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One trial turned medicine off HRT
The trial's design
A large body of epidemiology had tied hormones to lower rates of heart disease, fractures, and diabetes, and women reported feeling better. The Women's Health Initiative tested it with two parallel arms: estrogen alone against placebo in women without a uterus, and estrogen plus progesterone against placebo in women with one.
The women were all well past menopause, more than 10 years in many cases, because researchers wanted hard outcomes such as death rates within a seven to 10-year study. The group skewed unhealthy, with perhaps 30% to 40% smokers and high rates of obesity and diabetes. No one had symptoms, since symptomatic women assigned to placebo would drop out.
The hormones used
The hormones were conjugated equine estrogen, collected from horse urine, and MPA, a synthetic progesterone. They were chosen because they were what was in use at the time. Current practice uses bioidentical hormones.
The headline
Preliminary results went out in a press announcement before peer review, and the headline was that estrogen plus MPA raised breast cancer risk by 27%. Oral estrogen also raises clotting a little, while the more recent data on topical and patch estrogen show no such effect and the risk of heart disease going down.
How did timing change the HRT debate?
Later analyses split the Women's Health Initiative results by age and years since menopause. A 2007 JAMA analysis led by Jacques Rossouw found a lower trend in coronary events among women who started hormones within 10 years of menopause than among those who started 20 or more years afterward. Researchers called this the timing hypothesis. In 2016, the ELITE randomized trial in the New England Journal of Medicine, led by Howard Hodis, reported that estradiol started within six years of menopause slowed thickening of the carotid artery wall, while starting 10 or more years after menopause did not.
Why does oral estrogen raise clotting risk?
Estrogen taken by mouth passes through the liver before reaching the rest of the body, and the liver responds by making more clotting proteins. Estrogen absorbed through the skin skips that first pass. The ESTHER study, a French case-control study published in Circulation in 2007 by Marianne Canonico and colleagues, found a higher risk of venous clots with oral estrogen but not with skin patches or gels.
What happened to HRT use after 2002?
Prescriptions of menopausal hormone therapy fell steeply after the first Women's Health Initiative results were announced in July 2002. Adam Hersh and colleagues documented the decline in JAMA in 2004 using national prescription audits. A 2007 analysis in the New England Journal of Medicine by Peter Ravdin and colleagues linked a drop of roughly 7 percent in US breast cancer incidence in 2003 to the fall in hormone use.
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