)
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Hormone use causes zinc deficiency
- Ellen C G Grant (16 February 2005)
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Re: Hormone use causes zinc deficiency
- James M. Howard (16 February 2005)
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Hormone use causes zinc deficiency and strokes
- Ellen C G Grant (17 February 2005)
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A REVIEW OF A META-ANALYSIS ON HORMONE REPLACEMENT THERAPY AND SUBSEQUENT STROKE
- Robert L Cheifitz (17 February 2005)
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Talking Turkey
- Dr. Herbert H. Nehrlich (17 February 2005)
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Re: Hormone use causes zinc deficiency and strokes
- James M. Howard (18 February 2005)
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HRT progesterones and oestrogens cause all types of strokes
- Ellen C G Grant (18 February 2005)
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Re: Re: Hormone use causes zinc deficiency and strokes
- Ellen C G Grant (20 February 2005)
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An HRT users view of Bath & Gray - “association between Hormone Replacement Therapy (HRT) and subsequent stroke” a meta-analysis
- Nina K. Edge (21 February 2005)
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Remember the most important reason
- Christine B Singh (23 February 2005)
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Why women should not be given short term HRT.
- Ellen C G Grant (24 February 2005)
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Time to reflect
- Victor A. Palmer (12 March 2005)
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Game over for HRT promoters
- Ellen C G Grant (13 March 2005)
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Socio-economic confounding, HRT and stroke
- Shah Ebrahim, Debbie Lawlor, and George Davey Smith (18 March 2005)
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HRT is harmful for all women
- Ellen C G Grant (21 March 2005)
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Re: Remember the most important reason
- jane miners (2 May 2005)
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Neil D Burman, Research Internist Monism HealthSpan Foundation, PO Box 44285 Claremont 7735, Cape Town, South Africa.
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Bath and Gray found 29% more strokes only on oral hormone therapy HT. By trials design, most participants were adipose, asymptomatic, over 10years post menopause. Primary Care would not have put them on oral HT (estrogen E±P progestin). Their analysis discredits only HT, not proper SHR. It omits human physiology, androgens A and progesterone PG - the most prolific SH in all healthy young adults, crucial (way beyond sex) against all fattening degenerative aging diseases. But the 5 RCTs (Table A) testing estradiol E2 patch ie physiological systemic human SHR found no strokes in 740 patient years. Oral SHR - even human testosterone TT, E2 and PG - in both sexes requires over ten times the systemic dose for effect. Women systemically produce and thus need about 50ug E2/day – (not 50mg shown in table A) – compared to 0.6 -2mg/day oral ET- which promotes breast cancer and thrombosis. For 40 years E has been used to control haemorrhage; trials confirm that oral(1,2) but not transdermal2 E increases thrombosis. No studies of physiological systemic balanced SHR in proven deficient men or women show increased thrombotic tendency. In men, systemic TT replacement TRT appears both to supply needed E, and obviate other androgen replacement ART. But E/PG cannot be converted back to adrenal/ ovarian androgens – whose secretion they suppress. In careful Pubmed studies in animals or humans, E alone did not promote/preserve skeletal muscle / strength; in only a quarter of combined studies- 11 in Europe, 1 Australia – did P+E provide anabolism for women. More doctors(3) (and veterinarians) now distinguish commercial oral E±P - long-known inflammatory thrombogenic fattening HT/contraception - from permanent replacement systemic human SHR for physiological anabolic prevention. Profit, thyroid and cortisol aside, normal endocrinology is ancient physiological balance of systemic human eg insulin-, growth- and Sex-Hormone replacement. In sixty years’ use worldwide(4), as international meetings(5,6,7) highlight, individualized TT replacement - TRT- with PG +/or E2 in deficient women - has given adults needed longterm benefit for over forty years without reported adversity. Systemic SHR ( TRT for men, for women ART ±E2), has been available for sixty years(4), now still from $3/month. Whether by cream, patch, weekly subcutaneous injection, or implant, around TT 7mg/day for men, or TT ~0.7mg plus ~ 50ug E2 daily for women, restores the mean plasma TT and E2 of the youthful healthy slim. These bloodlevels may seem high for the aging. But gonadal- adrenal androgens often fall with aging- a risk factor for most diseases- and need balanced replacing. As was done with metformin, we need to test this in a 20year international RCT – but not deny SHR meantime to SH- deficient patients. ndburman@bigfoot.com refs: 1.E.M. Bladbjerg, S.O. Skouby, L.F. Andersen and J. Jespersen; Human Reproduction,2002.17,3235-3241: Effects of different progestin regimens in HRT on blood coagulation factor VII and tissue factor pathway inhibitor; 2. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M.Arterioscler Thromb Vasc Biol. 1997;17:3071-8 Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. a RCT). 3. The North American Menopause Society NAMS position statement: Treatment of menopause-associated vasomotor symptoms: Menopause. 2004;11(1):11-33 4. Medical Research Division: Sex Endocrinology: Schering Corp, Bloomfield NJ 1944 5. International Menopause Society statement 2004 http://www.imsociety.org 6. International Society for Study of Aging Males statements 2004 http:/www.issam.ch 7. eds Rosen R, Bachman G et al Androgen Insufficiency in Women: Proceedings of the Princeton Conference Fertil Steril 2002:77:Supp 4 S1 -S103 Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU, UK
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Bath and Gray express surprise that both oestrogen and combined HRT increase the risk of fatal and disabling strokes.1 Roughly speaking, progesterones promote vasoconstriction and oestrogens promote vasodilatation in menstrual and treated cycles. OC or HRT induced thrombosis is not only due to changes in clotting factors but is also due to dilatation of sinusoids and arteriolar thickening, both becoming unnaturally prominent during hormone use. Blood flow slows in dilated or thickened blood vessels promoting clotting. Numerous adverse vascular effects and abnormal blood vessel changes, which increased with duration of hormone use, were reported among previously healthy young women forty years ago.2,3 The rapid increase in heart attacks and strokes at the menopause is likely to be due to the widespread uptake of HRT, which also has synergistic effects with smoking and alcohol. In the 1970s women over age 35 were warned against taking OCs or HRT because of their greater absolute risk of thrombosis, strokes and heart attacks. The vigorous and successful promotion of HRT which then followed astounded me. The further sharp increases in breast cancer were predictable.4,5 Women who got ill or died because of HRT, were ignored. Some who were still well acted as recruiting agents, even running “women’s charities”. The continued search for a “safe” dose or form of HRT is absurd. Over 175 different formulations were used by women in the UK HRT study, increasing their risk of suicide, endometrial, ovarian and breast cancers.6 Transdermal HRT is not safe and increases the risk of breast cancer.7 Absorption of transdermal oestrogens is aided by dilatation of blood vessels, for example causing fainting in saunas after exercise. Transdermal oestrogens can upset liver function, without “hepatic first pass metabolism”. Oestrogens lower zinc and raise copper levels, which impairs liver clearance of carcinogens.8,9 Phytoestrogens act like oestrogens in any dose sufficient to have clinical effects and can cause endometrial hyperplasia. Taking sex hormones lowers endogenous production, which is how hormonal contraceptives work. Lower levels of endogenous sex steroid hormones, including testosterone and DHEA (dehydroepiandrosterone), in diseases are usually due to mineral deficiencies which can impair hormone production and the activities of hundreds of enzymes. Taking steroid sex hormone can make underlying mineral deficiencies more severe. Men have lower sweat zinc levels than women which may partly explain their higher risk of stroke, all else being equal.9 1 Bath PMW. Gray LG. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ, doi:10.1136/bmj.38331.655347.8F (published 7 January 2005) 2 Grant ECG. Relation between headaches from oral contraceptives and development of endometrial arterioles. BMJ 1968; 3: 402-5. 3 Grant ECG. Venous effects of oral contraceptives. BMJ 1969; 2: 73- 7. 4 Grant ECG. Increases in breast cancer incidence http://bmj.com/cgi/eletters/328/7445/921#55298, 1 Apr 2004 5 Grant ECG. Re: Rapid Responses; Authors' reply. http://bmj.com/cgi/eletters/328/7445/921#55843, 6 Apr 2004 6 Hunt K, Vessey M, McPherson K, Coleman M. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy.Br J Obstet Gynae 1987: 94: 620-635. 7 Beral V, Banks E, Reeves G, Bull D, on behalf of the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy: the Million Women Study. Lancet 2003; 362: 1331. 8 Capel ID, Grant ECG, Dorrell HM, Pinnock MH, Clifford Rose F, Williams DC. Disturbed liver function in migraine patients. Headache 1979;19:270-272. 9 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance. J Nutr Environ Med 1998; 8: 105- 116. Competing interests: None declared |
