Premenopausal Bilateral Oophorectomy More Strongly Linked to Cognitive Decline

New research provides additional evidence that bilateral oophorectomy before menopause increases the risk of cognitive decline.

In a retrospective case-control study of 2,732 women ages 50-89, bilateral oophorectomy before menopause and age 46 was associated with increased risk of mild cognitive impairment (OR 2.21, 95% CI 1.41-3.45, P<0.001), after adjusting for factors including age, education, and APOE genotype, reported Walter Rocca, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.

In their study online in JAMA Network Open, the team also noted that premenopausal bilateral oophorectomy before age 46 was associated with decreased global cognition z scores (β = -0.17, P=0.02), attention and executive domain z scores (β = -0.21, P=0.009), and Short Test of Mental Status scores (β = -0.51, P=0.02) compared with no bilateral oophorectomy.

“This finding suggests that physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment … and should consider implementing treatment-monitoring plans,” the study authors wrote.

The risk affected women who underwent bilateral oophorectomy for benign ovarian conditions (OR 2.43, 95% CI 1.36-4.33, P=0.003), but it did not affect those who underwent the procedure for cancer or non-ovarian conditions. In addition, there was no risk difference between women who had estrogen therapy and those who did not, the study found.

“These findings, in conjunction with the results of other studies finding associations of premenopausal bilateral oophorectomy with risk of multiple chronic conditions, may help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” the researchers wrote.

The hypothesis that surgical removal of the ovaries before menopause is associated with brain aging outcomes has been studied for more than a decade, the team noted.

Previous studies have reported similar results, but the association is not considered established, Rocca and co-authors explained.

“The major reasons for this lack of recognition are the association of age at which the bilateral oophorectomy is performed with cognitive decline or dementia and controversial data about the association of estrogen therapy after oophorectomy with cognitive decline or dementia,” the investigators said. “In this study, we addressed some limitations of previous studies by focusing on premature or early bilateral oophorectomy, focusing on mild cognitive impairment, and using a comprehensive cognitive battery (9 cognitive tests covering 4 domains).”

The study included women who participated in the Mayo Clinic Study of Aging. The researchers also used data from the Rochester Epidemiology Project medical record-linkage system. The population-based sample was comprised of primarily white women who lived in Olmsted County, Minnesota.

Median age at the time of cognitive evaluation was 74, and approximately 10% were found to have mild cognitive impairment. The median time between oophorectomy and cognitive evaluation was 30 years.

The study authors noted that potential mechanisms linking oophorectomy and cognitive decline include the abrupt and prolonged decrease in circulating levels of hormones such as estrogen, progesterone, and testosterone. In addition, the association could also be caused by disruption of the hypothalamus-pituitary-ovarian axis and the increased release of gonadotropins by the pituitary gland.

Alternatively, the mechanism might be more complex, including interactions among hormones, genetic variants, and risk factors such as smoking and obesity, the researchers hypothesized.

Writing in an accompanying editorial, Marios Georgakis, MD, PhD, of Massachusetts General Hospital in Boston, and Eleni Petridou, MD, PhD, of the University of Athens in Greece, said the study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature. Information on menopausal status at the time of the surgery and the exact procedure reduced misclassification of the exposure of interest.”

“Furthermore,” the editorialists added, “data on indication of bilateral oophorectomy allowed exploring unique insights about whether the higher risk associated with bilateral oophorectomy could be potentially preventable. Although the analyses were underpowered, the findings support an association between mild cognitive impairment and women who underwent bilateral oophorectomy for benign indications, such as adnexal masses, cysts, or endometriosis. This is important, because in many of those cases, removal of both ovaries could be avoided.”

Georgakis and Petridou also noted some important limitations to the study, including the potential for selection bias, since only women who survived to older ages were included. “This selection on survival might introduce collider bias, since both bilateral oophorectomy and cognitive impairment could affect mortality,” the editorialists explained.

Rocca and colleagues noted additional limitations, including that there was only one cognitive assessment for each participant and that it did not evaluate cognitive function over time. Furthermore, because the study included primarily white women living in Minnesota, the results might not be generalizable to other populations.

Last Updated November 11, 2021