The Women’s Health Initiative (WHI) study, a large randomized trial comparing combination hormone replacement therapy (HRT) to placebo, found that the increase in risk associated with long term therapy exceeded the benefits (1). In particular the promise of cardiovascular benefit from HRT was unfulfilled and therapy was found to increase the risk of cardiovascular events.

A further surprising result of the WHI study was an increase in the incidence of dementia with HRT using estrogen plus progestogen, and a failure to enhance cognitive function (2). The WHI study did, however, demonstrate protection against fracture with estrogen plus progestogen (1, 3) but this protection, even in women with the highest risk of fracture in the study, did not outweigh the other negative effects (3).

The Million Women Study (MWS), which had a prospective observational design, further emphasized the risks of HRT, indicating a higher risk of breast cancer with estrogen plus progestogen than with estrogen alone (4). The results indicated that the increase in the incidence of breast cancer with estrogen plus progestogen (compared to estrogen alone) was greater than the reduction in incidence of endometrial cancer associated with adding progestogen to oestrogen therapy (4). The MWS also reported a significant increase in the incidence of breast cancer with tibolone and with implanted and transdermal estrogen-only preparations.

Following its comprehensive review of these studies and other available data, the Australian Drug Evaluation Committee (ADRAC) has recommended “The use of HRT for any long term disease prevention cannot be generally justified as the potential harm may outweigh potential benefits. This concern also applies to the use of HRT to prevent osteoporosis.

“HRT has an established place in the short term management of symptoms of the menopause. For treatment of established osteoporosis, the selection of HRT by the patient and doctor should be based on a careful consideration and discussion of risks and benefits for that individual.”

In addition, ADRAC advises that HRT use be for as short a time as practical, and be reviewed regularly.

Extracted from Australian Adverse Drug Reactions Bulletin, Volume 23, Number 2, April 2004

References

1. 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 randomized controlled trial. Journal of the American Medical Association, 288: 321-333 (2002)

2. Shumaker, S.A., Legault, C., Rapp, S.R. et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study: a randomized controlled trial. Journal of the American Medical Association, 289: 2651-2662 (2003).

3. Cauley, J.A., Robbins, J., Chen, Z. et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density. The Women’s Health Initiative randomized trial. Journal of the American Medical Association, 290:1729-1738 (2003).

4. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet, 362: 419-427 (2003).