In the JournalsPerspective

Estrogen exposure influences cognitive status in late life

Longer endogenous estrogen exposure and use of hormone therapy are associated with higher cognitive status in late life, especially among older women when compared with younger women, according to findings published in Menopause.

Joshua Matyi

“Women who had longer reproductive windows and those who took HT had higher cognitive ability in late life compared to those who had shorter reproductive windows and who did not take HT,” Joshua Matyi, MS, a doctoral candidate in psychology at Utah State University, told Endocrine Today. “The degree of difference between these two groups is very small; however, our results are in contrast with other research that shows an increased risk for dementia when taking HT. Also, our study shows support for the ‘critical window’ hypothesis, such that women who initiated HT closer to menopause had higher cognitive status in late life compared with those that initiated later.”

In a longitudinal, population-based study, Matyi and colleagues analyzed data from 2,114 white women (mean age, 75 years) who were dementia-free at baseline participating in the Cache County Study on Memory in Aging, with the first wave beginning in 1995. Three triennial waves of dementia assessment were performed during 12 years of follow-up. Participants completed a women’s health questionnaire, asking questions regarding reproductive history and HT use. Endogenous estrogen exposure was calculated as the time of reproductive window (age at menarche to age at menopause), adjusted for pregnancy and breastfeeding. HT variables included duration of use, HT type and time of HT initiation. Researchers administered a modified version of the Mini-Mental State Examination (MMSE) at follow-up visits to assess cognitive status, and used linear mixed-effects models to examine the relationship between estrogen exposure and MMSE score.

Within the cohort, mean years of endogenous estrogen exposure was 32.99 years. Surveys revealed 833 women were never-users of HT. Researchers observed that the largest decrease in HT use was between the third and fourth waves, when 86% of users stopped.

Brain MRI 
Longer endogenous estrogen exposure and use of hormone therapy are associated with higher cognitive status in late life, especially among older women when compared with younger women.
Source: Adobe Stock

“This reduction in HT use chronologically coincided with the FDA ‘black box’ warning placed on HT after the WHI,” the researchers wrote.

Researchers found that endogenous estrogen exposure was positively associated with cognitive status (P = .054). In addition, longer duration of HT use was positively associated with cognitive status (P = .046) and interacted with age; older women had greater benefit compared with younger women.

The timing of HT initiation was associated with MMSE scores (P = .048), with higher scores for women who initiated HT within 5 years of menopause vs. those who initiated HT at 6 years or more after menopause. Women who used estrogen continuously or within 5 years of menopause had mean scores that were 1.02 and 1.23 points higher than nonusers of HT. In contrast, those who initiated HT later had mean scores that were 0.64 points higher vs. nonusers.

“As this was an observational study, I believe the clinical implications are broad,” Matyi said, “First, reproductive health has shown an effect on cognitive health in late life. Second, individuals who initiate HT derive the greatest benefit for cognitive health when initiated closer to menopause rather than later. When considering HT, the benefits and risks should be reviewed by a reproductive health specialist.”

by Regina Schaffer

For more information:

Joshua Matyi, MS, can be reached at Department of Psychology, Utah State University, 2810 Old Main Hill, Logan, UT 84322; email: matyiman@yahoo.com.

Disclosures: The National Institute on Aging funded this study. The authors report no relevant financial disclosures.

Longer endogenous estrogen exposure and use of hormone therapy are associated with higher cognitive status in late life, especially among older women when compared with younger women, according to findings published in Menopause.

Joshua Matyi

“Women who had longer reproductive windows and those who took HT had higher cognitive ability in late life compared to those who had shorter reproductive windows and who did not take HT,” Joshua Matyi, MS, a doctoral candidate in psychology at Utah State University, told Endocrine Today. “The degree of difference between these two groups is very small; however, our results are in contrast with other research that shows an increased risk for dementia when taking HT. Also, our study shows support for the ‘critical window’ hypothesis, such that women who initiated HT closer to menopause had higher cognitive status in late life compared with those that initiated later.”

