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Women who have stopped estrogen plus progestin therapy may be at increased risk of cancer

The JAMA Network Journals

A follow-up study of women who stopped taking the hormone therapy of estrogen plus progestin after this intervention was discontinued as part of a clinical trial indicates that these women may have an increased risk of cancer, compared to women in the placebo group, according to a study in the March 5 issue of JAMA. Cardiovascular disease and fracture risks were similar between the two groups, but women who took hormone therapy had an overall higher global risk index reflecting the balance of risks and benefits from a number of endpoints combined, including deaths.

The Women's Health Initiative (WHI) trial of estrogen plus progestin, which included 16,608 postmenopausal women, assessed whether conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) prevents heart disease and hip fractures and increases the risk of breast cancer. The trial was stopped in 2002 when data indicated an increased risk of breast cancer and a failure to demonstrate an overall health benefit of the therapy. Further analysis showed that women in the CEE plus MPA group had higher risks of cardiovascular disease (CVD), coronary heart disease (CHD), stroke and venous thromboembolism and lower risks of fracture and colorectal cancer.

Gerardo Heiss, M.D., of the University of North Carolina, Chapel Hill, N.C., and colleagues examined the risks and benefits experienced by 15,730 trial participants who had follow-up, from July 2002 to March 2005, after they stopped hormone therapy.

The researchers found that the annualized event rates for the outcome "all cancer" was higher during the postintervention follow-up for the CEE plus MPA group (1.56 percent per year [n = 281]) than the placebo group (1.26 percent per year [n = 218]). This reflects a greater risk of invasive breast cancer and other cancers in the CEE plus MPA group; the rates of colorectal cancer did not differ significantly between the two groups; rates of endometrial cancer were lower in the CEE plus MPA group. Though risk of breast cancer remained elevated during the follow-up, the risk was less than that experienced towards the end of the trial period.

The risk of cardiovascular events after the intervention were comparable, with an annualized rate of 1.97 percent in the CEE plus MPA (343 events) and 1.91 percent in the placebo group (323 events), meaning that the increased risks found during the trial period weakened after study drugs were stopped.

The risk of fractures during the postintervention follow-up was similar among women in both groups for each type of fracture considered: hip, vertebral and other osteoporotic fractures. "This reflects a greater increase in the annualized risk of fractures after the intervention in the women who had been assigned to CEE plus MPA compared with women assigned to placebo, particularly for hip and vertebral fractures. Thus, the protective effects of CEE plus MPA previously evident during the trial were not observed to carry over into the postintervention phase ...," the researchers write.

During the postintervention phase, the rate of death from all causes was higher by 15 percent in the group originally assigned to CEE plus MPA than in those assigned to placebo, but this difference was not statistically significant.

A summary of the risks and benefits, the global index, included outcomes for coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture and death due to other causes. The researchers found that this measure was 12 percent higher in women randomly assigned to receive CEE plus MPA compared with placebo and did not materially change after the intervention was stopped.

"This analysis of delayed and sustained health benefits and risks following randomized allocation to CEE plus MPA vs. placebo adds new information to inform the optimal use of postmenopausal CEE plus MPA. Over the course of [an average of] 2.4 years from termination of intervention with CEE plus MPA, rapid changes in hormone therapy-related risks and benefits were observed, as well as trends that suggest that continued follow-up of the study participants of this trial will be informative as regards possible delayed effects of CEE plus MPA," the authors write. "Following termination of use of CEE plus MPA of 3.5 to 8.5 years, clinical vigilance seems warranted with respect to a sustained higher risk of malignancies."


(JAMA. 2008;299[9]:1036-1045. Available pre-embargo to the media at

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