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PAPERS: Cosetta Minelli, Keith R Abrams, Alex J Sutton, and Nicola J Cooper Benefits and harms associated with hormone replacement therapy: clinical decision analysis BMJ 2004; 328: 371 [Abstract] [Full text]

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HRT-Slow withdrawal or reduced dose may be necessitated

Parvaiz A Koul   (17 February 2004)

HRT Addiction

Ellen C G Grant   (19 February 2004)

How useful are net benefit decision models to individual women?

Jean Hodson, Farook Al-Azzawi   (22 February 2004)

HRT and Periodontal Disease

Gregory S. Antonarakis   (22 February 2004)

HRT: is the pendulum swinging?

Beverley A Lawton, Sally B Rose, Des O'Dea.   (1 July 2004)

HRT-Slow withdrawal or reduced dose may be necessitated 17 February 2004
Parvaiz A Koul, Additional Professor of Internal and Pulmonary Medicine SKIMS, Soura, Srinagar 190011, Kashmir Send response to journal: Re: HRT-Slow withdrawal or reduced dose may be necessitated	In light of evidence of increased risk of coronary events, stroke, pulmonary embolism, and breast cancer 1 and no improvement in quality of life1,2 in patients on hormone replacement therapy (HRT),withdrawal of the therapy is desirable. However, recurrence of the symptoms may necessitate reintroduction. We attempted withdrawing HRT in 23 women (age 38-57, median 46 years). All of them had distressing vasomotor symptoms which were scored as 6-10(median 8) on a visual analog scale of 0-10 with post HRT scores of 0-2 ( median 2). Total withdrawal was possible in 14 cases, after a tapering over 6-12 months, the symptom score being 1-4 (median 2) after withdrawal of the therapy. Six patients started taking the drugs again at a reduced dosage but the remaining 3 desired to continue the therapy due to recurrence. Withdrawal of HRT is possible in a significant number (up to 60% cases) of patients. Since some HRT related side effects are dependent upon the dosage and duration of therapy3, a reduction in the dosage should be attempted in order to reduce the possible risks. REFERENCES 1. Hays J, Ockene JK, Brunner RL et al. for the Woman’s Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:1839-54. 2. Hlatky MA, Boothroyd D, Vittinghoff E, Sharp P, Whooley MA. Quality-of- life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial. JAMA 2002;287:591-597. 3. Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to the use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997;349:458-61. Competing interests: None declared
HRT Addiction 19 February 2004
Ellen C G Grant, physician and medical gynaecologist 20 Coombe Ridings, Kingston-upon-Thames, Surrey, KT2 7JU, UK. Send response to journal: Re: HRT Addiction	The use of progestogens and oestrogens for contraception or menopausal symptoms decreased from 1975 to 1985 because women over age 35 were warned not to use hormones and older women have higher absolute risks of venous thrombosis, strokes and heart attacks, especially if they smoke. Why then were ever more older women given Hormone Replacement Therapy (HRT) from the mid 1980s until the randomised Women's Health Inititiative Study results reconfirmed these previously well-known facts? It may be partly because so many women became menopausal prematurely. In some HRT studies nearly half of the women had become menopausal before age 50, often because of surgery. Why has hysterectomy and oophorectomy been used increasingly and on such a large scale? The follow-up results from the Walnut Creek Contraceptive Drug Study, which separated age groups and use of oral contraceptives and/or menopausal oestrogens, gave some answers in 1977.1 Women aged 18-39 using oral contraceptives had significantly more hysterectomies, cervical cancers, fibroids, acute episodes of iron deficiency anaemia, adenomyosis, pelvic inflammatory disease and ovarian retention cysts. It seemed illogical that these women should then be given more progestogens and oestrogens as HRT. One reason is that removal of endogenous oestrogen and progesterone production causes withdrawal vasomotor symptoms or mood changes in some women. Withdrawal symptoms can be even more intense when exogenous hormones are stopped.2 No doubt this is causing howls of protest from some of the millions of women who have been recently been advised to stop taking HRT. In 1997 Doctors against Abuse from Sex Hormones held a conference together with the British Society for Allergy, Environmental and Nutritional Medicine. Two women doctors detailed their personal experiences with HRT and also reviewed the evidence for the adverse mental and addictive effects of oestrogen and progesterone.2,3 It is our experience that severe withdrawal symptoms are signs of abnormal biochemistry, usually deficiencies of zinc, magnesium, copper, B vitamins and essential fatty acids. These abnormalities can be exacerbated by taking hormones. Breast cancer