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30 July 2002

Statement of the education subcommittee of the Australasian Menopause Society on the first report of the Women's Health Initiative.

On 17/7/02 the first report of the Women's Health Initiative (WHI) was published in the Journal of the American Medical Association ( The WHI is an important study - it is the first large randomized placebo controlled double blind trial of a form of hormone replacement therapy (HRT) and its contribution to the management of postmenopausal health problems is long awaited and welcomed.

The WHI is a US based study addressing a number of issues relating the use of HRT in postmenopausal women and chronic diseases. The investigators terminated the arm of the study investigating the use of conjugated equine oestrogens 0.625 mg daily (CEE or PremarinTM) and medroxyprogesterone acetate 2.5 mg daily (MPA or ProveraTM or RaloveraTM) in women with a uterus approximately 3 years early because the risk of continuing the treatment exceeded the benefit of continuing the treatment.

This arm of the study specifically addresses whether prescription of CEE and continuous MPA to all post menopausal women regardless of their symptoms or specific indications for HRT is of overall benefit to health in terms of chronic disease prevention. In simple terms this arm of the study addresses whether combined HRT should be prescribed to all post-menopausal women. To date this has not been standard practice - prescription of HRT to women has been individualized according to the need of the woman.

What this study indicates is that universal prescription of CEE and MPA to a population of American women aged 50 to 79 years (mean age 63 yrs) cannot be recommended. It shows that universal prescription of HRT may result in more adverse events than it prevents. The diseases studied were cardiovascular disease (heart attacks, strokes, pulmonary thromboembolism), breast cancer, endometrial cancer, bowel cancer and hip and vertebral fractures). There were no differences in death rates or overall cancer rates from these diseases between the women taking HRT and placebo for the duration of the study.

It should be noted that this population of women had some adverse health characteristics - one third were obese (BMI>30kg/m2 ), half were current or ex smokers at the time of randomization and one fifth had hypertension. Over two thirds of the women were over 60 years of age and 22% were over 70, however whether adverse events affected older participants in this study more than younger women has been omitted from the information provided.

This study confirms for the first time suspected risks of thromboembolic disease and breast cancer as adverse events of prescription of HRT. Previous observational studies have estimated the risks of these events on HRT but because the studies were not randomized it was unclear whether these risk estimates were accurate. The results of the WHI do not indicate a higher risk of thromboembolic disease and breast cancer than suspected from the previous studies. The study also identifies for the first time small increases in risk of cardiovascular events rather than substantial risk reduction as suggested in epidemiological studies. The WHI finding on cardiovascular risk are more in line with recent randomized studies of secondary prevention of cardiovascular events - the HERS study and the ERA study.

Women considering use of CEE and MPA now have clearer estimates of the risk of adverse events to consider in making a decision to take HRT or not. The risks are as follows: for every 10,000 women taking HRT for one year there are 7 more cases of coronary heart disease (37 vs 30) 8 more cases of breast cancer (38 vs 30), 8 more cases of stroke (29 vs 21), 8 mores cases of blood clots on the lungs (15 vs 7) but 6 fewer bowel cancer ( 10 vs 16) and 5 few hip fractures (10 vs 15) than in women not using HRT. In population terms these are small risks but it is up to the individual women to decide whether these risks outweigh any potential benefits for her. In keeping with the previous studies the increase in breast cancer was not seen until after 4-5 years of use of HRT

Another arm of the WHI investigating the use of CEE in women who have had a hysterectomy which is ongoing, did not show the same pattern of adverse events requiring premature termination of the trial. In particular the increased risk of breast cancer is not demonstrated in the CEE only arm of the WHI. It is uncertain why this is the case.

There are some limitations to this important study.

  • Only CEE and MPA were studied. Whether these results can be extrapolated to other forms of HRT is uncertain. Whilst transdermal routes of administration may be associated with less risk of venous thromboembolism most existing studies do not suggest that CEE and MPA are significantly different to other forms of HRT but further evaluation is required.

  • This study does not evaluate quality of life, vaginal and bladder symptoms, symptoms of osteoarthritis or dementia. In particular the women were post menopausal not perimenopausal and for many women the perimenopause is a time of adverse symptoms which may be treated effectively by HRT. Perimenopauseal women should not be denied HRT on the basis of the findings of the WHI.

  • The results of the WHI cannot necessarily be extrapolated to women of a younger age group as the prevalence of cardiovascular and breast disease is lower in younger women.
The results of this study do not necessarily mean that women cannot or should not take HRT. The results of this study mean that women can be better informed about the risks and benefits of taking HRT after menopause. It is important to remember that all drug therapies have side-effects and adverse events associated with their use and HRT is no exception.

Other agents such as tibolone, bisphosphonates and selective oestrogen receptor modulators (e.g. raloxifene) were not studied in the WHI. Tibolone has been studied to a lesser extent than HRT and the bisphosphonates and raloxifene, whilst investigated in large well-designed studies, have not been evaluated over a long period of time. It is unclear whether such agents are safer alternatives to HRT.

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