Women's Health Initiative

Richard S. Legro, MD

It has been more than 20 years since the Women's Health Initiative (WHI) commenced in 1991 and more than 12 years since the publication of its first bombshell article in 2002, which changed the course of menopausal management and radically reduced the routine prescribing of hormone replacement therapy (and we as Ob/Gyns were the largest prescribers of hormonal therapy) for primary prevention of cardiovascular disease in women. This remains the largest trial ever conducted in women's health and involved more than 160,000 women who were enrolled into the three clinical trials and observational trial which are well summarized in this issue of Seminars in Reproductive Medicine. The primary outcome parameter was coronary heart disease, and the primary safety parameter was breast cancer, but as it is extensively documented, these trials captured the full gamut of health effects, including quality of life, hormone replacement, and vitamin/calcium supplementation in postmenopausal women. There were several important and fascinating substudies, many of which, for example, the effects on cognition and bone, are summarized in this issue.

I am indebted to Dr. Robert Bryzski at the University of Texas at San Antonio, who initiated this issue and was able to corral an all-star cast of WHI investigators to summarize the WHI studies and reflect on their significance. Although he retired before this issue came fully to fruition, it would not have come together as nicely as it did without his vision and choice of authors. You will recognize these authors because they represent the key investigators both at academic institutions in the United States and the NIH who initiated and completed this landmark trial. It is somewhat premature to state that the trial is completed as analyses are still ongoing. The results of the biomarker, pharmacogenetic, and proteomic analyses are still appearing, and the mixed picture of their utility that has emerged to date can serve both as a lodestar and an admonition to other clinical investigators.

The authors embrace the controversies that the trial has raised, and they address head on critiques that have been raised about the recruitment of older postmenopausal women (as opposed to younger ones), gaps between ovarian senescence and hormone replacement, and the premature stoppage of the hormone replacement trials. A fascinating account is provided of the potential reasons for discrepancies between outcomes noted in the randomized WHI trials and observation trials and the Nurse's Health Studies. The results are closer than you think. Future directions for research in hormone therapy are provided, and there are still several important issues including use of other hormones, modality of administration, and their effects in younger postmenopausal women that should stir the fires of the next generation of clinical researchers. Finally, there are several clinical articles that integrate lessons from the WHI to improve care of postmenopausal women and will improve our care of these patients.

Note

Dr. Legro reports serving as a consultant to Ferring, Euroscreen, and Astra Zenca.