registrations have increased sharply in England and Wales since 1962, except for the decade between 1975 and 1985 when the use of hormones decreased.4 Beral and colleagues doubt that HRT acts solely by accelerating growth of pre-existent breast cancers as no deficit is seen in past users. They also write that many of the suggested mechanisms of action of HRT on the breast cannot be substantiated.5 The WHI trial found nearly twice as many abnormal mammograms after one year in the combined HRT group. Hormone takers had breast cancers that were larger and at a more advances stage than in the placebo group. These results indicate that the increased risk of breast cancer emerges soon after the initiation of hormone therapy. Estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis 6. Breast cancer is the commonest cause of premature death in women. Doctors and women need to have accurate scientific information to be able to make sensible and safe decisions. 1.Ramcharan S. Pellegrino FA, Ray R, Hsu J-P. The Walnut Creek Contraceptive Drug Study. A prospective study of the side effects of oral contraceptives. Vol 111, an interim report. NIH Publication Centre for Population Research Monograph, Bathesda, 1981. 2.Price EH. Increased risk of mental illness and suicide in oral contraceptive and hormone replacement therapy in studies. J Nutr Environ Med 1998; 8:121-127. 3.White M, Grant ECG. Addiction to oestrogen and progesterone. J Nutr Environ Med 1998; 8:117-120. 4.Grant ECG, Anthony HM, Myhill S, Price E, Steel CM. Breast cancer and hormone exposure. Lancet 1996 ;348:682. 5. Beral V, Banks E, Reeves, Bull D, on behalf of the Million Women Study Collaborators. Breast cancer ands hormone replacement therapy: the Million Women Study. Lancet 2003; 362:1330-1. 6.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. Competing interests: None declared
How useful are net benefit decision models to individual women? 22 February 2004
Jean Hodson, Clinical Research Fellow Leicester Royal Infirmary, LE1 5WW . Bridge House Medical Centre, Stratford upon Avon, CV37 6HE, Farook Al-Azzawi Send response to journal: Re: How useful are net benefit decision models to individual women?	Minelli et al conclude that the use of HRT should be tailored to individual risk/benefit assessment. This is not a new approach, however, but represents the standard practice of clinicians involved in menopause care and HRT prescribing. In addition to assessment of the severity of menopause symptoms, perceived quality of life, and breast cancer risk, careful consideration is also given to an individual’s medical history, family and personal risk factors for chronic disease and of course their informed choice. Furthermore, the benefits/risks of oestrogen alone, sequential or continuous combined therapy, options of route and dose are considered before a decision is made. This process requires clinical expertise together with common sense and could not easily be replaced by net benefit decision models. Although population based risks/benefits provide important background information to this process the current morbid preoccupation with the risks of HRT reported from recent studies has caused considerable and often inappropriate anxiety both to women and doctors alike. Extrapolation of data across different groups of women when assessing risk/benefit is particularly worrying, for example can we really assume that cardiovascular risk in women starting HRT in their sixties also applies to women in their early fifties? Many women who would benefit from HRT are now denied this therapy as a result of these assumptions; many of those who decide to go ahead with HRT become extremely anxious about serious adverse events rather than enjoying the benefits of therapy. We would suggest that recent population based decision making has seriously compromised the quality of life improvement that many menopausal women deserve. Jean Hodson and Farook Al-Azzawi The Menopause Clinic, Leicester Royal Infirmary. Competing interests: None declared
HRT and Periodontal Disease 22 February 2004
Gregory S. Antonarakis, Dental Student University of Wales College of Medicine, Dental School, Heath Park, CF14 4XN Send response to journal: Re: HRT and Periodontal Disease	EDITOR - The issue of Hormone Replacement Therapy (HRT) has recently become a very important but somewhat controversial issue in developed societies. As the recent article by Minelli et al.