Doctors often prescribe hormone therapy to help women cope with symptoms of menopause such as hot flashes and night sweats. However, there are concerns that hormone replacement causes cognitive decline. Now, scientists led by Susan Resnick, National Institute on Aging, Baltimore, Maryland, report that given soon after menopause, hormone therapy has no detrimental effect on women’s cognitive health. “It’s reassuring,” said Kristine Yaffe, University of California, San Francisco, explaining that it seems safe to take estrogen around the time of menopause. Yaffe was not involved in the study. The results appeared online June 24 in JAMA Internal Medicine.

Beginning in 1993, more than 27,000 women enrolled in the randomized, placebo-controlled arm of the Women’s Health Initiative trial to examine the effects of postmenopausal hormone replacement therapy (HRT). Half of the 16,608 women who had not undergone a hysterectomy received both estrogen and progestin, while the remainder took placebo. Half of the 10,739 who had undergone hysterectomies were given estrogen alone and the other half placebo. The treatment period for the estrogen plus progestin group ended in 2002, and for estrogen alone in 2004, with an average follow-up of 5.2 and 6.8 years, respectively, but researchers continued to monitor these women. A subset of those participants enrolled in the WHI Mental Study (WHIMS), which specifically looked at the effects of HRT on cognition. Researchers found that five years of HRT raised the risk of dementia by about 75 percent (see ARF related news story) and led to reduced brain volume in women 65 and older (see Espeland et al., 2009).

What about younger women? Some results from the WHI study suggested that while HRT boosts heart disease risk when given late in life, it may prevent heart disease and myocardial infarction when treatment starts earlier. Could it do the same for cognitive health? Epidemiological studies suggested that use of hormone therapy in midlife, as opposed to late life, helps prevent dementia (see Whitmer et al., 2011). Researchers including first author Mark Espeland, Wake Forest School of Medicine, Winston-Salem, North Carolina, put this hypothesis to the test in the WHIMS of Younger Women (WHIMSY), where they looked for long-term cognitive differences in women who had enrolled in WHIMS between the ages of 50 and 54.

About 1,300 WHI participants joined WHIMSY, which took place approximately seven years after the WHI treatment trial had ended. The women then averaged 67 years of age. About half of them had received HRT for approximately seven years in WHI, while the other half had been given placebo. Twice, Espeland and colleagues administered cognitive tests by telephone, including the modified Telephone Interview for Cognitive Status (TICS-m) for global cognitive function, as well as secondary measures of executive function, verbal memory and fluency, working memory, and attention. The two assessments occurred approximately one year apart. WHIMSY researchers looked for differences in cognitive test scores between those who took HRT versus placebo.

Overall, both intervention and control groups performed about the same on all of the cognitive tests. Verbal fluency dipped slightly in women who had used hormones before entering the study or who had undergone hysterectomies, but the research group did not control for false positives in the secondary cognitive outcomes, they wrote, so it could be a chance finding. About 4 percent of the women took additional hormone therapy after the treatment period ended, but their inclusion or exclusion in the data made no difference, Espeland said.

“The main message is that using these drugs in this age range does not appear to convey any long-term cognitive harm,” Espeland told Alzforum. However, WHIMSY enrolled women a few years past menopause, so the results may not extrapolate to women prescribed hormone therapy immediately after it, he said. Since the authors have no cognitive data from the women’s time on medication, the outcomes do not speak to any short-term effects, either, he said. WHIMS detected cognitive decline in much older women, so differences could show up as these women age, Espeland conceded. However, if the same pattern of prompt and sustained cognitive deficits seen in the WHIMS trial applied to those in WHIMSY, he would expect to see cognitive changes already. He and his colleagues will continue to test these participants for cognition.

