How does lifetime estrogen exposure affect late-life cognition?

Results from a recent study appearing in Menopause indicate that higher endogenous estrogen exposure (EEE) and hormone therapy (HT) may lead to higher cognitive status for women in later life. The results are based on a 12-year population study that included over 2000 adult women.

Methods
The study used data from the Cache County Study on Memory in Aging - a population based-sample of over 5,092 residents (2,928 women) living in Cache County, Utah. The study relied on four triennial waves of dementia ascertainment over the course of 12 years to identify factors for Alzheimer’s Disease. Because Alzheimer’s disease is more prevalent in women, and possibly influenced by sex-dependent effects of estrogen, this study explored the effect of lifetime estrogen exposure on late-life cognitive decline. Lifetime estrogen exposure was based on endogenous exposure (time of menarche to menopause), number of pregnancies, duration of breast feeding and HT use.

The baseline sample for this study included 2,114 women (mean age=74.94 years, standard deviation [SD] =6.7) who were dementia-free at baseline and completed an adaption of the 100-point modified Mini-Mental State Examination (3MS) questionnaire. The questionnaire focused on the participant’s reproductive history and HT use. EEE was calculated by taking the reproductive window (age at menarche to age at menopause) and was adjusted for pregnancy and breastfeeding. Relevant HT variables included duration of use, HT type (unopposed vs opposed), and time HT initiation. The authors used linear mixed-effects models to examine the relationship between estrogen exposure and 3MS scores over time.

Results
The authors found that:

• EEE was positively associated with cognitive status (ß =0.03, P = 0.054).

• Longer duration of HT use was positively associated with cognitive status (ß = 0.02, P = 0.046) and interacted with age.

• Older women had a greater benefit from HT use compared to younger women

• Use of either type of HT (opposed or unopposed) was associated with higher 3MS scores (P = 0.001) compared with no HT use.

• The timing of HT initiation was significantly associated with 3MS scores (ß = 0.55, P = 0.048).

• Women who initiated HT within 5 years of menopause had higher 3MS scores than women who initiated HT at 6 years or more since menopause. Those who initiated HT regardless of time since menopause had higher 3MS scores than nonusers.

Conclusion
The authors believe their findings indicate that longer EEE and HT use, especially in older women are associated with higher cognitive status later in life. Future research might investigate factors known to disrupt endogenous estrogen, such as cancer, or focus on the initiation of HT in late-life in order to compare health-related factors between participants to help clarify the effects of HT on late-life cognition.