Women with a history of hormonal birth control, menopausal hormone therapy, or later menopause showed structural brain differences associated with healthier brain aging, offering new insight into how lifetime hormone exposure may influence the aging brain.
Study: Lifespan exposure to hormone therapies and structural brain morphometry in older women. Image credit: Faizal Ramli/Shutterstock.com
A recent study published in the journal NeuroImage found that exposure to endogenous or exogenous ovarian hormones was associated with differences in structural brain measures in older women.
Lifetime hormone exposure may shape brain aging
Menopause is accompanied by symptoms that affect brain aging and cognitive function. Prior research suggests that, compared to men or premenopausal women of the same age, women at or beyond menopause have sharper drops in cognitive function and brain glucose metabolism. A more rapid drop in hippocampal volume and a higher rate of beta-amyloid deposition also indicate a greater tendency towards neurodegeneration.
Estrogens are associated with greater neuroplasticity and neurogenesis in adults and with improved neural signaling. The role of progesterone remains under-studied but is also likely to be involved in brain connectivity and cognitive function.
Despite such evidence, imaging studies have proved inconclusive. Moreover, most studies have investigated either early or midlife exposures to exogenous hormones, through hormonal birth control and menopausal hormone therapy (MHT; also known as hormone replacement therapy, HRT), respectively, separately rather than together.
MRI study compares hormone history with brain health
In the current study, the authors built on their earlier work from the 12-month Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE) study. They had demonstrated that the use of hormonal birth control in early life was linked to better working memory and executive function in older adults.
They also relied on other work suggesting that MHT initiated close to menopause is linked to brain protection against dementia, both functional and structural. The Critical Window Hypothesis suggests that the timing of estrogen exposure shapes its neuroprotective effects.
The investigators used neuroimaging (MRI, or magnetic resonance imaging) and self-reported hormone use in a cohort of 459 women aged 65–80 years from the IGNITE study.
They examined whether the timing of estrogen exposure during early versus midlife, the duration of endogenous estrogen exposure (reflected by later menopause), and the duration of exogenous estrogen exposure through hormonal birth control and menopausal hormone therapy (MHT) were associated with structural markers of brain health, including cortical thickness and gray matter volume.
Birth control and MHT use differed across participants
About 73% of the women were White, and 23% Black, with similar proportions being APOE4 non-carriers and carriers, respectively. APOE4 gene variants increase the risk of dementia.
About 77% of participants had used hormonal birth control, starting at an average of 22 years, for a mean duration of eight years. About 40% used MHT, beginning at an average age of 47, for a mean of 9 years. The use of hormonal birth control showed no association with the age at natural menopause.
Natural menopause occurred at a mean of 51 years, versus surgical menopause at 45 years.
Birth control linked to higher gray matter volume
Women who had ever used hormonal birth control had greater gray matter volume in the temporal, occipital, and frontal brain lobes, compared with never-users. This showed a dose-response relationship across several temporal, occipital, and frontal gyri, particularly the fusiform gyrus, with longer use correlating with larger brain volumes. Notably, this region is involved in visual processing and recognition.
However, the age of start showed no significant associations. Notably, hormonal birth control suppresses cyclic ovarian activity while providing exogenous synthetic hormones. The group of MHT users who also used birth control had almost twice the rate of oophorectomy (surgical ovarian removal) prior to menopause, suggesting that factors other than hormonal exposure may have differed between the groups.
MHT linked to greater gray matter volume
Overall, MHT use was associated with greater volumes in the cuneus, temporal, parietal, and precuneus regions of the brain, as well as greater cortical thickness in the left middle temporal cortex. However, there was no association with duration of use or age of initiation.
Combined hormone exposure associated with thicker cortex
The use of both hormonal birth control and MHT was associated with greater cortical thickness in the posterior cingulate cortex when compared with women who had used neither therapy. Related analyses also suggested greater gray matter volume and cortical thickness in parietal and temporal regions, although a direct comparison between women who used both therapies and never-users did not show significant differences in gray matter volume.
Later menopause associated with increased thickness
Finally, women with later menopause had greater cortical thickness in posterior cortical regions: the precuneus, occipital, temporal, and parietal cortices.
The timing of hormonal birth control or MHT did not appear to be associated with any change in brain structure.
Lifetime hormone exposure linked to healthier brain structure
Taken together, these findings suggest that widely varying exposures to exogenous and endogenous ovarian hormones were associated with differences in brain volumes in brain regions implicated in aging and dementia. Such exposures in early adulthood and at menopause were correlated with structural brain differences generally considered consistent with preserved brain aging.
The results support the idea that both hormonal contraceptive use by young women and MHT are linked to increased volume and thickness in parietal and temporal cortices, although evidence for the Critical Window Hypothesis was only partial.
Specifically, the study found no association between the timing of MHT initiation, its duration, or the interval between menopause and MHT initiation and brain structure. However, the use of hormonal birth control in young women is likely to drastically reduce endogenous estrogen exposure.
Limitations
The study has several limitations. Being observational, it cannot prove that hormonal exposure caused the measured differences in brain structure.
Retrospective self-reported exposure data, without distinguishing different formulations, may introduce misclassification and measurement errors. Many other factors could contribute to the associations, such as varying formulation, dosing, timing, and other health factors. Most participants were relatively inactive at baseline, which limits the generalizability.
The role of progestins was not evaluated, despite their being a key component of many formulations and their ability to alter how estrogens affect the brain. Reverse causation cannot be excluded.
The number of associations tested could also increase the likelihood of false findings. Finally, hormone use decisions often involve the consideration of other risk factors for cognitive decline, including vascular disease, body weight, and psychosocial factors.
Lifetime hormone exposure associated with healthier brain morphology
The study shows that in older women, a history of exposure to hormonal birth control and/or MHT, or of late menopause, is associated with higher brain volumes or greater cortical thickness in some regions linked to cognition.
Larger longitudinal studies would be required to establish exposure-brain structure trajectories over time, while accounting for different formulations, hormone types, biological actions on endogenous hormones, and timing of use.
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