Given that there is a seven-year gap between treatment and assessment, it is hard to make a solid conclusion about the effects of hormone therapy on cognition, said Howard Hodis, University of Southern California, Los Angeles. WHIMSY was limited by a lack of baseline data, since the examination of cognition occurred post-treatment, he added. Also, people with dementia or cognitive impairment may have declined to participate in WHIMSY, so researchers could have missed a key group, he said. Epidemiological studies suggest that HRT may weakly protect against AD (see AlzRisk). However, the results suggest there are no long-term effects on cognition in this younger WHI cohort, he told Alzforum. Hodis is leading the Early Versus Late Intervention Trial With Estradiol (ELITE) study that specifically examines cardiovascular and cognitive effects of hormone therapy prescribed in early versus late menopause. He expects data to be processed this year.

“These are important data for many menopausal women,” as hormone therapy is widely prescribed, wrote Francine Grodstein, Brigham and Women’s Hospital, Boston, Massachusetts, in an accompanying commentary. The results agree with preliminary findings reported last year from the Kronos Early Estrogen Prevention Study (KEEPS) that suggest hormone therapy taken within three years of menopause provides no cognitive benefit, she added. Some might find these outcomes disappointing since they refute the “window of opportunity” hypothesis for cognitive health, she said. That hypothesis proposes that HRT, given early in menopause, prevents chronic disease. “Whether therapy will have any protective effect against cognitive problems 30 years down the line is still an open question,” Yaffe pointed out.—Gwyneth Dickey Zakaib.

References:
Espeland MA, Shumaker SA, Leng I, Manson JE, Brown CM, Leblanc ES, Vaughan L, Robinson J, Rapp SR, Goveas JS, Lane D, Wactawski-Wende J, Stefanick ML, Li W, Resnick SM; for the WHIMSY Study Group. Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years. JAMA Intern Med. 2013 Jun 24. Abstract

Grodstein F. Hormone Therapy in Younger Women and Cognitive Health: Comment on "Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years." JAMA Intern Med. 2013 Jun 24. Abstract

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References

News Citations

  1. Dementia Risk Increases, at Least in Those Who Start Hormone Therapy Late

Paper Citations

  1. . Brain volumes, cognitive impairment, and conjugated equine estrogens. J Gerontol A Biol Sci Med Sci. 2009 Dec;64(12):1243-50. PubMed.
  2. . Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol. 2011 Jan;69(1):163-9. PubMed.
  3. . Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years. JAMA Intern Med. 2013 Jun 24;:1-8. PubMed.
  4. . Hormone Therapy in Younger Women and Cognitive Health: Comment on "Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years". JAMA Intern Med. 2013 Jun 24;:1-2. PubMed.

External Citations

  1. Women’s Health Initiative
  2. AlzRisk
  3. Early Versus Late Intervention Trial With Estradiol
  4. Kronos Early Estrogen Prevention Study

Further Reading

Papers

  1. . Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiol Aging. 2012 Jul;33(7):1129-37. PubMed.
  2. . Alzheimer's disease: Review of hormone therapy trials and implications for treatment and prevention after menopause. J Steroid Biochem Mol Biol. 2013 May 28; PubMed.
  3. . Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2959-68. PubMed.
  4. . Brain volumes, cognitive impairment, and conjugated equine estrogens. J Gerontol A Biol Sci Med Sci. 2009 Dec;64(12):1243-50. PubMed.
  5. . Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol. 2011 Jan;69(1):163-9. PubMed.
  6. . Sex steroids to maintain cognitive function in women after the menopause: a meta-analyses of treatment trials. Maturitas. 2010 May;66(1):56-71. PubMed.
  7. . A multi-center, randomized, double blind placebo-controlled trial of estrogens to prevent Alzheimer's disease and loss of memory in women: design and baseline characteristics. Clin Trials. 2008;5(5):523-33. PubMed.
  8. . Hormone Therapy in Younger Women and Cognitive Health: Comment on "Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years". JAMA Intern Med. 2013 Jun 24;:1-2. PubMed.
  9. . Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years. JAMA Intern Med. 2013 Jun 24;:1-8. PubMed.

Primary Papers

  1. . Hormone Therapy in Younger Women and Cognitive Health: Comment on "Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years". JAMA Intern Med. 2013 Jun 24;:1-2. PubMed.
  2. . Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years. JAMA Intern Med. 2013 Jun 24;:1-8. PubMed.