Dr. John Studd
clinical gynaecologist

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Women's Health Initiative s(JAMA 228, 3, 17th July 2002)

The Women's Health Initiative (WHI) study hit the Press in July causing great anxiety as part of the study, the continuous-combined oestrogen/progestogen group, showed an increase in strokes, in heart attacks, as well as an increase in breast cancer. It did show a decrease in osteoporotic fractures and a decrease in colon cancer but the view was that the dangers exceeded the benefits and this part of the study was discontinued. They have continued the oestrogen-alone part of the study.

The problem with the study is that they used the wrong oestrogen and the wrong age population for the study. Premarin, a mixture of equine oestrogens is alone in elevating triglycerides which is a risk factor for cardiovascular disease. No doubt the risk is not reduced by daily low dose progestogens which attenuate the beneficial effects of oestrogens on cholesterol. There is no evidence that the more logical oestrogen, oestradiol, the normal oestrogen found in male and female humans has this effect. If administered transdermally it reduces both cholesterol and triglycerides.

The MRC, in their current trial, are also using Premarin. No doubt they, like the WHI study, chose Premarin because the Company offered to supply free drugs and placebos but this can now be seen as a false economy as it has jeopardised the validity of the whole study.

The other despairing aspect of the study is that 68% of patients were over the age of 60 and 22% of patients over the age of 70 with many patients recruited aged 79. Thus this is not a primary prevention study of younger post-menopausal women starting oestrogen therapy at about the age of 50-55. These patients, because of their age, will have a higher incidence of cardiovascular disease, diabetes, hypertension which makes these results virtually irrelevant to the question of the safety of these hormones in the appropriate younger age group.

One can see how it happened. Originally the WHI wished to recruit 10,000 women to placebo and 10,000 women to the active preparation but no American woman who reads the newspapers would stick to either group for a long time - hence the 75% drop-out rate. Women on the active group dropped out when bad news occurred and women in the placebo group dropped out when they were clearly not receiving benefits. It is also likely that the placebo patients would have taken more statins in order to reduce the risk of heart attacks knowing that they were on placebo. Although the incidence of statin consumption was the same at the beginning of the study, there is no mention of the incidence at the time the study was discontinued. They were clearly desperate for recruits for this well-paid study. The centres which needed recruitment included these inappropriate older women who were certain to have more cardiovascular disease.

I think the Press, in fact, got it right. The error was the committee that set up these trials ignoring the advice of many American and British clinicians and experts in the field. I regret the study is just about worthless to answer the question of primary prevention but I very much doubt whether the MRC study would be of any more use because it is using the same oestrogen.

Our patients at the Chelsea & Westminster Hospital can be reassured that we very rarely use any Premarin products preferring oestradiol either by tablet, by patch, by gel, by implant, by vaginal ring or by intra-nasal administration.