(1) The results of a randomised placebo-controlled double-blind trial in 16 000 women (the WHI trial), published in 2002, showed that post-menopausal
hormone replacement therapy based on sulphoconjugated equine oestrogen and
medroxyprogesterone led to an excess risk of serious adverse events (
pulmonary embolism, coronary events,
stroke, and invasive
breast cancer). (2) Further analysis showed that invasive
breast cancer diagnosed in women treated with the
hormone combination had a similar histology and grade to
cancers diagnosed in the placebo group, but that they were larger and more advanced. (3) The excess risk of
stroke was mainly due to ischaemic events. In the group treated with the
hormone combination, the only identifiable risk factor was lengthy use of
hormone replacement therapy before enrollment in the trial. (4) No subgroup of women at risk of coronary events was found apart from women with elevated
LDL-cholesterol at enrollment. (5) In the WHIMS subtrial in women aged 65 years or more, the risk of
dementia was twice as high in women receiving
hormone therapy as in those receiving placebo. (6) In the British
ESPRIT placebo-controlled trial, oral
estradiol valerate, at a dose of 2 mg/day, was ineffective as
secondary prevention of
myocardial infarction. (7) Follow-up of a very large British cohort (the Million Women Study) showed a significantly increased risk of
breast cancer with all types of
hormone replacement therapy, including oestrogen-
progestin combinations (relative risk 2.00; 95% confidence interval 1.88-2.12), oestrogen monotherapy (RR 1.30; 95% CI 1.21-1.40) and
tibolone (RR 1.45; 95% CI 1.25-1.68). There was no significant difference between
oestradiol and equine oestrogen, between
medroxyprogesterone acetate and
progestins derived from
nortestosterone, between oral, transdermal and implanted oestrogen preparations, or between sequential and continuous regimens. (8) A Swedish cohort study and an American case-control study also showed a higher risk of
breast cancer linked to
progestin use. (9) In a small French epidemiological case-control study, the risk of
thromboembolism was higher among women taking oral rather than transdermal
estradiol as part of their
hormone replacement therapy. (10) In practice, the risk-benefit ratios of the
hormone replacement therapies most commonly used in France are poorly characterised. It is therefore logical to use the drugs with which we have most experience (in clinical trials or during lengthy follow-up). The benefits and drawbacks should be regularly discussed with women using
hormone replacement therapy, and they should be closely monitored for signs of
breast cancer or
cardiovascular disease.