253 ‒ Hormone replacement therapy and the Women’s Health Initiative: re-examining the results

KEYPOINTS

• 01

  The WHI tested hormone therapy for preventing disease in older women, not for treating menopause symptoms.

  Manson, a Harvard endocrinologist and epidemiologist and a principal investigator of the Women's Health Initiative, explains the background. By the early 1990s, observational studies suggested women on hormones had less heart disease and cognitive decline and lower mortality. Doctors had started prescribing hormones for prevention, sometimes to women 10–30 years past menopause. Hormones were already accepted and FDA-approved for hot flashes. The open question was whether they prevented chronic disease, and no randomised trial had tested it.

• 02

  Design: two trials, about 27,000 women, average age 63.

  Women aged 50–79 were enrolled: close to 17,000 with a uterus got conjugated equine estrogen plus medroxyprogesterone acetate (MPA) or placebo, and close to 10,000 without a uterus got estrogen alone or placebo. The main outcome was coronary heart disease, and the main safety outcome was breast cancer. The trial was powered to detect about a 20% heart-disease reduction. Manson corrects a common misconception: women with hot flashes weren't excluded. About 45–50% had mild to moderate symptoms, though women with severe symptoms tended to opt out. These were the formulations behind the observational data, partly because a pharmaceutical company dominated with pregnant-mare-derived estrogen.

• 03

  Manson expected a small heart benefit, not the 40–50% the observational studies showed.

  Women on hormones tended to be wealthier, better educated and more health-conscious. Manson thought starting estrogen early in menopause might modestly reduce heart risk, since women's own estrogen seems to delay heart disease by about a decade compared with men. She doubted the large observational effects would hold up in a randomised trial.

• 04

  The combined-therapy arm was stopped early; the absolute breast-cancer increase was small.

  Estrogen plus MPA was halted after 5.6 years, 3.3 years early, because of more breast cancer, no heart benefit, and an unfavourable overall balance across all outcomes. The relative increase in breast cancer was about 25%. Attia emphasises the absolute figures: roughly 4 versus 5 cases per 1,000 women. Manson describes most harms as about one extra case of breast cancer, heart attack or blood clot per 1,000 women per year. That's low, but it can add up with long-term use.

• 05

  Estrogen alone did not increase breast cancer; with longer follow-up it was linked to a reduction.

  With estrogen alone, breast cancer fell by about 20% with longer follow-up, and breast-cancer deaths were significantly lower. With estrogen plus MPA, breast-cancer deaths trended higher but weren't significant. Breast density rose more with the combination. Manson and Attia agree the excess risk is mostly attributable to MPA. But Manson cautions that this result may be specific to conjugated estrogen, which may act partly like tamoxifen, and that other evidence (such as ovary removal lowering recurrence) still points to a role for estrogen. Total invasive cancer didn't rise in either arm, and the combination reduced endometrial cancer.

• 06

  Timing matters.

  In the 2017 JAMA mortality analysis, women aged 50–59 had about a 30% lower all-cause mortality on either regimen. This wasn't significant in either trial alone. Results were neutral at 60–69. Women aged 70–79 on estrogen alone had about 22% higher mortality, borderline significant. Women in their 50s on estrogen alone also had favourable heart-attack signals. Both arms raised stroke risk, and cognition worsened in women 65 and older.

• 07

  The practice changed in a good way and a bad way.

  Hormone use fell by 70–80%. Ending prescriptions for disease prevention in older women was appropriate. Extending the fear to healthy women in their 40s and 50s with distressing hot flashes was not, because their absolute risks are even lower. Attia calls it one of medicine's greatest missteps and speaks of a 'lost generation' of women, including his mother and mother-in-law. Manson says the pendulum is settling: hormones are good for some women, not all. The best candidates are healthy women in early menopause with moderate to severe symptoms.

• 08

  Manson questions Attia's case for long-term use to prevent fractures.

  Attia argues that hip-fracture protection, which he estimates at about 1.5% absolute, would far outweigh a small breast-cancer increase over 30 years of use. Manson points out that bone loss resumes quickly after stopping. No subgroup at high fracture risk had a clearly favourable overall balance on combined therapy for prevention. And women who stay on hormones long-term in observational studies are a self-selected, healthier group. A 30-year trial has never been done.