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David A Hanley, Professor Department of Medicine, University iof Calgary, Calgary Alberta, Canada
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I certainly agree with the conclusion that postmenopausal estrogen +/- progestin therapy (HRT) should not be recommended for the primary or secondary prevention of stroke, and accept the findings of this meta-analysis as supporting a true increase in risk of non-fatal stroke for users of HRT. However, the meta-analysis derives most of its strength from the Women's Health Initiative (WHI) studies, and lists the subjects in the WHI as "healthy". The participants in the WHI HRT trials may have met a crude definition of health, but they were obviously at increased risk for cardiovascular events including stroke, as evidenced by the following: 1. The participants, on average, were seriously overweight, and over 1/3 met the BMI > 30 criterion for obesity. In the Estrogen alone arm, almost half of the subjects met this criterion. 2. Over 1/3 of the subjects had hypertension requiring medical therapy. Again, in the Estrogen alone arm, the women were at even greater risk - almost half of the subjects were on antihypertensive therapies. (1,2) While the increased risk of non-fatal stroke in HRT users is undoubtedly real, the absolute risk is small. The risk may still be overestimated in the meta-analysis, as it has mainly been demonstrated in individuals who were at higher risk for these events. Further, by design (and in retrospect), the subjects in the WHI HRT studies had no obvious indication for the therapy in the first place. It should be noted that potential subjects were excluded from the WHI studies of HRT if they had the major recognized indication for HRT (menopausal symptoms), and although prior HRT use was permissible, potential subjects were also excluded if they had been treated with HRT for osteoporotic fracture (3). This leads to a point that seems to be ignored or downplayed in discussions of the WHI: although the subjects were likely at higher than average risk for cardiovascular disease or stroke, they were also likely at very low risk for osteoporosis, based on their overweight status (4) and the above exclusion criteria. In spite of this, there was a reduced incidence of hip fracture in both the estrogen and estrogen plus progestin arms of the WHI. A stroke is often a medical catastrophe, but so is a hip fracture. Vertebral fractures were also reduced by HRT in the WHI, and vertebral fractures have been associated with increased morbidity and mortality (5). Given the devastating effects of a hip fracture in terms of individual disability and cost to society, and the growing awareness of the clinical importance of vertebral fractures, it would be interesting to see an analysis comparing the individual and societal costs of disability due to the increased risk of non-fatal strokes associated with HRT, versus the benefit of preventing osteoporotic fractures with HRT. References: 1. Writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333. 2. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701-12. 3. The Women's Health Initiative Study Group, Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials 1998;19:61-107. 4. van der Voort DJ, Geusens PP, Dinant GJ. Risk factors for osteoporosis related to their outcome: fractures. Osteoporos Int 2001;12:630-8. 5. Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet 1999;353:878-82. Competing interests: On 2 or 3 occasions since 1980, but not since the publication of the WHI results, I have received an honorarium from Wyeth Ayerst for speaking to physicians about osteoporosis |
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Sergio Stagnaro, Specialist in Blood, Gastrointestinal, and Metabolic Diseases. Researcher in Biophysical Semeiotics Via Erasmo Piaggio 23/8 16037 Riva Trigoso (Genova) Italy
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Sir, In the latest issue the BMJ deals with an interesting argument, stroke prevention, unfortunately nowadays difficult to resolve, due to doctors' present lack of information about cerebral microcirculatory bed-side evaluation. From a systematic review of randomised controlled trials identified from the Cochrane Library, Embase, and Medline; reviews; and reference lists of relevant papers, Bath PMW and Gray LG. conclude that “Hormone replacement therapy was associated with an increased risk of stroke, particularly of ischaemic type. Among subjects who had a stroke, those taking hormone replacement therapy seemed to have a worse outcome” (1). In my opinion, however, in a “personalized” stroke prevention, as well as in all other similar prevention procedures, there is a fundamental bias at starting point, typical of EBM: we dare speak of “global” prevention in individuals not rationally selected, independently from the real efficaciousness of diet, according to its etymological sense, and/or drugs therapy (e.g., HRT), but especially ignoring or unfortunately overlooking the actual existence of different biophysical-semeiotic “constitutions”, which affect exclusively some individuals, but surely not all, because not all subjects are created equal: “diabetic constitution” (3), or "hypertensive, dyslipidemic, arteriosclerotic, constitution”, a.s.o.(2) (See also the web site, HONCode ID N° 233736, www.semeioticabiofisica.it). First of all, doctors around the world must know that, in healthy, the microcirculatory bed shows autonomous and autoctonus, non-linear dynamics in both small arteries and arterioles (vasomotility), according to Hammersen, as well as in nutitional capillaries and post-capillaries venules (vasomotion) (2-6). By contrast, in individuals apparently healthy, but “at real risk” for well-defined disorders, such as stroke, microcirculation deterministic chaos is already significantly and characteristically impaired since birth in well-defined biological systems, obviously in a “silent” form, from clinical view- point, exclusively in those tissues, which “can” in the future be involved by precise diseases. Interestingly, in these biological systems, the always present mitochondrial cytopatology - Congenital Acidosis Enzyme- Metabolic Histangiopathy = conditio sine qua non of all common and serious human diseases) (2-6) is particularly severe. Ultimately, in diseased organs such “chaotic-deterministic” microcirculatory behaviour is almost completely lost and consequently local parenchymal oxygenation appears to be worsened, reduced (techically speaking, microcirculatory activation shows the pathological III type, dissociated), due to a large variety of factors, when evaluated at the bed side by Biophysical Semeiotics (See also www.semeioticabiofisica.it/microangiologia.it. As a consequence, to underlie the value of Single Patient Based Medicine, only in some but not all women, HRT acts to ameliorate blood-flow in the brain, kidney, heart, bone, a.s.o., tissue-microvasculare unit, beside their more known action on the large arteries. 1) Bath PMW. Gray LG. Association between hormone replacement therapy and subsequent stroke: a meta-analysis BMJ 2005;330:342 (12 February), doi:10.1136/bmj.38331.655347.8F (published 7 January 2005) 2) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico- Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Ediz. Travel Factory, Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm 3) Stagnaro S., West PJ., Hu FB., Manson JE., Willett WC. Diet and Risk of Type 2 Diabetes. N Engl J Med. 2002 Jan 24;346(4):297-298. [MEDLINE]. 4) Stagnaro-Neri M., Moscatelli G., Stagnaro S., Biophysical Semeiotics: deterministic Chaos and biological Systems. Gazz. Med. It. Arch. Sc. Med. 155, 125,1996. 5) Stagnaro-Neri M., Stagnaro S., Deterministic chaotic biological system: the microcirculatoory bed. Theoretical and practical aspects. Gazz. Med. It. – Arch. Sc. Med. 153, 99, 1994. 6) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Una Patologia Mitocondriale Ignorata. Gazz Med. It. – Arch. Sci. Med. 144, 423, (Infotrieve) Competing interests: None declared |
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Michelle C Bird, retired consul;tant psychiatrist not working (retired) Formerly at Roundway Hospital, Devizes, SN10 (no longer exists)
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HRT is risky for postmenopausal women. What advice should be given to those who have had gender reassignment surgery (male to female) since most continue taking oestrogens in order to preserve their valued female secondary sexual development? Is there an alternative? Competing interests: None declared |
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James M. Howard, independent biologist Fayetteville, Arkansas, U.S.A.
