Does HRT Improve Cognitive Function?

Abstract & Commentary

By Jeffrey T. Jensen, MD, MPH, Dr. Jensen is Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Editor for OB/GYN Clinical Alert.

This article originally appeared in the March issue of OB/GYN Clinical Alert. At that time it was peer reviewed by Catherine Leclair, MD, Associate Professor, Department of OB/GYN, Oregon Health & Science University, Portland, OR. Dr. Leclair reports no financial relationships relevant to this field of study. Dr. Jensen receives research support from, is a consultant to, and serves on the speakers bureau of Bayer Healthcare and Merck; he also receives research support from Abbott Pharmaceuticals and Medicines360.

Synopsis: In a cross-sectional sample of postmenopausal women not using hormonal therapy, higher serum levels of estrogen were associated with improved semantic memory and verbal episodic memory abilities.

Source: Ryan J, et al. Hormone levels and cognitive function in postmenopausal midlife women. Neurobiol Aging 2012; 33:617.e611-e622.

To investigate whether gonadal hormones influence cognitive function in postmenopausal women, the authors administered a comprehensive battery of neuropsychological tests on two occasions (2 years apart) to participants enrolled in the population-based, longitudinal Melbourne Women's Midlife Health Project. A total of 148 women (mean age 60 years) who had undergone natural menopause and were not using hormone therapy underwent the neuropsychological testing at year 11 of the study, with 108 completing retesting at year 13. Total and free estradiol, estrone, and testosterone levels were measured at the time of the first testing. The tests included an adaption of the California Verbal Learning Test II, using semantically related words and a 10-item list learning task using unrelated words. Both of these tests assessed immediate and delayed recall. A variety of other tasks related to immediate and delayed recognition, letter-number sequencing, category fluency, and naming also were administered. To reduce the number of cognitive outcomes examined and thus the risk of a Type 1 error, the investigators incorporated a principal-component analysis to identify four groupings of correlated cognitive tests: verbal episodic memory, visual episodic memory, semantic memory (the ability to recall words or names), and executive function-visuospatial skills.

Initial analyses compared the characteristics of women at the time of baseline testing, according to cognitive factor scores, using correlations and t-tests. The change in cognitive function over the 2-year period was calculated by subtracting each baseline test score from the corresponding score 2 years later. Low change scores indicated a decline in cognitive function. Linear regression analysis was used to model the association between individual hormone measures and cognitive function at baseline, and analyses were adjusted a priori for potential confounders (age, education level, depressive symptoms, and age at menopause).

In the multiple linear regression analyses, better semantic memory performance was associated with higher total (P = 0.02) and free (P = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (P = 0.007). There were no statistically significant associations between hormone levels and verbal episodic memory (although this was at the P = 0.08 level), verbal episodic memory, visual episodic memory, or executive function-visuospatial skills. The authors concluded that in postmenopausal women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities.


Although most of the basic research in nonprimate species and functional studies in nonhuman primates and women support that estrogen has a profound effect on memory and executive function,1 we lack strong clinical data to support whether postmenopausal women should consider estrogen replacement therapy for cognitive protection. This is unfortunate, as memory complaints are common in midlife, and many women would choose to use a product that would improve or prevent these symptoms if one existed. Although cognitive protection is not a labeling indication for any hormonal product, a number of other interventions designed for healthy brain aging have been accepted by the public, unencumbered by the regulatory burden of evidence of efficacy and with no comprehensive evaluation of risk. Ginkgo biloba anyone?

Since the publication of the main results from the Women's Health Initiative (WHI) almost 10 years ago, the public debate on hormone replacement therapy (HRT) has focused primarily on risk. When I talk to young clinicians, I find they have limited experience counseling women regarding postmenopausal hormone therapy. I think it is important to discuss the very real possibility of benefit with my patients, and put risk in perspective. But how should a clinician counsel a newly menopausal women presenting for HRT for cognitive protection? Is the evidence compelling? What if she has no other menopausal symptoms?

The Women's Health Initiative Memory Study, a planned substudy of the WHI that evaluated the incidence of dementia and mild cognitive impairment in postmenopausal women, concluded that HRT not only failed to protect against cognitive decline, but actually increased the risk of dementia.2 But we know that the WHI enrolled a group of women with cardiovascular risk factors at an average age of 10 years after menopause. Do these results apply to otherwise young, healthy recently menopausal women? They do not seem to when cardiovascular outcomes are evaluated, and I suspect the brain is the same. For the cardiovascular system, clinical trials and surrogate studies support that timing is critical: protection occurs with early (shortly after onset of menopause) and continued exposure while prolonged estrogen deprivation results in irreversible changes that limit the benefit of estrogens in older initiators.3

Similar data exist for the brain, suggesting that early and often applies to HRT initiation if the goal is cognitive protection.4 The Ryan study puts a slightly different perspective on this, showing that semantic memory (the ability to recall words or names) is correlated with serum estrogen levels in postmenopausal women not using HRT. A couple of observations: First, the mean estrogen levels were quite low in this study, certainly in the range we expect with menopause. Does this mean that we are measuring an effect that takes many years to develop? Second, testosterone/estrogen levels were inversely related to semantic memory. In other words, as women move to a more androgen-dominant endocrine environment (due to ovarian production of androstenedione and testosterone following the loss of follicular activity and rising luteinizing hormone), their memory declines. This is a red flag for women with intact ovaries in natural menopause; they may be more at risk for memory problems. I would want to hedge my bet with a little exogenous estradiol to move to a more favorable balance.

Brain function is another extremely important potential benefit of hormonal therapy. Although there is some inconsistency in the results of current clinical information, animal studies and functional imaging studies in women suggest benefit. High-quality longitudinal studies will be needed to determine whether the Timing Hypothesis is true with respect to brain function. Women taking estrogen now may be in a position to remember the question when the story is complete!


1. Boulware MI, et al. The impact of age-related ovarian hormone loss on cognitive and neural function. Curr Top Behav Neurosci Apr 30 2011 [Epub ahead of print].

2. Rapp SR, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women's Health Initiative Memory Study: A randomized controlled trial. JAMA 2003;289:2663-2672.

3. Harman SM, et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med 2011;124:199-205.

4. Manson JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356:2591-2602.