Among postmenopausal women with prior hysterectomy who had used estrogen therapy for about 6 years and then stopped, longer-term follow-up indicates that the increased risk of stroke seen during the intervention period had dissipated, the decreased risk of hip fracture was not maintained, while the decreased risk of breast cancer persisted, according to a study in the April 6 issue of JAMA.
"The Women's Health Initiative (WHI) Estrogen-Alone Trial was a double-blind, placebo-controlled, randomized clinical trial evaluating the effects of conjugated equine estrogens (CEE) on chronic disease incidence among postmenopausal women with prior hysterectomy," the authors write. The trial intervention was stopped 1 year early after an average of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned termination date. All previous reports of this trial were limited to health outcomes occurring during the intervention phase, according to background information in the article.
Andrea Z. LaCroix, Ph.D., of the Fred Hutchinson Cancer Research Center, Seattle, and colleagues analyzed data on health outcomes after the CEE intervention through an average of 10.7 years of follow-up, through August 2009. The intervention phase was a clinical trial of 0.625 mg/d of CEE compared with placebo in 10,739 U.S. postmenopausal women, ages 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7,645 surviving participants (78 percent) who provided written consent.
The researchers found that the risk for coronary heart disease (CHD) during the postintervention follow-up period was similar to that observed during the intervention. The increased stroke risk seen during the intervention phase was not present during the postintervention phase (0.36 percent [n = 66]) in the CEE group vs. 0.41 percent [n = 77] in the placebo group. Similarly, the increase in deep vein thrombosis and pulmonary embolism with CEE use compared with placebo during the intervention phase was not maintained during the postintervention phase.
The risk of invasive breast cancer in women randomized to CEE vs. placebo was similar during the intervention and postintervention phases. "Consequently, a statistically significant lower cumulative breast cancer incidence of 0.27 percent was seen in the CEE group (n = 151) compared with 0.35 percent in the placebo group (n=199). Colorectal cancer incidence did not differ between the women in the CEE group and the placebo group during the intervention or postintervention periods," the authors write.
They add that the reduced hip fracture risk seen during the intervention phase with CEE was not maintained in the postintervention phase, with hip fracture incidence slightly higher in the CEE group compared with the placebo group during the postintervention phase. Randomization to CEE did not influence total mortality during the intervention or postintervention phase. Health outcomes were more favorable for younger compared with older women for CHD, heart attack, colorectal cancer, total mortality, and a global index of chronic diseases .
"Our results emphasize the need to counsel women about hormone therapy differently depending on their age and hysterectomy status. A postmenopausal woman who has had a hysterectomy and is considering initiation of CEE should be counseled about the increased risks of venous thromboembolism and stroke during treatment, which diminish with treatment cessation. Among younger women, no new safety concerns emerged and some risk reductions became apparent during the postintervention period. Among older women, risks of colorectal cancer, death, and the global index of chronic diseases were elevated over the cumulative follow-up period. The risks and benefits of CEE use for periods of longer than 5 to 6 years cannot be inferred from these data for any age group. Mechanisms underlying the reduced risks of breast cancer in all women, and coronary events in younger but not older women, warrant further study," the authors conclude.
Editorial: Short-term Use of Unopposed Estrogen -- A Balance of Inferred Risks and Benefits
In an accompanying editorial, Emily S. Jungheim, M.D., M.S.C.I., and Graham A. Colditz, M.D., Dr.P.H., of the Washington University School of Medicine, St. Louis, write that findings from the WHI have been an important guide for clinicians on the overall risks and benefits of hormone therapy (HT).
"There may still be a role for short-term use of unopposed estrogen for treating some women with menopausal symptoms, but this role may be vanishing as existing and emerging data continue to be better understood in terms of application to patients. In the meantime, the symptoms of menopause can be significant and require thoughtful management. This would include careful consideration and discussion of the long-term risks and short-term benefits of HT as well as thorough discussion of other treatment strategies and optimization of lifestyle to ensure the best outcomes for women in the many years they should enjoy post-menopause."
- Andrea Z. Lacroix, Rowan T. Chlebowski, Joann E. Manson, Aaron K. Aragaki, Karen C. Johnson, Lisa Martin, Karen L. Margolis, Marcia L. Stefanick, Robert Brzyski, J. David Curb, Barbara V. Howard, Cora E. Lewis, Jean Wactawski-Wende, for the WHI Investigators. Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled Trial. JAMA, 2011; 305 (13): 1305-1314 DOI: 10.1001/jama.2011.382
- Emily S. Jungheim, Graham A. Colditz. Short-term Use of Unopposed Estrogen: A Balance of Inferred Risks and Benefits. JAMA, 2011; 305 (13): 1354-1355 DOI: 10.1001/jama.2011.405
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