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The following is a treatise which I wrote yesterday regarding low DHEA as a cause of thrombosis. It certainly applies here as hormone replacement therapy reduces DHEA and is a cause of thromobosis. (For those who only read a couple of lines, other connections of low DHEA and thromobosis are inlcuded.) Thrombosis May Be Caused by Low DHEA Copyright 2005, James Michael Howard,Fayetteville,Arkansas, U.S.A. It is my hypothesis that thrombogenesis results from low levels of dehydroepiandrosterone (DHEA). DHEA naturally begins to decline around age twenty, reaching very low levels in old age. Thrombosis is "markedly higher in elderly than in younger patients," (Arch Intern Med. 2004 Nov 8;164(20):2260-5). Hormone replacement therapy and "estrogen replacement therapy" both reduce DHEA (Metabolism. 2001 Apr;50(4):488-93). Thrombosis is increased by "estrogen plus progestin" hormone therapy (JAMA. 2004 Oct 6;292(13):1573-80). Extended use of oral contraceptives increases risk of thrombosis (Clin Appl Thromb Hemost. 2004 Jul;10(3):259- 63). DHEA is also low in the very young. Also, testosterone may reduce DHEA by increasing DHEAS. DHEAS is the background source of DHEA, from which DHEA is converted. In some circumstances such as the effect of testosterone on DHEAS, this may indicate that DHEA levels are reduced when DHEAS increases. These effects of low DHEA are seen this report: "Pulmonary embolism (PE), deep venous thrombosis (DVT), and the combination were not rare in pediatric patients in the United States from 1979 to 2001. They were more frequent in infants 0 to 1 year of age and in teenagers 15 to 17 years of age than in children 2 to 14 years of age. Pregnancies doubled the rate of DVT in teenage girls." (J Pediatr. 2004 Oct;145(4):563-5). Thrombosis may be increased in infants because of low DHEA. Once puberty occurs, in boys and girls, testosterone increases and reduces DHEA levels and may account for the increase in the teenagers who have reached puberty compared to children "2 to 14 years of age." Pregnancy is a time when maternal DHEA is shared between the mother and the fetus. This would reduce maternal DHEA and increase the risk of thrombosis. It is known that thrombosis is increased in pregnancy and "may be higher in the second and third trimesters." (Am J Obstet Gynecol. 2004 Aug;191(2):412-24). If fetal growth is dependent upon maternal DHEA, then thrombosis should increase with fetal growth from the first through the third trimester and then decline with time postpartum. This has been found: "The deep vein thrombosis event rate during the first trimester was 21.9 percent (95 percent CI 17.4 to 27.3), 33.7 percent (95 percent CI 28.1 to 39.8) during the second trimester, and 47.6 percent (95 percent CI 39.2 to 56.2) for the third trimester. Heterogeneity testing was not significant. Nine studies compared deep vein thrombosis events between the antepartum and puerperium periods, with 65.5 percent (95 percent CI 58.1 to 72.1) arising during pregnancy, and 34.5 percent (95 percent CI 27.9 to 41.9) postpartum (P = .08, not heterogeneous). Using these figures, the estimated relative distribution of 100 deep vein thrombosis events during pregnancy and the puerperium would be 0.23 per day during pregnancy, and 0.82 per day in the postpartum period. During pregnancy and the puerperium, deep vein thrombosis is more likely to arise in the left leg. More than half of all deep vein thromboses during pregnancy occur during the first and second trimesters. Furthermore, during the puerperium, the risk of developing deep vein thrombosis is significantly higher than antepartum." (Obstet Gynecol Surv. 1999 Apr;54(4):265-71). It is my hypothesis that low DHEA may cause cancer. DHEA is low in the elderly and cancer occurs more often in the elderly. Thrombosis is often found with cancer and increased with metastatic disease (J Thromb Haemost. 2004 Oct;2(10):1760-5). I suggest that once started, cancer is able to use available DHEA for growth at the expense of the host, thereby reducing DHEA overall. Therefore, metastasis may further decrease DHEA levels and further increase thrombosis. Low DHEA has been connected with increased thrombosis in some form in the past (Acta Chir Scand. 1985;151(6):515-9). Cortisol, which I suggest evolved to counteract DHEA, may participate in thrombosis formation. I suggest that the major cause of thrombosis is low dehydroepiandrosterone. Competing interests: None declared |
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Ellen C G Grant, Physician and medical gynaecologist Kingston-upon-Thames, Kt2 7JU,UK
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HRT causes zinc deficiency and zinc deficiency reduces endogenous steroid hormone production, including DHEA.1 It is zinc deficiency which impairs the function of hundreds of enzymes and is a common underlying cause of numerous illnesses, including vascular diseases, cancers and mental illnesses. 1 Grant ECG. Schizophrenics need zinc and not DHEA or testosterone supplements. http://bmj.com/cgi/eletters/330/7484/158#95066,1 Feb 2005 Competing interests: None declared |
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Dr. Herbert H. Nehrlich, Private Practice Bribie Island, Australia 4507
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Dr. Howard seems a trifle infatuated with DHEA. Maternal lack of it may be involved in Schizophrenia and HRT may lead to strokes by way of reducing DHEA. I think this would be one more reason to encourage people to eat plenty of animal fats, make sure their cholesterol production and intake are not compromised in any way.... Could someone elaborate on the connection between DHEA and statin use? Perhaps there is a way to stop that insanity! Competing interests: None declared |
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James M. Howard, independent biologist Fayetteville, Arkansas, U.S.A.
