Association of Bilateral Salpingo-Oophorectomy Before Menopause Onset With Medial Temporal Lobe Neurodegeneration

Abstract

Importance: There is an increased risk of cognitive impairment or dementia in women who undergo bilateral salpingo-oophorectomy (BSO) before menopause. However, data are lacking on the association of BSO before menopause with imaging biomarkers that indicate medial temporal lobe neurodegeneration and Alzheimer disease pathophysiology.

Objective: To investigate medial temporal lobe structure, white matter lesion load, and β-amyloid deposition in women who underwent BSO before age 50 years and before reaching natural menopause.

Design, setting, and participants: This nested case-control study of women in the population-based Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) and in the Mayo Clinic Study of Aging (MCSA) in Olmsted County, Minnesota, included women who underwent BSO from 1988 through 2007 and a control group from the intersection of the 2 cohorts. Women who underwent BSO and control participants who underwent a neuropsychological evaluation, magnetic resonance imaging (MRI), and Pittsburgh compound B positron emission tomography (PiB-PET) were included in the analysis. Data analysis was performed from November 2017 to August 2018.

Exposure: Bilateral salpingo-oophorectomy in premenopausal women who were younger than 50 years.

Main outcomes and measures: Cortical β-amyloid deposition on PiB-PET scan was calculated using the standard uptake value ratio. White matter hyperintensity volume and biomarkers for medial temporal lobe neurodegeneration (eg, amygdala volume, hippocampal volume, and parahippocampal-entorhinal cortical thickness) on structural MRI and entorhinal white matter fractional anisotropy on diffusion tensor MRI were also measured.

Results: Forty-one women who underwent BSO and 49 control participants were recruited. One woman was excluded from the BSO group after diagnosis of an ovarian malignant condition, and 6 women were excluded from the control group after undergoing BSO after enrollment. Twenty control participants and 23 women who had undergone BSO completed all examinations. The median (interquartile range [IQR]) age at imaging was 65 (62-68) years in the BSO group and 63 (60-66) years in the control group. Amygdala volume was smaller in the BSO group (median [IQR], 1.74 [1.59-1.91] cm3) than the control group (2.15 [2.05-2.37] cm3; P < .001). The parahippocampal-entorhinal cortex was thinner in the BSO group (median [IQR], 3.91 [3.64-4.00] mm) than the control group (3.97 [3.89-4.28] mm; P = .046). Entorhinal white matter fractional anisotropy was lower in the BSO group (median [IQR], 0.19 [0.18-0.22]) than the control group (0.22 [0.20-0.23]; P = .03). Women were treated with estrogen in both groups (BSO, n = 22 of 23 [96%]; control, n = 10 of 19 [53%]). Global cognitive status test results did not differ between the groups.

Conclusions and relevance: Abrupt hormonal changes associated with BSO in premenopausal women may lead to medial temporal lobe structural abnormalities later in life. Longitudinal evaluation is needed to determine whether cognitive decline follows.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jack consults for Lily and serves on an independent data monitoring board for Roche (uncompensated); he also receives research support from NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. Dr Kantarci serves on the data safety monitoring board for Takeda Global Research and Development Center, Inc; receives research support from Avid Radiopharmaceuticals and Eli Lilly; and receives funding from the National Institutes of Health. Dr Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the National Institute on Aging and National Cancer Institute. Dr Mielke served as a consultant to Eli Lilly and Lysosomal Therapeutics Inc, receives research support from the National Institutes of Health (grant R01 AG49704) and the Department of Defense (grant W81XWH-15-1), and receives unrestricted research grants from Biogen and Lundbeck. Dr Miller receives funding from the National Institutes of Health. Dr Petersen receives funding from the National Institutes of Health, has served on the National Advisory Council on Aging and on the scientific advisory boards of Pfizer, GE Healthcare, Elan Pharmaceuticals, Wyeth Pharmaceuticals, and Janssen Alzheimer Immunotherapy, has received publishing royalties from Oxford University Press, and has been a consultant for Roche Incorporated, Merck, Genentech, Biogen, and Eli Lilly. Dr Schwarz receives funding from the National Institutes of Health.

Figures

Figure 1.. Study Sample

BSO indicates bilateral salpingo-oophorectomy; MCSA, Mayo Clinic Study of Aging; MOA-2, Mayo Clinic Cohort Study of Oophorectomy and Aging-2; MRI, magnetic resonance imaging; PET, positron emission tomography; PiB, Pittsburgh compound B.

Figure 2.. Imaging Characteristics in Women Who Underwent Bilateral Salpingo-Oophorectomy (BSO) vs Control Participants

Box plots show median and interquartile ranges. Amygdala volume was smaller and parahippocampal-entorhinal cortex was thinner on structural magnetic resonance imaging, and entorhinal white matter fractional anisotrophy was lower on diffusion tensor imaging in women who had undergone BSO than in control participants. Hippocampal volume was calculated as raw right plus left hippocampal volumes, adjusted for total intracranial volume. To derive the total intracranial volume–adjusted hippocampal volume, we fit a linear regression model among 133 participants with normal cognitive function aged 30 to 59 years to predict hippocampal volume from total intracranial volume. There were no statistically significant differences in hippocampal volume, cortical Pittsburgh compound B (PiB) standard uptake value ratio, or white matter hyperintensity volume between women who had undergone BSO and control participants.