Lifetime Estrogen Exposure and Cognition in Late Life

The Cache County Study

Joshua M. Matyi, MS; Gail B. Rattinger, PharmD, PhD; Sarah Schwartz, PhD; Mona Buhusi, MD, PhD; JoAnn T. Tschanz, PhD


Menopause. 2019;26(12):1366-1374. 

In This Article


In a sample of 2,114 women from a longitudinal, population-based study, longer duration of endogenous estrogen was associated with higher late-life cognitive status. The results with EEE were consistent with the results of other studies, demonstrating an association of a longer reproductive window with better cognitive health in late life.[6,8,10] Estrogen has been shown to be neuroprotective in cellular and animal models,[37] promoting brain-derived neurotrophic factor (BDNF) and increasing synaptic spine density in the hippocampus. It is possible that these effects help maintain neural health into late life. In addition, although the effect is small, it may have important implications for those who experience amenorrhea (no menstrual cycles) or early menopause (of surgical or nonsurgical origin).

When examining whether the beneficial effects of EEE were extended with HT, results varied by age. Older women (75 y and older) seemed to benefit from longer duration of HT compared with those who were younger (65–74 y). An earlier examination of this issue in the CCSMA data from wave 1 to 2 was similar, in that women older than 75 years had significant cognitive benefit from HT use, though duration was not directly measured.[16] We also found greatest benefit of HT when initiated within 5 years of menopause, consistent with a critical window of initiating HT.[20] Our results, however, also suggested that HT initiated more than 5 years postmenopause still resulted in beneficial effects compared with those who never used HT. Other factors may modify the effects of HT. As reviews discuss,[3,38] the differential effects of HT timing on cognition may depend on the health of the participant, such that healthy individuals (including less brain disease) will experience cognitive benefits of HT. As participants age and exhibit greater incidence of age-related health concerns, the initiation of HT, however, may be ineffective or even deleterious to cognitive health. Note, a recent paper of 84,739 women in Finland found a slight (9%-17%) increase in AD with long-term use of HT.[39] Although the authors included age of initiation, time from menopause was not examined. Other factors that may modify the effects of HT are dosage (higher doses posing greater risk of thrombosis), preparation (with or without progesterone), and APOE genotype with some suggestion that APOE E4 carriers show less cognitive benefit from HT.[40]

Notably, in the present study, HT use (or endogenous estrogen exposure) did not affect rate of change in cognition, suggesting that any beneficial effects of estrogen occur earlier in the lifespan. This is consistent with data collected, such that the majority of HT duration or use took place before the study. Alternatively, confounding factors (healthy user bias) in our sample may have played a role as women using HT had higher 3MS scores at baseline, were younger, had completed more years of formal education, and were more physically active compared with women not using HT. We did attempt to address these concerns by statistically controlling for relevant factors in all analyses. No significant interaction in endogenous estrogen exposure or HT and APOE genotype was observed. Furthermore, there was a significant reduction in HT use between waves 3 and 4 of the study. This reduction chronologically coincided with the FDA "black box" warning placed on HT[35] that followed the discontinuation of the WHI HT trial[41] due to a greater incidence of coronary heart disease, stroke, and breast cancer in the treatment groups. This event may have resulted in earlier termination of HT by participants in our sample. In analyses comparing those who terminated HT use after wave 3 to those who continued use through wave 4, no significant difference in 3MS score was found. This suggests that any beneficial effects of HT on cognition occurred before the drop-out and that discontinuation of long-term HT use had little to no effect on cognition, at least within the 3-year period of observation in this study (wave 3 to wave 4).

Limitations of the present study included the exclusion of women who did not complete the WHQ, who at baseline were older, had completed fewer years of education, and had lower cognitive status than women included in the current analyses. Therefore, with our younger, highly educated sample, the use of the 3MS as a cognitive measure may introduce a ceiling effect and have reduced sensitivity to change.[22] In addition, although the 3MS allows for a general measure of cognitive ability, it is limited regarding assessment of specific cognitive domains. Another potential limitation is the reliance on retrospective recall of age at menarche and menopause to determine duration of the reproductive window, as well as other reproductive variables (eg, duration of breastfeeding). It is possible that those with worse cognitive status underestimated age at menopause, resulting in an erroneously shorter reproductive window. The reliability of retrospective report of estrogen variables (eg, age at menarche and menopause; HT initiation) has been shown to be moderate to strong, although the reports of older women (≥66) are less reliable.[42] The strengths of the present study include a large, population-based sample collected longitudinally over a significant duration of 12 years of follow-up. The present study also included relevant covariates that have previously been associated with endogenous estrogen, HT, and cognition that have not been well investigated. Although the present study highlights the effects of the reproductive window and HT on late-life cognition, future research may focus on specific reproductive health-related variables associated with endogenous estrogen and HT efficacy (eg, cancers and cancer treatment).