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Apparently you are wrong: HRT produces a "beneficial effect of HRT on serum levels of trace elements... ;" see citation below. Clin Exp Obstet Gynecol. 2003;30(1):32-4 Trace elements and vitamin levels in menopausal women receiving hormone replacement therapy. Meram I, Balat O, Tamer L, Ugur MG. Department of Biochemistry, Medical Faculty, University of Gaziantep, Turkey. Trace elements are extremely important in human metabolism, growth, and tissue repair. The risk of nutritional disturbances, in particular, vitamin and trace element deficiencies, are striking during menopause. The aim of this longitudinal study was to evaluate the effect of estrogen treatment on serum levels of copper, zinc, magnesium, calcium, vitamin E, and vitamin A in menopausal women. Thirty-eight menopausal women were included in the study, and were administered a continuous hormone replacement therapy (HRT) of 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA). Blood samples were obtained before and six months after HRT. There was a statistically significant difference between levels of serum copper, zinc, magnesium, calcium, vitamin E and vitamin A before and after HRT (p < 0.001). In conclusion we observed a beneficial effect of HRT on serum levels of trace elements, vitamin A, and vitamin E in addition to the well known other benefits. Competing interests: None declared |
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Ellen C G Grant, Physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU
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John Howard, who advocates use of androgenic DHEA, writes I am wrong to know that exogenous steroid use can cause zinc deficiency. He cites a Turkish study of 38 women which claimed a beneficial effect of progesterone-dominant HRT on serum levels of trace minerals and also “well known other benefits”.1 The benefits of HRT are so well established that the world’s major HRT studies have been terminated early because of increases in vascular diseases and breast and endometrial cancers. The HABITS study found (hormonal replacement therapy after breast cancer-is it safe?) trial was terminated after 2 years because 28 patients, mostly current HRT users, had new breast-cancer events, compared with 5 non users.2 The MWS found a significant 45% increased relative risk of incident invasive breast cancer in current users of the synthetic steroid tibolone which has progestogenic, androgenic and oestrogenic activities.3 The most important mineral abnormalities caused by exogenous progesterone and oestrogen hormone use are lowering zinc and elevating copper levels, as first reported in 1968.4 I have confirmed this fundamental finding in numerous patients since the 1970s. Abnormally high copper levels in my patients are invariably due to exogenous hormone use, except for occasional acute infections. Since the start of the London oral contraceptive trials in the1960s, very few women consulting me have never used hormones. Often past users have residual zinc deficiency or copper store deficiencies after stopping OCs or HRT because of side- effects. In 1998 I reported the results of 3 groups of patients tested at Biolab Medical Unit in London.5 Current hormone takers had significantly higher copper levels in sweat, serum and hair compared with either men or past hormone takers (all significant at p < 0.0001). Among hormone takers abnormally high copper values were found in 90% of sweat samples, 80% of serum samples and 60% of hair samples. Hormone takers and past hormone takers had lower serum zinc levels than men (p< 0.001). The mean sweat zinc value for men was at the lower end of the male reference range among men who seemed healthy but were accompanying their partners for preconception care. The mean sweat zinc for the women was below the female reference range and all were or had been exposed to exogenous hormones. There was little or no overlap in sweat, serum or hair in copper/zinc ratios in the three groups, with current hormone takers having the highest copper/zinc ratios. We had previously found that an abnormally high copper/zinc ratio related to abnormal liver clearance of carcinogens, like benzpyrenes, which helps to explain the adverse synergistic effects of OCs, HRT and smoking.6 Furthermore, John McLaren-Howard’s nutritional osteoporosis profile results found that among women with osteoporosis, all those taking HRT had abnormally high serum copper levels.7 HRT users also had significantly lower white cell zinc, red cell magnesium, lower serum bone specific alkaline phosphatase (ALP) concentrations and higher mean serum phosphate levels, than other women with osteoporosis. HRT users also had lower serum manganese, tartrate-resistant acid phosphatase (a measure of bone resorption) and vitamin C levels, and higher urinary zinc and hydroxyproline excretion. These results suggested that exogenous steroid sex hormones are associated with a reduction in bone essential nutrients, especially zinc and magnesium, and reduced bone formation. A repletion study found the lowest serum bone ALP values in women on HRT with osteoporosis and a slower improvement with nutritional supplements. Since then, I have followed up individual women who have maintained excellent nutritional and bone formation profiles without HRT but with monitored nutritional supplementation. The international incidence of fractures has increased dramatically in women age 35-95 years in hormone prescribing countries.8 HRT beneficial claims have been mistaken, due to underestimations of risks caused by lack of never-ever takers of hormones for valid comparisons, which is also likely to apply to the WHI study results. Taking exogenous steroids lowers endogenous steroid production because of feed-back mechanisms but zinc deficiency also further impairs steroid production. 1 Meram I, Balat O, Tamer L, Ugur MG. Trace elements and vitamin levels in menopausal women receiving hormone replacement therapy. Clin Exp Obstet Gynecol. 2003; 30: 2-4. 2 Holmberg L, Anderson H; et al. HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363: 453- 5. 3 Beral V, Banks E, Reeves G, Bull D, on behalf of the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy: the Million Women Study. Lancet 2003; 362: 1331. 4 Halsted HJ, Hackly BM, Smith JC. Plasma zinc and copper in pregnancy and after oral contraceptives. Lancet 1968; 2: 278-83. 5 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance .J Nutr Environ Med 1998; 8: 105- 116. 6 Capel ID, Grant ECG, Dorrell HM, et al. Disturbed liver function in migraine patients. Headache 1979; 19: 270-272. 7 McLaren-Howard Grant ECG, Davies S. Hormone replacement therapy and osteoporosis: bone enzymes and nutrient imbalances. J Nutr Environ Med 1998; 8: 129-138. 8 Little K. Progestogens: thrombosis and osteoporosis. J Nutr Environ Med 1998; 8: 139- 152. Competing interests: None declared |
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James M. Howard, independent biologist Fayetteville, Arkansas, U.S.A.You
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You still have not provided support for your statement that zinc deficiency reduces DHEA production: "HRT causes zinc deficiency and zinc deficiency reduces endogenous steroid hormone production, including DHEA." Now, I agree that HRT has been connected with a bunch of very negative effects. Again, I suggest the reason is due to reduction of DHEA by HRT. The citation, Clin Exp Obstet Gynecol. 2003;30(1):32-4, was simply to show that HRT does not reduce zinc, so HRT does not reduce DHEA by reducing zinc. Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU
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John Howard’s vigorous advocacy of dehydroepiandrosterone (DHEA) supplements does not seem to be impeded by actually testing for zinc deficiency. He chooses to ignore the evidence detailed in previous responses that hormonal contraceptives and HRT cause zinc deficiency and therefore more risk of headaches and strokes. I have included biochemical studies co-authored by me during 35 years of analysing the mineral status in patients.1-3 In my experience, women with post-contraceptive (progestogen/oestrogen) amenorrheoa and anovulation usually regain normal ovarian function when zinc and magnesium and other essential nutrient deficiencies are repleted and become headaches-free. Zinc deficiency has a direct action on steroidogenesis in gonads and in adrenal glands.4,5 In vitro acute stimulation by hCG on testicular tissue preparation obtained from marginal zinc deficient (MZD) rats resulted in much less androgen production (sum of androstenedione, testosterone, and androstanediol), 72.4%, p < .001, and a marked decrease in sperm counts (by 22.9%, p < .05) compared with controls compared with controls. Severe zinc deficient (SZD) showed the greatest decrease and were asospermic.6 In zinc-deficient rats, testosterone supplements inhibited endogenous synthesis of testosterone and caused further atrophy of testes.7 Dietary zinc restriction in normal young men significantly decreased serum testosterone concentrations after 20 weeks of zinc restriction (39.9 versus 10.6 nmol/L, p = 0.005). Zinc supplementation of marginally zinc- deficient normal elderly men for six months resulted in an increase in serum testosterone from 8.3 to 16.0 nmol/L (p = 0.02).8 It seems unethical to promote androgenic steroid DHEA supplements without ensuring that such use is not increasing zinc deficiency, an important cause of decreased endogenous steroid hormone production in the first place. I notice the massive internet advertising of DHEA supplements often includes exhortations to add unmonitored zinc supplements, which could cause copper deficiency. 1 Grant ECG. HRT causes thrombosis: HRT reduces DHEA by causing zinc deficiency.http://bmj.com/cgi/eletters/330/7487/342#96685, 13 Feb 20057 2 Grant ECG. Schizophrenics need zinc and not DHEA or testosterone supplements. http://bmj.com/cgi/eletters/330/7484/158#95066, 1 Feb 2005 3 Grant ECG. Does zinc deficiency in early foetal life cause schizophrenia? http://bmj.com/cgi/eletters/330/7484/158#95339, 3 Feb 2005 4 Flynn A, Pories WJ, Strain WH, Hill OA. Zinc deficiency with altered adrenocortical function and its relation to delayed healing. Lancet 1973; 1: 789-90. 5 Quarterman J. The effect of zinc deficiency on the activity of the adrenal glands. Proc Nutr Soc. 1972; 31: 74A-75A. 6 Hamdi SA, Nassif OI, Ardawi MS. Effect of marginal or severe dietary zinc deficiency on testicular development and functions of the rat. Arch Androl. 1997; 38(3):243-53. 7 Ai H, Chen J, He S. The effects of zinc deficiency and testosterone supplement on testosterone synthesis and skeletal muscle of rats. Wei Sheng Yan Jiu. 1997;26 (3):211-5. 8 Prasad AS, Mantzoros CS, Beck FW, Hess JW, Brewer GJ. Zinc status and serum testosterone levels of healthy adults. Nutrition 1996; 12: 344- 8. Competing interests: None declared |
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Robert L Cheifitz, Obstetrician & Gynaecologist 1141 Chris Barnard Memorial Hospital, Cape Town, RSA.
