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Controversies in Practice

Interviews With Two Women’s Health Experts On the Use of Estrogen Therapies

Maribeth Maher

The Women’s Health Initiative (WHI), established in 1992, included two parallel, randomized, controlled clinical trials that sought to evaluate, respectively, the overall safety of estrogen combined with progestin in women with an intact uterus and unopposed estrogen in women without a uterus.1 Both studies were terminated early because of safety concerns.

The estrogen-plus-progestin arm of the WHI was stopped in 2002, after a mean follow-up of 5.2 years (more than 3 years before its scheduled completion), because women assigned to treatment had higher rates of invasive breast cancer, cardiovascular disease, and stroke.2 The unopposed estrogen arm was terminated in 2004, after nearly 7 years of follow-up (8 months before its scheduled completion), because women assigned to treatment gained no cardiovascular benefit; in fact, they had an increased risk of stroke, similar to that found in the estrogen-plus-progestin arm of the WHI.3

Subsequently, the FDA issued a boxed warning to be included in the labeling for all estrogen products, stating in part that “Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.”4 This labeling continues to be a source of controversy among health care professionals.

Critics of the WHI proposed a “timing hypothesis,” suggesting that cardiovascular risks associated with estrogen therapies were confined largely to older women, 10 or more years past menopause, and called for the FDA to revise estrogen labeling.5 Along similar lines, in 2010, the Endocrine Society issued a scientific statement on postmenopausal hormone therapy in which they concluded that for women younger than 60 years of age, the benefits of such therapy “outweigh the risks in many instances.”6

A very different type of timing hypothesis was suggested by an updated analysis of the Million Women Study in the United Kingdom. The study authors concluded that the risk of breast cancer was significantly higher in women who began using hormone therapy before or soon after the start of menopause rather than after a longer period of time.7

To obtain different perspectives on best practices regarding estrogen therapies, I interviewed two experts who have published articles about hormone therapy. I asked each of them, separately, the same questions, with two slight exceptions, to see how their views on prescribing hormone therapy might differ.

Anthony R. Scialli, MD, is an Adjunct Professor of Obstetrics and Gynecology and of Biochemistry and Molecular Biology at Georgetown University School of Medicine in Washington, D.C.; a Clinical Professor of Obstetrics and Gynecology at George Washington University School of Medicine; and a health risk assessment consultant for several governmental agencies, including the FDA.

David F. Archer, MD, is a board member of the International Menopause Society; a past President and board member of the North American Menopause Society; and a Professor of Obstetrics and Gynecology and Director of the Clinical Research Center, the Obstetrics and Gynecology Residency Program, and the Reproductive Endocrinology and Infertility Fellowship Program at Eastern Virginia Medical School, Norfolk, Va. He is also a coauthor of the Endocrine Society scientific statement.6

References

  1. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998;19:61–109.
  2. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288;(3):321–333.
  3. Anderson GL, Limacher M, Assar AR, Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 2004;291;(14):1701–1712.
  4. Premarin (conjugated estrogen tablets), package insert. Philadelphia: Pfizer/Wyeth. October 2011;
  5. Harman SM, Vittinghoff E, Brinton EA, et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med 2011;124;(3):199–205.
  6. Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal hormone therapy: An Endocrine Society scientific statement. J Clin Endocrinol Metab 2010;95;(7 Suppl 1):s1–s66.
  7. Beral V, Reeves G, Bull D, Green J, for the Million Women Study Collaborators. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst 2011;103;(4):296–305.