(1) highlights there are several associated benefits and harms which in the long term can lead to changes in the quality of life of women on HRT. A benefit not mentioned in the article however is the influence of HRT on periodontal disease. It has been shown that postcranial and oral bone mass are increased in postmenopausal women receiving HRT and this improvement in oral bone health constitutes an additional benefit of HRT(2). This can be extended further to say that postmenopausal HRT protects against tooth loss and reduces the risk of edentulism(3) and thus the requirement for dentures at a later stage in life. Tooth loss and alveolar residual ridge resorption are significant oral health problems in older adults, having adverse psychological effects. Oral health is vitally important to total health and overall quality of life. Retaining natural teeth improves the quality of life by maintaining the ability to chew and digest food, and improving the ability to interact and socialise with peers. For example, a reduced number of remaining teeth is associated with decreased physical activity in elderly persons(4). People wearing dentures report lower health-related quality of life than dentate people(5). Overall systemic health is intimately related to oral health and quality of life. This added perspective may have been an interesting addition to the study. REFERENCES: 1. Minelli C, Abrams KR, Sutton AJ, Cooper NJ. Benefits and harms associated with hormone replacement therapy: clinical decision analysis. BMJ 2004;328:371-5. 2. Civitelli R, Pilgram TK, Dotson M, Muckerman J, Lewandowski N, Armamento-Villareal R, Yokoyama-Crothers N, Kardaris EE, Hauser J, Cohen S, Hildebolt CF. Alveolar and postcranial bone density in postmenopausal women receiving hormone/estrogen replacement therapy: a randomized, double -blind, placebo-controlled trial. Arch Intern Med 2002;162:1409-15. 3. Krall EA, Dawson-Hughes B, Hannan MT, Kiel DP. Postmenopausal estrogen replacement and tooth retention. Compend Contin Educ Dent Suppl 1998;22:S17-22. 4. Tada A, Watanabe T, Yokoe H, Hanada N, Tanzawa H. Relationship between the number of remaining teeth and physical activity in community- dwelling elderly. Arch Gerontol Geriatr 2003;37:109-17. 5. Allen PF, McMillan AS. A longitudinal study of quality of life outcomes in older adults requesting implant prostheses and complete removable dentures. Clin Oral Implants Res 2003;14:173-9. Competing interests: None declared
HRT: is the pendulum swinging? 1 July 2004
Beverley A Lawton, Senior Research Fellow Wellington School of Medicine and Health Sciences, PO Box 7343, Wellington 6002, New Zealand, Sally B Rose, Des O'Dea. Send response to journal: Re: HRT: is the pendulum swinging?	EDITOR - The clinical decision analysis presented by Minelli et al(1) concerning the benefits and harms associated with hormone replacement therapy (HRT) helps to enlighten the ongoing dilemma faced by clinicians and women. Minelli et al focus on Quality Adjusted Life Years (QALYs) and the 2002 results of the Women’s Health Initiative (WHI)(2) to calculate the risks and benefits of HRT use. The model also takes into account self- perceived severity of symptoms and personal risk for breast cancer. Using their model, we see that women with menopausal symptoms generally benefit from HRT, whereas HRT use by asymptomatic women is associated with a net harm. The recently closed WHI oestrogen-alone arm showed no statistically significant difference in rates of breast cancer or coronary heart disease between placebo and oestrogen-alone arms of the study.(3) If these new results were taken into account in the model presented by Minelli et al, there would be an even greater beneficial effect on QALYs for the symptomatic woman taking HRT, regardless of breast cancer risk. If the risks of coronary heart disease, pulmonary embolism and breast cancer were removed along with the benefits of endometrial and colorectal cancer, an overall net benefit might then be observed for women using oestrogen-alone HRT regardless of symptom status. Any benefits of oestrogen-alone HRT must be considered alongside a potential negative effect of possible increased dementia in older women suggested by the WHI Memory Study.(4) The short-term use of HRT for symptom relief is justified in the model presented by Minelli et al; therefore subsets of women would have an increasing benefit over harm on HRT. For example women with osteopaenia or osteoporosis who are flushing and have a strong family history of bowel cancer may well find greater benefit than risk on either combined or oestrogen-alone HRT. These conjectures point to the urgency of further research to try to define who is most at risk for disease and who will most benefit from combined or oestrogen-alone HRT. (1) Minelli C, Abrams KR, Sutton AJ, Cooper NJ. Benefits and harms associated with hormone replacement therapy: clinical decision analysis. BMJ 2004; 328: 371-6 (2) Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomised controlled trial. JAMA 2002; 288: 321-33 (3) The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004; 291: 1701-1712 (4) Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al for the Women's Health Initiative Memory Study. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women: Women's Health Initiative Memory Study. JAMA 2004; 291: 2947-2958 Competing interests: None declared