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Since 1998 generally accepted contraindications for starting hormone replacement therapy (HRT) include longer than 5 or maximum 10 years since the menopause and exclusion of previous cardiovascular or cerebro-vascular disease. This excludes most of the studies in figure 2 of the Bath/Gray meta- analysis including the overall results from the two Womens Health Initiative Trials (WHI)(2)(W28)(3)(W26), average age over 63 years, and negates the statement "These results seem to be driven by the large WHI trial". None of the studies Pepi (w7) Mosekilde (w14) Arrhenbrecht (w22) Giske (w24) or Wessertheil (2) is statistically significant by 95% Confidence Interval, since their 95% confidence limits varied from a lower of .01 to 0.77 to the upper of 2.79 to 18.42. The HR for the entire cohort of the estrogen arm (W28)(3) is 1.41 with a nominal 95% CI of 1.07- 1.85 and an adjusted CI of 0.86 to 2.31. The statement in the Bath/Gray Meta-analysis introduction that a meta -analysis by Paganini-Hill (4) "have suggested that HRT may increase risk of stroke especially ischaemic stroke" is not in accordance with the conclusion of Paganini-Hill et al "None the less the preponderance of evidence suggests that HRT does not increase stroke risk" and "estrogen may prevent the most lethal form of stroke or may improve survival" (4). Eight studies looked at ischaemic stroke with 6 showing no effect of ever or current use. The Framingham heart study had a relative risk (RR) of 2.6 but also an elevated risk of coronary heart disease. The Nurses Health Study had a RR of 1.3 for current use which included a RR of 2.0 for 1.25mg use Conjugated Equine Estrogen (CEE), 1.4 for 0.625mg CEE and 0.4 for 0.3mg CEE. References 1. Bath PMW and Gray LJ et al. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ, 2005:doe:10:1136/bmj.38331.655347.8F. 2. Wassertheil-Smoller S et al. Effects of Estrogen plus progestin in postmenopausal women. A women's health initiative randomized trial. JAMA 2003;289:2673-81 3. The Womens Health Initiative Steering Committee. Effects of Conjugated Equine Estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701-12 4. Paganini-Hill A et al. Hormone replacement therapy and stroke: risk, protection or no effect? Maturitas 2001;38:243-61 Competing interests: sponsored by HRT manufacturers to attend congresses; lecturer on appropriate HRT. |
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Dr. Herbert H. Nehrlich, Private Practice Bribie Island, Australia 4507
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....."in addition to the other well known benefits..." Sounds like this study was rather small and the results somewhat unconvincing. However, the authors appear smitten with "the other benefits" of HRT. I was under the impression that those other benefits had been somewhat discredited. It is interesting how, in this day and age, people undertake studies the eventual results of which appear to be foregone conclusions. Far be it from me to accuse anyone of letting expectations cloud their judgment, but it is a thought. To this observer, it seems very clear that Hormone Replacement Therapy, regardless of modifications and application, is of no benefit to women and there is a fair chance that it will do great harm. We will come to the same crossroads with statin therapy, I do not think that statins will be in use in five years. You can fool all of the poeple some of the time, but not all of the people all of the time. Competing interests: None declared |
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James M. Howard, independent biologist Fayetteville, Arkansas, U.S.A.
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"Thyroid and adrenal functions do not appear to change as a result of zinc deficiency." Spec Top Endocrinol Metab. 1985;7:45-76 Competing interests: None declared |
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Ellen C G Grant, physician and medical gyanecologist Kingston-upon-Thames. KT2 7JU, UK
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The re-emergence of the old chestnut, that adverse effects of HRT (progesterones and oestrogens) depends on the age since the menopause, betrays a lack of understanding of how hormones act. I observed adverse changes in endometrial blood vessels, which matched increases in headaches, migraines and strokes, in previously healthy young women who volunteered to take these hormones as oral contraceptives in the early 1960s.1 What is the age of the menopause? Post-Pill amenorrhoea and anovulation at age 20 because of starting OCs at age 15? Hysterectomy and bilateral oophorectomy at age 30 because of OC-induced wide-spread endometriosis? Women with ovarian failure at age 40, due to years of tobacco smoking and Pill taking and who take further hormones as HRT, already have higher risks of vascular diseases. In the WHI combined HRT study concluded that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin.2 The intention-to-treat hazard ratio (HR) for ischemic stroke was 1.44 (95% CI, 1.09-1.90) which is statistically significant. As OCs and HRT cause hypertension, which is, or should be, a contra- indication to further hormone use. Only one in 5 strokes were therefore haemorrhagic. Small numbers in subgroups make statistically significant results less likely. The WHI studies underestimate risks because most women randomised to take either combined or oestrogen-only HRT, or placebos, had previously used these hormones as HRT or for contraception. Also in 1965 OCs were reported to cause cerebral insufficiency.3 In 1967 neurologists noticed that OCs also caused subarachnoid haemorrhages and in 1981 the RCGP OC study reported an increased risk of mortality of 4.0 (1.3-12.9) from this condition.4,5 The increased mortality risks were estimated to be 2.9 (1.3-6.4) for all cerebrovascular diseases and 5.6 (2.0-16.6) for all non-rheumatic heart disease and hypertension. How many times does the wheel have to be reinvented ? 1 Grant ECG. Relation between headaches from oral contraceptives and development of endometrial arterioles. Lancet 1965; 1: 1143-4. 2 Wassertheil-Smoller S et al. Effects of Estrogen plus progestin in postmenopausal women. A women's health initiative randomized trial. JAMA 2003;289:2673-81. 3 Illis L, Kocen RS, McDonald WI, Mondkar VP. Oral contraceptives and cerebral arterial occlusion. BMJ 1965; 2: 1164-66. 4 Bickerstaff ER, Holmes JM. Cerebral arterial insufficiency and oral contraceptives. Cerebral arterial insufficiency and oral contraceptives. BMJ 1967; 1: 726. 5 Royal College of General Practitioners’ Oral Contraception Study. Further analyses of mortality in oral contraceptive users. Lancet 1981; i: 541-546. Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU, UK
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Zinc deficiency impairs endogenous sex hormone productions, increases side-effects form OCs and HRT, impairs adrenal steroid hormone metabolism and also interferes with thyroid function. “Zinc deficiency and thyroid function” brings up 26 citations in PubMed. Arthur and Beckett’s review from the Rowan Research Institute at Aberdeen states that normal thyroid status is dependent on the presence of many trace elements for both the synthesis and metabolism of thyroid hormones. Iodine is most important as a component of the hormones, thyroxine and 3,3',5-tri-iodothyronine (T3) and iodine deficiency may affect approximately one billion people throughout the world. Selenium is essential for normal thyroid hormone metabolism being involved with selenium-containing iodothyronine de-iodinases that control the synthesis and degradation of the biologically active thyroid hormone, T3. The roles of iron, zinc and copper in the thyroid are less well defined but sub- or supraoptimal dietary intakes of all these elements can adversely affect thyroid hormone metabolism. Zimmermann and Kohrle write that coexisting deficiencies of iodine, iron, selenium, and zinc can impair thyroid function.2 Children who were zinc deficient in their sweat had normal range serum zinc levels, therefore seem to have more stable serum zinc homeostasis than adults.3 However, Bucci et al found that plasma zinc levels are commonly detected below the normal range in subjects with trisomy 21 (Down syndrome). Zinc deficiency also impairs immune response and growth rate but hypothyroidism is the most common endocrinological deficit. After months of zinc supplementation, TSH significantly decreased in treated hypozincemic children (4.48 versus 2.96 mUI/mL) and was no longer different to normozincemic children.4 Nishiyama et al found disabled patients with elevated levels of serum T3 showed an enhanced reaction of serum thyrotropin (TSH) after TRH injection. Nine of 13 patients had mild to moderate zinc deficiency evaluated by body zinc clearance and increased urinary zinc excretion. After oral supplementation of zinc sulphate for 12 months, levels of serum free T3 and T3 normalized, serum T3 decreased, and the TRH-induced TSH reaction normalized.5 As with HRT, progesterone and DHEA supplements, there is a huge internet promotion of thyroid extracts which are claimed to “treat” every imaginable symptom. Abnormal hormone levels signal the need for investigations of basic causes such as zinc, copper, magnesium, selenium, glutathione or iodine deficiencies. 1 Arthur JR, Beckett GJ. Thyroid function. Br Med Bull. 1999; 55: 658 -68. 2 Zimmermann MB, Kohrle J. The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health. Thyroid. 2002; 12: 867-78. 3 Grant ECG, Howard JM, Davies S,Chasty H,Hornsby B, Galbraith J. Zinc deficiency in children with dyslexia: concentrations of zinc and other minerals in sweat and hair. BMJ 1989;296:607-9. 4 Bucci I, Napolitano G, Giuliani C, et al. Zinc sulfate supplementation improves thyroid function in hypozincemic Down children. Biol Trace Elem Res. 1999; 67: 257-68. 5 Nishiyama S, Futagoishi-Suginohara Y, Matsukura M, et al. Zinc supplementation alters thyroid hormone metabolism in disabled patients with zinc deficiency. J Am Col Nutr. 1994; 13: 62-7. Competing interests: None declared |
