The removal of both ovaries before natural menopause occurs has been associated with reduced cognitive ability later in life. However, it remains unclear what pathological changes within the brain contribute to these symptoms.
A recent study published in the journal Alzheimer’s & Dementia examines white matter integrity after premenopausal bilateral oophorectomy (PBO) at various ages.
Study: Premenopausal bilateral oophorectomy and brain white matter brain integrity in later-life. Image Credit: Photoroyalty / Shutterstock.com
Hormones and the female brain
Following PBO, there is a significant reduction in estrogen, progesterone, and testosterone levels, all of which are produced by the ovaries. This is accompanied by a rise in gonadotropins.
Females consistently exhibit fractional anisotropy (FA) during magnetic resonance imaging (MRI) of the brain white matter compared to males, which may be due to the effect of sex hormones rather than genetic sex. Women also exhibit higher white matter hyperintensity (WMH) volumes from midlife onwards.
Previous studies suggest that following PBO, women are more likely to develop dementia and cognitive impairment. However, the changes in the brain due to PBO are poorly understood, thus motivating the current neuroimaging study.
About the study
All study participants were females who had undergone PBO at various ages. More specifically, 22 women underwent PBO at 40 years of age or younger, whereas 43 and 39 women underwent PBO between 40-45 and 46-49 years of age, respectively.
For this study, premature menopause was considered to have happened if the woman had PBO before 40 years of age, with those undergoing PBO at 40-45 years considered to have experienced early menopause.
The control group consisted of 907 women who did not undergo PBO by age 50. As compared to controls, all post-PBO women were more likely to use estrogen replacement therapy (ERT) with equine estrogens and for a longer duration.
Most women who underwent PBO had no ovarian indication for the procedure. Brain MRI scans of the patients were used to assess and compare FA, mean diffusivity (MD), and WMH volumes within different brain regions.
What did the study show?
Compared to the controls, women who underwent PBO before age 40 had lower FA in the anterior corona radiata, genu of the corpus callosum, and superior occipital white matter. Women who underwent PBO also had higher MD in the corona radiata, genu of the corpus callosum, inferior fronto-occipital fasciculus, posterior thalamic radiation, superior temporal white matter, and superior occipital white matter.
Thus, a significant reduction in white matter integrity was observed in women following PBO. Even after compensating for the use of hormonal replacement therapy, which restored some estrogen levels, the results remained significantly different in the PBO group as compared to controls.
Similar though less marked changes were observed in women who underwent PBO between 45 and 49 years of age. However, these alterations were not observed among women who underwent PBO between 40 and 45 years of age.
The presence of the apolipoprotein ɛ4 (APOE ɛ4) gene is an independent risk factor for white matter integrity loss. In the current study, adjusting for APOE ɛ4 did not alter the results. Similarly, the consideration of cardiovascular risk factors, use of estrogen replacement therapy, gravidity, or hormonal contraception also failed to modify the results.
Conclusions
The current study suggests a reduction in white matter integrity that extends across multiple brain regions among women who underwent PBO before the age of 40.
These findings support previous studies indicating reduced volume of the amygdala, hippocampus, and other white matter regions of the brain. These regions are associated with vascular dementia to a greater extent than AD; however, some of the observed changes in the temporal lobes are also suggestive of AD.
Brain vascular changes often accompany and contribute to cognitive decline in AD. Moreover, these alterations typically predate and predict the development of AD-related disease in the brain cortex.
The decrease in white matter integrity may be due to the loss of androgens rather than estrogens; however, this requires further validation. Future studies with larger cohorts are also needed to explore the effect of estrogen replacement by other estrogens than equine, which was the only form used by participants in the current study.
Journal reference:
- Mielke, M. M., Frank, R. D., Christensen, L. R., et al. (2024). Premenopausal bilateral oophorectomy and brain white matter brain integrity in later-life. Alzheimer’s & Dementia. doi:10.1002/alz.13852.
