Have we come full circle - or moved forward? The Women's Health Initiative 10 years on

In mid-summer 2002, the announcement that the Women's Health Initiative (WHI) trial of combination hormone therapy (HRT) had stopped jolted the field of women's health. It set off a cascade that first stunned, then meaningfully changed the future for millions of women, their partners, and tens of thousands of clinicians and scientists. With 10 years' hindsight, we can begin to put the lessons learned from the WHI HRT trials into perspective. These trials were primarily designed to test whether women considerably past menopause, and mostly asymptomatic, experienced treatment benefits from HRT expected from studies of generally symptomatic women who started near menopause. The definitive answer was 'no'. Unfortunately, the findings were generalized to all postmenopausal women regardless of age. Data accumulated from the WHI and other studies over the past decade have shown that, in women with symptoms or other indications, initiating HRT near menopause - the classic pattern of use - will probably provide a favorable benefit : risk ratio. Spurred by the WHI, many hypotheses and some insights about potential mechanisms for HRT effects on diverse organ systems have emerged, along with new perspectives on regimens, compounds, and routes of administration. This overview provides an historical perspective on the WHI design and the evolution of its message; summarizes current perspectives and insights contributed by eminent colleagues; reviews the state of the art; and looks to the future. We have come full circle in some ways, with mounting evidence supporting benefit for HRT started near menopause and with hard lessons learned about pathophysiology, publicity and interpreting data. Now we move on.