In a longitudinal, population-based study, Matyi and colleagues analyzed data from 2,114 white women (mean age, 75 years) who were dementia-free at baseline participating in the Cache County Study on Memory in Aging, with the first wave beginning in 1995. Three triennial waves of dementia assessment were performed during 12 years of follow-up. Participants completed a women’s health questionnaire, asking questions regarding reproductive history and HT use. Endogenous estrogen exposure was calculated as the time of reproductive window (age at menarche to age at menopause), adjusted for pregnancy and breastfeeding. HT variables included duration of use, HT type and time of HT initiation. Researchers administered a modified version of the Mini-Mental State Examination (MMSE) at follow-up visits to assess cognitive status, and used linear mixed-effects models to examine the relationship between estrogen exposure and MMSE score.

Within the cohort, mean years of endogenous estrogen exposure was 32.99 years. Surveys revealed 833 women were never-users of HT. Researchers observed that the largest decrease in HT use was between the third and fourth waves, when 86% of users stopped.

Brain MRI 
Longer endogenous estrogen exposure and use of hormone therapy are associated with higher cognitive status in late life, especially among older women when compared with younger women.
Source: Adobe Stock

“This reduction in HT use chronologically coincided with the FDA ‘black box’ warning placed on HT after the WHI,” the researchers wrote.

Researchers found that endogenous estrogen exposure was positively associated with cognitive status (P = .054). In addition, longer duration of HT use was positively associated with cognitive status (P = .046) and interacted with age; older women had greater benefit compared with younger women.

The timing of HT initiation was associated with MMSE scores (P = .048), with higher scores for women who initiated HT within 5 years of menopause vs. those who initiated HT at 6 years or more after menopause. Women who used estrogen continuously or within 5 years of menopause had mean scores that were 1.02 and 1.23 points higher than nonusers of HT. In contrast, those who initiated HT later had mean scores that were 0.64 points higher vs. nonusers.

“As this was an observational study, I believe the clinical implications are broad,” Matyi said, “First, reproductive health has shown an effect on cognitive health in late life. Second, individuals who initiate HT derive the greatest benefit for cognitive health when initiated closer to menopause rather than later. When considering HT, the benefits and risks should be reviewed by a reproductive health specialist.”

by Regina Schaffer

For more information:

Joshua Matyi, MS, can be reached at Department of Psychology, Utah State University, 2810 Old Main Hill, Logan, UT 84322; email: matyiman@yahoo.com.

Disclosures: The National Institute on Aging funded this study. The authors report no relevant financial disclosures.

    Perspective
    Pauline Maki

    Pauline Maki

    This was an internally valid study and the authors reached the appropriate conclusions based on their data. The Cache County Study publication on hormone therapy (HT) and dementia predated the WHI Memory Study (WHIMS) and was the first study to indicate that use of HT soon after the onset of menopause may confer the most protection against dementia, while use later could have more neutral or even detrimental effects. This study is another example from that line of work. The modified Mini-Mental State Examination predicts dementia outcomes well. Broadly, these findings are quite consistent with past studies as well as newer studies that do suggest that the longer the reproductive period, the more protected women are. What might be new here is that the authors also have published other important and reliable findings using their HT records, and adding the HT data is a strength of this study. It is important to note that the Cache County Cohort is healthier than most. They live in Utah and, for religious reasons, they drink and smoke less, and have a lower BMI compared with other cohorts. These findings may demonstrate the effects of estrogen exposure in healthy women, as opposed to a more nationally representative population of women. Data from the WHI suggests that women with diabetes, for example, may be especially vulnerable  to negative cognitive effects of HT. We also know from other work that early surgical menopause, without estrogen therapy, is a risk factor for cognitive impairment and dementia. This study adds additional data to support the claim that early loss of estrogen is a risk factor for adverse cognitive outcomes.

    • Pauline Maki, PhD
    • Senior Director of Research, Center for Research on Women and Gender
      Professor of Psychiatry and Psychology, University of Illinois at Chicago

    Disclosures: Maki reports no relevant financial disclosures.