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Abstract:
(1) The WHI study was published in 2002: a randomised double-blind placebo-controlled clinical trial in more than 16 000 women with an average age of 63 years at enrollment. The paper reports data on the long-term adverse effects of combined equine estrogen-progestin hormone replacement therapy, taken for 5 years. (2) On average, a yearly excess of 19 severe adverse events per 10 000 women occurred in the estrogen-progestin group. Relative to the placebo group, there were an extra 8 pulmonary embolisms, 7 coronary events, 8 strokes and 8 cases of invasive breast cancer. In contrast, there were 6 fewer colorectal cancers and 5 fewer hip fractures in the active treatment group. (3) The differences in the frequency of coronary events and venous thromboembolism emerged after the first year of treatment, while the curves for stroke and breast cancer diverged after the second and fifth years, respectively. (4) The overall mortality rate did not differ between the two groups. (5) A placebo-controlled trial of the same hormone combination (HERS trial), given for 4.1 years as secondary prophylaxis against coronary heart disease was published in 1998. The drug was ineffective during the trial, and during unblinded post-trial follow-up of 2 321 women for an average of 2.7 years (HERS II study). (6) The estrogen-progestin combination used in these trials did not reduce the risk of coronary heart disease (in primary or secondary prophylaxis) or the risk of stroke. On the contrary, both risks increased. (7) The increased incidence of deep venous thrombosis and/or pulmonary embolism associated with estrogen-progestin replacement therapy was confirmed in these trials, even among women with no relevant history. (8) The WHI trial also confirmed the increased risk of breast cancer in women on hormone replacement therapy, but did not study its impact on outcome or mortality. (9) The WHI trial confirmed the beneficial impact of estrogen-progestin combination therapy on the risk of osteoporotic fracture. An average of 5 hip fractures were avoided each year per 10 000 women treated (10 versus 15 observed cases per 10 000 women per year), together with 6 symptomatic vertebral fractures (9 versus 15 cases) and 44 osteoporotic fractures (147 versus 191 cases). It is not known whether the benefit observed at the end of the trial persisted after the end of treatment. (10) In practice, the decision to prescribe hormone replacement therapy, and the optimal duration of treatment, must be weighed up according to each individual's risk factors. And the decision to treat or not to treat must be regularly re-assessed. Women must be informed of the potential risks and benefits, and must be monitored. They should also be advised not to use less well assessed treatments such as phytoestrogens, DHEA and tibolone. (11) Health authorities, especially in Europe, must organise comparative trials to assess the benefits and risks of other hormone combinations used by perimenopausal and postmenopausal women.