Time for new long-term trials of postmenopausal hormone therapies!

The Women’s Health Initiative (WHI) has shown the value of a well-conducted, medium-term, randomized, placebo-controlled trial. Specifically, it showed that there was no cardioprotective or neuroprotective benefit from combined hormone therapy (HT) when initiated in late menopause in the population studied1. It also showed a small increase in breast cancer with this regimen after 5 years of therapy. Subanalyses of its results do not show an increase in cardiovascular events when therapy was initiated within 10 years of menopause (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.17–0.86), as opposed to therapy initiated more than 20 years after menopause (HR 1.75, 95% CI 1.18–2.40)2. Blood vessels appear to lose their estrogen receptors in early postmenopause and the potential protective effect of estrogen on the vessel wall may be lost after several years3. The elegant monkey studies by Clarkson’s group support the hypothesis of a cardioprotective effect when estrogen is initiated early after surgical menopause but not when initiated in later postmenopause4. The challenge of WHI should be to help justify, design and fund a safer and more effective therapeutic regimen, to be tested long term in an appropriate population where there may be a primary protective effect. Most randomized trials of HT to date, including WHI, have unsuccessfully sought a secondary protective effect in women with established atherosclerosis or with risk factors for this disease. The hypothesis that estrogen may have a primary cardioprotective and neuroprotective effect when used from around menopause has not been tested in randomized trials, despite observational study evidence for both5,6. As well as choosing more appropriate target populations, part of the challenge also will be to choose potentially safer regimens to be tested in such trials. There is an assumption that the estrogen-only arm of WHI continues because this regimen has not yet been shown to be associated with a significant increased risk of breast cancer. If this proves to be true, then WHI has again pointed the way to the safer use of hormone therapy. In women with a uterus, it would be wise to use a progestogen or a regimen that did not affect the breast or the cardiovascular system. In this issue of Climacteric, Thomas and colleagues present interesting evidence that progestogens may also have an adverse effect on the arterial wall, further warranting a change to a safer delivery system, for example intrauterine progestogen7 or the addition of selective estrogen and progestogen receptor modulators8. Such regimens would also be much less likely to give long-term bleeding in placebo-controlled trials and resulting unblinding of the HT regimen. This was a problem in WHI and in the opinion of Shapiro, in an Invited Editorial in this issue, this turned WHI into an observational study because of the potential for detection bias after the unblinding9. Another potentially safer therapeutic option worthy of trial is to give estrogens by a non-oral route, as a recent study suggests transdermal estrogen may not be associated with the increased risk of thromboembolism seen with oral HT10. There are few effective alternatives to estrogen for the management of menopausal symptoms, and none that are as effective, despite a burgeoning and inadequately controlled complementary medicine industry in most countries. Amato and Marcus, in this issue of Climacteric, review alternative therapies for menopausal symptoms and conclude that nearly all such complementary therapies have no greater effect than a placebo and their long-term side-effects are unknown11. In another Invited Editorial in this edition, Breen strongly argues that the prescription or advocacy of such placebo therapies without informing the public of the therapy’s lack of efficacy is unethical12. Thus, it would follow that it is CLIMACTERIC 2003;6:265–267