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Nina K. Edge, Couturier/Designer Sweetbriar, Beltie Road, TORPHINS, Aberdeenshire, AB31 4JT
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Two years ago (2003) as a 53-year-old slim fit businesswoman who had experienced an early menopause, I found myself during an HRT review at the receiving end of the HERS trial “Women had died”! Women who use HRT are advised to be informed. Even at that time there were conflicting opinions. This led me to read research, my computer now holds over 20Gb on the subject which has included reading the full version of the Million Women Study (MWS) the day after release and the recent Royal College of Gynaecologists (RCOG) book. The morning of 7th January I was alerted to an HRT item on GMTV (Bath & Gray paper - 1). A Doctor commenting on the latest paper informed viewers-- it was drawn from a wide range of studies, it could not be criticised in the way some experts had criticised the American studies, ie. many of the women obese and much older than women using HRT in the UK. Later that day I read the paper, I was astonished to find: · 59.32% Drawn from the 2 WHI HRT arms; not immediately obvious as one of the WHI arms is referred to as “Wasserheil et Al” (2)(3) · 16.21% the HERS trial this appears as “Simon et Al” women mean age 68, BMI mean 29 CEO/MPA with pre-existing cardio-vascular disease (4) · 11.31% Viscoli – 1Mg oral Oestradiol – women mean age 71 HRT following stroke (5) · 6.24% Veterans Co-operative – all men, age unknown – with cerebrovascular disease – 1966 large men, large dose? 93% of this meta-analysis has been drawn from these 5 studies, 3 of these papers are unquestionably secondary prevention. The WHI has received critical comment by many menopause specialists questioning its presentation as a Primary Prevention “healthy” study. Quoting from American Association of Reproductive Medicine (ASRM) “Drawing from several WHI reports, the doctors calculated that WHI participants in the 50-59 year-old age group were an average of 12 years past menopause. They also noted that there were only 574 moderately to severely symptomatic women in the 50 to 54 year-old age group, half of them receiving hormone therapy, half placebos. Based on the small number of women studied in this age group, it is not possible to conclude that, for those women in the menopausal transition, hormone therapy has no cardioprotective effect” (6). Recruitment was spread from 50-79 yrs which must have led to some women being into their 80s when the trial was terminated early. The level of obesity 36% BMI>30, even higher on the Oestrogen only arm. To a layperson this appears extraordinary. 34% of participants’ were hypertensive on medication and an even a higher percentage on the Oestrogen only arm fell into this category. The UK public are bombarded with information advising them that obesity and hypertension lead to strokes, heart attacks, DVT and also breast cancer. Many women believe obesity and hypertension are a contra-indication for use of HRT. Most women on HRT receive regular BP checks. The Bath/Gray meta-analysis is dominated by an · 86.07% usage of Conjugated Equine Oestrogens (CEO) used with Medroxyprogesterone acetate (MPA) when uterus present. Numbers on trials total 32941 (including some men). This is one of the earliest HRTs, which appears to be considered by some Doctors in the UK to be less desirable. · 13.93% - trialed Oestradiol and some variations (numbers 3771) · The four transdermal trials contributed no stroke events The Authors correctly conclude that HRT cannot be recommended for Secondary prevention of stroke (note – the authors suggest possible reasons for results - high doses and method of delivery). Is this meta- analysis a fair analysis of Primary Prevention treatments for younger women commencing Oestradiol at the time of the menopausal transition? HRT in the UK is prescribed for menopausal symptoms and prevention of osteoporosis. Is it prescribed as a prevention treatment for stroke to women considered to be at increased risk? After reading the paper, the day of release, I emailed the author and did receive an immediate interesting response from Professor Bath. His final comments, “future research will address whether alternative doses or forms of oestrogen, or delivery (transdermal) are better”. Over the last two years after reading many papers, I came across the IMS position statement (7) and was grateful to find it was in line with my thinking. Hopefully further research will commence using HRT not HT as used on the WHI and HERS trials etc using other more modern treatments. I also have come across a paper (8) "Looking for the Pony in the HERS Trial" offering more or less the opposite view to the IMS. On balance unless the premise that there is deterioration to the heart and bones beyond menopause caused by lowering levels of Oestrogen is fundamentally flawed - it seems reasonable to hypothesise that replicating these hormones that have been reduced might be beneficial. This begs the question can this be done effectively and safely? There is evidence to suggest HRT commenced at the menopause is beneficial (9)(10) and may not produce the same results as the WHI. Many women in there 40s and 50s are working hard in a competitive world to fulfil career commitments etc. so why should women be frightened off HRT by what appears to be an amplification of the risks that may lead to their using unproven treatments. Ms Nina Edge 1. Bath PMW. Gray LG. Association between hormone replacement therapy and subsequent stroke: a meta-analysis BMJ 2005;330:342 (12 February), doi:10.1136/bmj.38331.655347.8F (published 7 January 2005) 2. Writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333. 3. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701-12. 4. Simon JA, Hsia J, Cauley JA, Richards CL, Harris F, Fong J, et al. Postmenopausal hormone replacement therapy and risk of stroke. The heart and estrogen-progestin replacement study (HERS). Circulation 2001;103:638- 42. 5. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243-9. 6. ASRM Bulletin Volume 6, Number 32 June 23, 2004 Highlights from Fertility & Sterility Volume 81, Number 6, June 2004 7. International Menopause Society statement 2004 http://www.imsociety.org 8. Barrett-Connor, E. (2002). Looking for the Pony in the HERS data. Circulation 105:902-903 9. Salpeter SR, Walsh JM, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med 2004;19:791-804. 10. Lobo RA. Evaluation of cardiovascular event rates with hormone therapy in healthy, early postmenopausal women: results from two large clinical trials. Arch Intern Med 2004;64:482–4 Competing interests: None declared |
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Christine B Singh, family physician/women's health scholar Women's College Hospital Toronto Canada
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Women take HRT to function better in their day to day lives so that their sleep, mood and other basic health building blocks are better. The WHI trial and other articles such as this one do well to warn women of possible effects, however I would make the criticsm that the context is rarely explained in brief headlines, leaving our patients anxious and confused. And all this on top of terrible hot flashes. Also important to note that not all cultures have "menopause" as a concept like the "western biomedical' model. This is one area of life where we might be better to leave more medical research aside and promote healthy living for our patients. Let them choose therapy for a short term if they wish and understand what they stand to gain or lose. And by the way, why was one of the studies exclusively with male patients.... did I misread or does there seem to be something a bit funny about that. Thanks. Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU
