Hormone Replacement Therapy Loses Again
The bad news about hormone replacement therapy for menopausal women continued in the May 28, 2003, issue of The Journal of the American Medical Association when researchers from the Women’s Health Initiative Memory Study (WHIMS) reported that estrogen plus progestin therapy increased older women’s risk for probable dementia and does not protect against the development of cognitive impairment (JAMA. 2003;289:2651–2662). In another report from the same group, the combination hormone therapy was found not to improve global cognitive function in the women (JAMA. 2003;289:2663–2672), and in another study, the combination was found to increase stroke risk (JAMA. 2003;289:2673–2684).
Last year, the portion of the Women’s Health Initiative (WHI) that involved testing the effects of estrogen and progestin was ended early because of increased risk for breast cancer and heart disease associated with the combination (JAMA. 2002;288:321–333). The estrogen-alone portion of the study in women who have had hysterectomies continues. WHIMS is a substudy of the larger WHI trial.
A total of 4532 postmenopausal women aged 65 or older who were free of probable dementia entered WHIMS between May 1996 and December 1999—all of them also part of the WHI study. Cognitive functioning was tested at baseline and annually after that. The researchers, under the writing leadership of Sally Shumaker, MD, of Wake Forest University School of Medicine in Winston-Salem, NC, wrote, “Of the 4532 participants in the estrogen plus progestin component of the WHIMS trial, 61 were diagnosed with probable dementia: 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group.” They noted. “Overall, the risk of probable dementia for women in the estrogen plus progestin group was twice that of women in the placebo group, and evidence of an increased risk began to appear as early as 1 year after randomization, with differences persisting over 5 years of follow-up.”
They called their results “unexpected and in striking contrast to most of the earlier research on the effects of hormone therapy on AD [Alzheimer’s disease] and dementia.” They cautioned against overestimating the risk of Alzheimer’s disease, however. For every 10 000 postmenopausal women aged 65 or older with risks similar to those in WHIMS, 45 would be diagnosed with dementia, compared with 22 in the group that took placebo. They concluded, “Thus, estrogen plus progestin should not be prescribed with the expectation that it will enhance cognitive performance in postmenopausal women. When considered in conjunction with the WHI results reported earlier [JAMA. 2002;288:321–333.], the WHIMS estrogen plus progestin data reinforce the conclusion that the risks of estrogen plus progestin outweigh the benefits.”
In the second study, WHIMS researchers led by Stephen R. Rapp, PhD, also from Wake Forest University School of Medicine, analyzed the data from 4381 women in the WHIMS study who had at least one follow-up cognitive function score after initial baseline testing.
The researchers wrote: “More women in the estrogen plus progestin group had a substantial and clinically important decline in Modified Mini-Mental State Examination total score (6.7 percent) compared with the placebo group (4.8 percent). In conclusion, this study adds important new information to the discussion regarding the effect of estrogen plus progestin on cognitive function in older postmenopausal women,” the researchers state. “Results from this analysis within a large, randomized trial do not support the use of combined estrogen plus progestin treatment to protect cognition in older women. Moreover, while most women did not experience a negative treatment effect on cognition, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group.”
In the third study, WHI researchers with lead writer Sylvia Wassertheil-Smoller, PhD, of the Albert Einstein College of Medicine in Bronx, NY, found that 151 or (1.8%) of the 16 608 subjects in this part of the WHIMS study who took estrogen-progestin and 107 of those who took placebo suffered strokes. The researchers determined that those who took the hormone combination had a 31% increased risk of stroke. They found that 79.8% of the strokes were ischemic, meaning that the subjects who took the combination hormone replacement had a 44% increased risk of ischemic stroke.
“Together with other findings reported from WHI of increased risk of invasive breast cancer, myocardial infarction, and venous thrombosis, the stroke data indicate that the risks of estrogen plus progestin outweigh the potentially beneficial effects,” the researchers concluded.
In an accompanying editorial (JAMA. 2003:289:2717–2719), Kristine Yaffe, MD, of the University of California at San Francisco, wrote, “The addition of progestin may have a differential effect on risk of development dementia because progestins, especially medroxyprogesterone, have been reported to modify the beneficial effects of estrogen and possibly increase the risk of thromboembolic events.” However, she noted: “The findings in this issue of JAMA underscore that hormone therapy should be prescribed only for temporary use to treat menopausal symptoms.”