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


Out of 2,654 eligible women to be administered the WHQ, 521 women did not complete the interview. Of the remaining 2,133 women, 19 had unknown cognitive status at baseline (screened positive on cognitive measures but failed to complete additional assessments) and were excluded from the present analyses. This resulted in a final sample of 2,114 women. Mean (SD) age of the sample was 74.94 (6.71) years and mean (SD) education was 12.89 (2.27) years. Women who were included in the analyses were among other factors, younger, had completed more years of education, were more physically active, had higher BMI, and had significantly higher 3MS scores at baseline compared with those who were excluded (see Table 1).

The mean years of endogenous estrogen exposure (EEE) for the sample was 32.99 (SD = 6.89) with a range of 2 to 61 years. Table 2 includes descriptive statistics for variables included in deriving EEE, including age at menarche and age at menopause. With respect to HT use, 833 of the 2,114 women included in the EEE analyses were never on HT. Compared with never HT users, women who ever used HT were significantly younger (mean age of 73.51 vs 77.14), had completed more education (mean 13.06 vs 12.63 y), had higher 3MS scores (mean 93.06 vs. 90.40), were significantly more physically active, and had higher frequency of major depression at baseline (data not shown).

Among HT users, Table 3 shows descriptive statistics for timing of HT initiation, HT duration, and HT type across all four waves. For women who were not using HT at baseline, the majority (>95%) did not initiate HT across the remaining waves. For women who took HT at baseline, the pattern of use across the remaining waves generally reflected either continued use with the same HT type (ie, women using unopposed HT at baseline continued to use unopposed HT if taking HT at subsequent waves; waves 1–2 = 94%; waves 2–3 = 94%; waves 3–4 = 91%) or a shift to discontinuing HT use (waves 1–2 = 43%; waves 2–3 = 57%; waves 3–4 = 86%). The largest decrease in HT use was seen between waves 3 and 4, where 86% of women who were using HT at baseline stopped. This reduction in HT use chronologically coincided with the FDA "black box" warning placed on HT[35] after the WHI (FDA black box: 2002; wave 4 initiation: 2004).

Model 1—Endogenous Estrogen Exposure and Cognition

In the unadjusted model, EEE duration was significantly associated with 3MS such that for each additional year of EEE there was a 0.05-point higher score on the 3MS (P = 0.008). With the inclusion of covariates, EEE remained a predictor of overall 3MS score (P = 0.054) but was not predictive of rate of change in 3MS. Table 4 shows the results for the unadjusted and fully adjusted mixed models.

Model 2—Hormone Therapy and Cognition

In an unadjusted model with EEE duration, time and time,[2] HT duration (in years) was significantly associated (P = 0.046) with 3MS score. For each additional year of HT duration there was a 0.02-point higher score on the 3MS. HT duration was, however, modified by age (interaction: P = 0.024). To illustrate the nature of the interaction, a dichotomous age variable (median split of 65–74 vs 75 or older) was entered in place of the continuous age variable in the fully adjusted model. Results showed that in older women, higher total estrogen duration was associated with higher 3MS scores, but the opposite pattern was found in women in the younger age group. Figure 1 displays the interaction between HT duration and age group on the 3MS. Table 5 presents the unadjusted and fully adjusted models.

Figure 1.

Interaction between duration of hormone therapy (HT) use and age on Modified Mini-Mental State Examination (3MS) scores with greater benefit for longer duration of HT in women who were above the median of the sample (age 75 or older). Reference lines are added for comparison showing the estimated means of both age groups for women who never used HT.

Model 3—Hormone Therapy Type

Use of either type of HT (opposed or unopposed) was associated with higher 3MS scores (P = 0.001) when compared with no HT use in the unadjusted model. Women who used unopposed estrogen scored 0.57 points higher (P = 0.002) on the 3MS and women who used opposed estrogen scored 0.93 points higher (P = 0.001) on the 3MS than women not using HT. Type of HT was, however, no longer significant (P = 0.365) with the inclusion of significant covariates of age, EEE, education, APOE genotype, physical activity, and overall health (see Table 6).

Model 4—Timing of Hormone Therapy

The timing of HT use relative to menopause was significantly associated with 3MS score (P = 0.001). Those who initiated HT regardless of time since menopause had higher 3MS scores than nonusers. In the fully adjusted model and compared with nonusers of HT, women who used estrogen continuously or within 5 years of menopause scored 1.02 and 1.23 points higher on the 3MS, respectively, whereas those who initiated HT 6 or more years after menopause scored 0.64 points higher on the 3MS (see Table 7).

Analyses of Discontinuing HT use

Women who used estrogen through wave 3 or wave 4 were younger (P < 0.001), had higher education (P < 0.001), higher 3MS at baseline (P < 0.001), more physical activity (P < 0.001), and higher levels of depression (P = 0.001) compared with those who never used HT. Comparing those who used HT through wave 3 to those who used through wave 4, no significant differences were found in any variable (data not shown). In a mixed model including all relevant covariates from previous models, both HT groups (continuous use through wave 3 and continuous use through wave 4) had significantly higher 3MS scores through waves 3 and 4 (HT through wave 3: β = 0.89, P = 0.037; HT through wave 4: β = 1.78, P = 0.004) compared with never users. In a model restricted to HT users only, a comparison between HT users through wave 3 to HT users through wave 4 was not significant (β = −0.78, P = 0.142).