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Oestrogen plus progestogen increased coronary heart disease and breast cancer events in postmenopausal women
  1. Julia Lowe, MD
  1. John Hunter Hospital
 Newcastle, New South Wales, Australia

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 QUESTION: In postmenopausal women, what are the risks and benefits of oestrogen plus progestogen use, particularly with respect to coronary heart disease (CHD) events?


    Randomised (allocation concealed*), blinded (clinicians, participants, data collectors, outcome assessors, and monitoring committee),** placebo controlled trial with a mean 5.2 years of follow up.


    40 US clinical centres.


    16 608 postmenopausal women who were 50 to 79 years of age (mean age 63.3 y). Exclusion criteria included probable survival of < 3 years, previous breast cancer or other cancer in the past 10 years, and low haematocrit or platelet counts. Follow up was 96.5%.


    Women were allocated to 1 daily tablet of conjugated equine oestrogen, 0.625 mg, and medroxyprogesterone acetate, 2.5 mg (Prempro, Wyeth Ayerst, Philadelphia, PA, USA) (n=8506), or placebo (n=8102).

    Main outcome measures

    CHD (non-fatal myocardial infarction [MI] or CHD death) and invasive breast cancer. Other outcomes included stroke, venous thromboembolism (VTE), colorectal cancer, fractures, and death from other causes.

    Main results

    Analysis was by intention to treat. Because of early increases in breast cancer, follow up was stopped at a mean of 5.2 years instead of the expected 8.5 years of follow up. Women who received oestrogen plus progestogen had more total cardiovascular disease than did women who received placebo, including CHD (mainly non-fatal MI), stroke, and VTE (table). Invasive breast cancer was increased to a nearly statistically significant extent (table). Colorectal cancer and fractures were reduced (table). Groups did not differ for mortality.

    Oestrogen plus progestogen (Est + Prog) v placebo for postmenopausal women†


    In postmenopausal women, oestrogen plus progestogen use increased the risk for cardiovascular disease, particularly coronary heart disease events.


    Since the publication 38 years ago of Feminine Forever,1 the view that menopause (and vascular disease in women) is a disease of oestrogen deficiency requiring treatment has dominated medical thinking. The results of the Women’s Health Initiative are a major challenge to this view. On the debit side, for every 10 000 women receiving combination hormone replacement therapy (HRT) for 1 year, there are 7 more coronary events, 8 more occurrences of breast cancer, 8 more strokes, and 8 more pulmonary embolisms. On the credit side, there are 6 fewer occurrences of colorectal cancer and 5 fewer hip fractures. Put another way, for every 100 women treated for 5 years, 1 additional woman will have a serious adverse event. The finding of excess coronary events, breast cancer, and VTE events is consistent with the results of HERS,2 re-analyses of epidemiological studies,3 and a meta-analysis by Miller et al.4 This is more than enough evidence to conclude that long term treatment with oestrogen and progestogen combinations to prevent cardiovascular disease is not appropriate.

    Women cannot be confident that combination HRT is safe for short term relief of menopausal symptoms because the increased risk for CHD is apparent within the first year. For those requesting treatment for hot flushes, the benefit and harm of both HRT and alternative treatments should be explained. Individual women can be reassured that the absolute risks associated with short term HRT use are small; on average, the risk is < 0.1% for either of the main outcomes. For postmenopausal osteoporosis, bisphosphonates should be considered first-line treatment. A substantial drawback to these drugs is their high cost.

    Unfortunately, in this study predictors of cardiovascular outcomes associated with HRT were not identified. While the results do not necessarily apply to other forms of HRT, proof of safety is lacking. Women currently receiving HRT should review the reasons they take it and discuss continuation with their healthcare provider.


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    • Sources of funding: National Heart, Lung and Blood Institute; Wyeth-Ayerst Research (active and placebo medication).

    • For correspondence: Dr J E Rossouw, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. rossouw{at}

    • * See glossary.