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How on earth can women “choose therapy for a short term if they wish and understand what they stand to gain or lose” when leading international experts are surprised that, “Breast cancer risk increases with shorter use than previous evidence suggested”?1 Both the WHI and the MWS confirmed increases in breast cancer within the first 12 months of current use of HRT including doubling of abnormal mammograms.2 In the MWS, up to a year’s of most HRT formulations increased breast cancer risks by 45% - 63%. Any current use doubled the risk of breast cancer and increased the risk of breast cancer being fatal by at least a 22%. The HABITS (hormonal replacement therapy after breast cancer-is it safe?) trial was terminated after 2 years because 28 patients, mostly current HRT users, had new breast-cancer events, compared with 5 non users.3 What else causes more than 5 times more cancer in such a short time? The WHI combined HRT study confirmed no clinically meaningful effect on health-related quality of life.4 Both combined and oestrogen-only HRT studies were terminated early because of unacceptable increases in potentially fatal diseases including breast cancer, vascular diseases and dementia. “Terrible hot flashes” are a sign of vascular over-reactivity, usually due to increased reactions to common foods and chemicals, unmasked by falling hormone levels, even from very high concentrations as in tachyphylaxsis. Like migraine, which is also increased in HRT users, hot flushes can be easily and safely prevented by correction of immune system defects due to nutritional deficiencies, along with low allergy diets, and avoiding smoking and alcohol. 5,6 Flawed epidemiological studies, like the Salpeter et al meta- analysis, have helped HRT promotions to continue.7-9 Women do not need to be fooled any longer by the false claims that the menopause is a disease entity. 1 Beral V, Banks E, Reeves G, Bull D, on behalf of the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy: the Million Women Study. Lancet 2003; 362: 1331. 2 Chlebowski RT, Hendrix SL, Langer RD et al, for the WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women’s Health Initiative randomised trial. JAMA 2003; 289: 3243-53. 3 Holmberg L, Anderson H; et al. HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363: 453- 5. 4 Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003; 348: 1839 -54. 5 Grant ECG. Grant ECG. Food allergies and migraine. Lancet 1979; 1: 966-69. 6 Grant ECG. Food allergy and migraine. Lancet 1979; 2: 358-59. 7 Grant ECG. Epidemiologists’ long-term underestimation of harm from hormones http://bmj.com/cgi/eletters/329/7456/2#65645, 3 Jul 2004 8 Grant ECG. Pill and HRT Epidemiologists http://bmj.com/cgi/eletters/329/7463/467#72387, 27 Aug 2004 9 Grant ECG. Re: Meta analyses and misleading claims about HRT mortality. http://bmj.com/cgi/eletters/329/7474/1093#85813, 17 Nov 2004 Competing interests: None declared |
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Victor A. Palmer, Medical Writer Saxthorpe Hall, Saxthorpe, Norfolk NR11 7DE
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Two months after publication of the Bath and Gray meta-analysis, perhaps it is time to reflect on what the paper itself and the responses to it add to our knowledge of the hazards and possible benefits of HRT. The answer must surely be very little: the slightly increased thrombotic tendency of any type of oestrogen therapy has been recognised for some years and is the reason why women with any history of, or predisposing factors for, thromboembolism are contra-indicated for either HRT or oral contraceptive therapy. Nevertheless these results have been seized upon once again by the anti-HRT brigades who are so concerned that women should be "fully informed" that they are quite happy to feed the tabloid press with scare stories (HRT doubles the risk of breast cancer AND strokes) with never a mention of relative risk, or of the proven benefits of HRT. As Mrs Edge's response demonstrates, women who are indeed FULLY informed are well able to make their own decisions and have only scorn for those who distort the facts in pursuit of their own agenda. (Dr Banks informed me in a reply to my rapid response to the MWS Personal Characteristics paper (1) that both the WHI and MWS had to be terminated due to the increased risk of breast cancer. I do not understand why a study of mammographic records would need to be terminated whatever its findings. Still, we should not let the facts get in the way of a good story!) However as the first respondent, Dr Burman, notes despite its title Prof Bath's meta-analysis includes few studies that fall under the heading of physiological sex hormone therapy. Most are secondary intervention studies that assess the effects of hormonal therapy on a variety of conditions: UTI, RA, IHD, MI and a range of thrombo-embolic conditions, including secondary prevention of stroke! The classification of the patients in the two legs of the WHI (which together make up almost 60% of the Bath meta-analsis)as "healthy" is a matter of some debate. Let us suppose for a moment that Prof Bath's study had shown a small but significant decrease in strokes - and had been sponsored by a pharmaceutical company. How would the anti-HRT lobby have responded? Might I Suggest that the would have "rubbished" it by noting that: -three of the analysed studies are almost 40 years old -one of the studies is exclusively in men, two others include,respectively, 63% and 75% men -the treaments are completely untypical of current HRT, at least in Europe ( over 80% of patients received equine oestrogens and in 50% this was in combination with MPA: the current British National Formulary lists 18 products suitable for women with a uterus, of these there is one CEO/MPA combination,one other product contains MPA and one contains CEO). - the mean age of the subjects is mid-60s, much older than actual candidates for "real" HRT (in 4 of the analysed studies mean age was >70 and in one >80). A final point: in her rapid response above, Dr Banks suggests that women cannot choose therapy for a short term because breast cancer risk increases much more rapidly than previously thought. She goes on to say that: "Both the WHI and the MWS confirmed increases in breast cancer within the first 12 months of current use of HRT including doubling of abnormal mammograms. In the MWS, up to a year's (sic) of most HRT formulations increased breast cancer risks by 45%-63%. Any current use doubled the risk of breast cancer and increased the risk of breast cancer being fatal by at least 22%." However the MWS also showed a great reduction in risk one year after discontinuation of HRT and a return to baseline within 5 years. The latest market data I have seen reports that HRT use peaked at 90 million prescriptions in the USA in 2002, falling,as a result of scare stories, to less than 60 million prescriptions in 2003 and continuing to fall in 2003. The situation in Europe paralleled that in the USA. I look forward to seeing evidence of this in a significant decrease in the incidence of, and mortality from, breast cancer when 2004 statistics become available. (1)Rapid responses to: Influence of personal characteristics...........in the Million Woman Study:cohort study. Banks E, Reeves G, Beral V et al. BMJ 2004;329:477 Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU, UK
