The removal of both ovaries before natural menopause, known as premenopausal bilateral oophorectomy (PBO), has been associated with a decline in cognitive abilities later in life. Despite this, the specific brain changes responsible for these cognitive deficits are not well understood. A recent study published in the journal Alzheimer’s & Dementia explores the impact of PBO on white matter integrity in the brain.
Hormones and the Female Brain
PBO results in a significant drop in levels of estrogen, progesterone, and testosterone, accompanied by an increase in gonadotropins. These hormonal changes are believed to affect brain structure and function. Studies have shown that females typically exhibit higher fractional anisotropy (FA) in brain white matter on MRI compared to males, which is likely due to the influence of sex hormones rather than genetic sex. Additionally, women tend to have higher volumes of white matter hyperintensities (WMH) from midlife onwards.
Previous research indicates that PBO increases the risk of dementia and cognitive impairment in women. However, the specific brain alterations post-PBO remain poorly characterized, prompting the current neuroimaging study.
About the Study
The study included female participants who had undergone PBO at different ages. Specifically, 22 women had PBO at 40 years or younger, 43 women had PBO between 40-45 years, and 39 women had PBO between 46-49 years. Premature menopause was defined as PBO before 40, and early menopause was defined as PBO between 40-45.
The control group consisted of 907 women who did not undergo PBO by age 50. Compared to controls, post-PBO women were more likely to use estrogen replacement therapy (ERT) with equine estrogens for longer durations.
Most women who underwent PBO had no specific ovarian indication for the procedure. Brain MRI scans were utilized to assess and compare FA, mean diffusivity (MD), and WMH volumes across different brain regions.
Study Findings
The study found that women who underwent PBO before age 40 exhibited lower FA in the anterior corona radiata, genu of the corpus callosum, and superior occipital white matter compared to controls. Additionally, these women had higher MD in several brain regions, including the corona radiata, genu of the corpus callosum, inferior fronto-occipital fasciculus, posterior thalamic radiation, superior temporal white matter, and superior occipital white matter.
These findings indicate a significant reduction in white matter integrity post-PBO. Even after accounting for hormonal replacement therapy, the results remained significantly different between the PBO group and controls. Less pronounced changes were observed in women who underwent PBO between 45 and 49 years, while no significant changes were noted in the 40-45 age group.
The study also considered the presence of the apolipoprotein ɛ4 (APOE ɛ4) gene, a known risk factor for white matter integrity loss. Adjusting for APOE ɛ4, cardiovascular risk factors, use of estrogen replacement therapy, gravidity, or hormonal contraception did not alter the study’s results.
Conclusions
The study suggests that PBO before age 40 leads to a reduction in white matter integrity across multiple brain regions. These findings align with previous studies indicating reduced volumes in the amygdala, hippocampus, and other white matter regions. These areas are more closely associated with vascular dementia than Alzheimer’s disease (AD), though some observed changes in the temporal lobes suggest AD involvement.
Vascular changes in the brain often accompany and contribute to cognitive decline in AD, typically preceding and predicting the development of AD-related disease in the brain cortex. The observed decrease in white matter integrity may result from the loss of androgens rather than estrogens, though this hypothesis requires further investigation.
Future research should include larger cohorts and explore the effects of different forms of estrogen replacement beyond equine estrogens. These studies will be crucial in understanding the mechanisms behind PBO-induced brain degeneration and developing effective strategies to mitigate these effects.