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Victor Palmer quotes from my Rapid Response above his which was not written by the MWS author Emily Banks. Hormone promoters have long described hard scientific evidence as “scare stories”. Increases in thrombosis risks of 4-8 times are not slight for a major cause of death. What exactly are the proven benefits of HRT? Perhaps a male journalist can tell me what I have failed to confirm pathologically, immunologically or biochemically in any woman patient taking hormones for any reason over the last 45 years. In Chlebowski’s WHI paper estrogen plus progestin increased total (245 /185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P =.003) breast cancers compared with placebo.1 The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (P =.04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P =.04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001). This pattern which continued for the study duration. In the WHI studies nearly all the women in the placebo group had previously used hormones and some restarted HRT (?addicted) during the study, which would underestimate HRT- induced increases in cancers, vascular diseases and fractures. Progesterones also cause thrombosis although progesterone and oestrogen combinations cause most adverse vascular changes, as I first described in the 1960s. The warnings over increased thrombosis risk with newer progesterones led to falls in HRT use and there is evidence of a corresponding fall in breast cancer mortality.2 Oral contraceptive use 20 years earlier doubles the numbers of breast cancers with cyclin D1 overexpression.3 There is also evidence of cumulative effect of oral contraceptive use followed by HRT. When joint effects of longer term use of both agents were considered, subjects who reported use of oral contraceptives for 10 or more years and hormone replacement for 3 or more years had a relative risk of 3.2 (95% CI 1.4- 7.4) compared with nonusers of either preparation.4 By the 1990s the greatest increases in breast cancer incidences since the 1960s were in women who were likely to have taken oral contraceptives when younger and were currently taking HRT. The changes in breast cancer incidences, mostly huge increases, match the changes, mostly huge increases, in hormone use since 1962. 1 Chlebowski RT, Hendrix SL, Langer RD et al, for the WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women’s Health Initiative randomised trial. JAMA 2003; 289: 3243-53. 2 Grant ECG. Fall in HRT use would have reduced breast cancer mortality http://bmj.com/cgi/eletters/330/7485/220#94525, 27 Jan 2005 3 Terry MB, Gammon MD, Schoenberg JB, Brinton LA, et al. Oral contraceptive use and cyclin D1 overexpression in breast cancer among young women. Cancer Epidemiol Biomarkers Prev. 2002 ; 11: 1100-3. 4 Brinton LA, Brogan DR, Coates RJ, et al. Breast cancer risk among women under 55 years of age by joint effects of usage of oral contraceptives and hormone replacement therapy.Menopause. 1998 ; 5: 145- 51. Competing interests: None declared |
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Shah Ebrahim, Professor Department of Social Medicine, University of Bristol, Bristol BS8 2PR, UK, Debbie Lawlor, and George Davey Smith
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Bath and Gray consider that the reasons for the discrepancy between the observational studies and randomised trials of the effects of hormone replacement therapy are unclear.[1] Two explanations are relevant: first, that women who took part in the trials are different from those included in observational studies; and second, that the observational findings were confounded. Both selection effects and confounding deserve greater recognition by clinicians as they can produce powerful distorting effects. In a cohort of British women aged 60 to 79 years, we have shown that adverse socioeconomic indicators from across the life course were associated with use of HRT. Indicators of socioeconomic deprivation in childhood were associated with reduced odds of using HRT, and these associations were independent of adult socio-economic position, behavioural and physiological risk factors.[2] Since adverse social circumstances in childhood show a particularly strong association with risk of stroke in adulthood [3] these findings indicate that typical adjustments for confounders in most observational studies would still result in residual confounding of sufficient amount to produce spurious findings, despite influential assertions to the contrary.[4] As long ago as 1986, it was shown in observational studies that HRT was apparently equally protective against accidental and violent deaths as it was against death resulting from cardiovascular disease.[5] The lack of any biologically plausible link between HRT and external causes of death should have highlighted the likely role of residual confounding in explaining associations with either outcome. 1. Bath P, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ 2005;330:342 2. Lawlor DA, Davey Smith G, Ebrahim S. Socioeconomic position and hormone replacement therapy use: explaining the discrepancy in evidence from observational and randomised controlled trials. American Journal of Public Health 2004; 94: 2149-2154 3. Davey Smith G, Hart C, Blane D, Hole D. Adverse socioeconomic conditions in childhood and cause specific adult mortality: prospective observational study. BMJ 1998;316:1631-1635. 4. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63 5. Petitti DB, Perlman JA, Sidney S. Postmenopausal estrogen use and heart disease. N Engl J Med. 1986; 315:131–132 Competing interests: None declared |
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Ellen C G Grant, physician and medical gyanecologist Kingston-upon-Thames, KT2 7JU,UK
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Professor Ebrahim and colleagues confirm that HRT has been used mostly by higher social class women. Hormone prescribing has been a major part of the private practice of gynaecologists since the 1960s. Observational studies have underestimated relative risks of HRT-induced increases in mortality precisely because comparisons were made with mortality risks of women in the general population. Women in lower socio-economic classes have an increased risk of premature death. They are also more likely to smoke, which has a synergistic adverse effect with HRT. By the mid 1970s, because the absolute numbers of thrombosis cases increases with age, women over age 35 were advised not to use hormones. In my responses above I have referred to some of the reasons for HRT-induced increases in cancers, vascular and mental illnesses and immune dysfunction. Ebrahim and colleagues could study the publications on blood vessel and clotting changes, interferences with amine metabolism, especially lowering zinc and raising copper levels, B vitamin deficiencies and variations the activities of catechol-o-methyl-transferase and monoamine oxidase enzymes. In 1987 the UK HRT study, the authors acknowledged a “healthy volunteer” effect as “high risk” women, those deemed to have contraindications to HRT (perhaps because of illnesses due to past use of contraceptive hormones), would be less likely than others to be prescribed HRT.1 The authors considered that the selected nature of the populations might account for the low mortality ratios and low cardio-vascular morbidity in their study and those of Stampfer, Bush and Wilson. Also by study design, women with short or intermittent use (e.g. those with immediate adverse vascular and mental effects) were excluded from enrolment and therefore from mortality follow-up. Among 4544 women, enrolled at ages 45 -54 who had used HRT continuously for at least 12 months and were followed up for an average of 67 months, the relative risk of mortality from suicide or suspected suicide was 2.53 (95% C I 1.26- 4.54). Nevertheless, and regardless of the obvious reasons observational studies were underestimating HRT-induced mortality, “HRT halves mortality” became the rallying cry of hormone-promoters. Belief in misleading epidemiological evidence is ingrained. Meir Stamper and others at an HRT meeting in Milan in 1999 agreed that, in spite of lack of proof, the evidence was sufficiently strong to claim that HRT lowered the risk of coronary heart disease. I objected, saying that this claim to be published in the consensus statement of the meeting,2 was ignoring long established basic scientific facts. Even the alarming results from randomised double blind trials, which led to early terminations of large international trials, still underestimate the true scale of Pill and HRT disasters because few women now have never taken hormone and most control women are previous hormone users. From 1961 to 2005 I have been consulted by women of any age or socio-economic background who have had severe and frightening side-effects with one or two pills. Very wisely, these sensitive women often recognise warning symptoms even if their doctors don’t, and they choose not to return to clinics where the offending hormones were prescribed. 1 Hunt K, Vessey M, McPherson K, Coleman M. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Obstet Gynae 1987: 94: 620-635. 2 Clinical Synthesis panel on HRT. Hormone replacement therapy. Editorial. J Epidemiol Biostat 1999; 4: 123-128. Competing interests: None declared |
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jane miners, chartered accountant exeter ex5 5er
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Thank you Christine Singh for your common sense comment. As a post- menopausal woman suffering the most horrendous symptoms I can live with the miniscule real increase in any of the risks associated with HRT because it quite simply gives me back a life. Competing interests: None declared |
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