Premenopausal bilateral oophorectomy (PBO) is associated with later-life cognition, but the underlying brain changes remain unclear. We assessed the impact of PBO and PBO age on white matter integrity.

METHODS

Female participants with regional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity (MD) were included (22 with PBO < 40 years; 43 with PBO 40-45 years; 39 with PBO 46-49 years; 907 referents without PBO < 50 years). Linear regression models adjusted for age and apolipoprotein E (APOE) genotype.

RESULTS

Females with PBO < 40 years, compared to referents, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto-occipital fasciculus, superior occipital, and superior temporal white matter. Females who underwent PBO between 45 and 49 also had some changes in white matter integrity.

DISCUSSION

Females who underwent PBO < 40 years had reduced white matter integrity across multiple regions in later-life. These results are important for females considering PBO for noncancerous conditions.

Highlights

Females with premenopausal bilateral oophorectomy (PBO) < 40 years had lower FA versus referents.
Females with PBO < 40 years had higher MD in many regions versus referents.
Adjusting for estrogen replacement therapy use did not attenuate results.
Females with PBO 45-49 years also had some white matter changes versus referents.

1 BACKGROUND

Premenopausal bilateral oophorectomy (PBO) causes abrupt endocrine dysfunction (e.g., loss of estrogen, progesterone, testosterone, and an increase in gonadotropins). Studies suggest that females with PBO are at an increased risk of cognitive impairment and dementia,^1-9 but few neuroimaging studies have been conducted to clarify the underlying pathogenesis. One small study reported PBO was associated with smaller amygdala volume, thinner parahippocampal-entorhinal cortex, and lower entorhinal white matter fractional anisotropy (FA) compared to referent females.¹⁰ Another study reported lower hippocampal volume as early as 6 months, and up to 5 years, post-PBO.¹¹

Long-term ovarian hormone deprivation in rats is associated with reduced white matter integrity.¹² Among humans, females have lower white matter FA compared to males across multiple brain regions, potentially reflecting differences in sex hormone exposure.¹³ Similarly, white matter hyperintensity (WMH) volumes have been shown to be higher for females beginning in midlife.¹⁴ Given sex differences in white matter integrity and the impact of ovarian hormone deprivation on white matter, we hypothesized that females who underwent PBO would have lower FA, and higher mean diffusivity (MD) and WMH volume across brain regions, and that the findings would be strongest for females undergoing PBO at younger ages.

2 METHODS

2.1 Study population

The Mayo Clinic Study of Aging (MCSA) is a population-based cohort study of cognitive aging, initiated in 2004, among a representative sample of Olmsted County, Minnesota, residents.¹⁵ Residents were enumerated using the Rochester Epidemiology Project (REP) medical records-linkage system in a random sampling design stratified by age and sex.¹⁶ In the current study, we included all females enrolled in the MCSA aged 50 years and older with available 3T FLAIR MRI and diffusion tensor imaging (DTI) for measurement of white matter integrity and WMH. Compared to the 1,011 females included in the study with imaging, the 1,817 females excluded due to a lack of imaging were older (76.3 vs. 71.8, p < 0.001), had fewer years of education (13 vs. 14, p < 0.001), where less likely to be an apolipoprotein E (APOE) E4 carrier (25.3% vs. 30.2%, p = 0.005) and were more likely to have a history of myocardial infarction (10.5% vs. 7.1%, p = 0.002) or chronic kidney disease (10.1% vs. 7.2%, p = 0.006).

2.2 Standard protocol approvals, registrations, and patient consent

The study was approved by the Mayo Clinic and Olmsted Medical Center Institutional Review Boards. All participants provided written informed consent.

2.3 Description of medical record abstraction and definitions of females with PBO and referent females

Details regarding the abstraction of PBO in the MCSA have been described.³ Briefly, the REP was searched for surgical procedure codes for unilateral or bilateral oophorectomy. Details about age at bilateral oophorectomy, surgical indication, and use of estrogen replacement therapy (ERT) after oophorectomy were abstracted from medical records by trained abstractors. We grouped females by age at PBO: < 40 years, 40-45 years, and 46-49 years. The age groupings were chosen a priori in line with previous studies by our group and by others.³ The age group < 40 years aligns with the definition of premature menopause and the age group 40-45 years aligns with the definition of early menopause. However, we emphasize that all age groupings for menopause are arbitrary and follow the idea of 5-year age groups that is very common in medicine.

PBO was considered to have a noncancerous indication if it was performed for a presumed nonmalignant ovarian condition, such as adnexal mass, cyst, or endometriosis. We used the term no ovarian condition if the PBO was performed at the time of hysterectomy in the absence of any ovarian condition.

Referents included all women who did not undergo PBO before the age of 50. For referents, details regarding the average age at menopause, gynecological surgeries, use and duration of ERT were abstracted.

2.4 Covariates

Demographic information included self-reported age at the study visit and years of education. APOE ε4 genotyping was performed from a blood sample drawn at the clinical examination. Medical record abstraction was used to assess cardiovascular conditions including hypertension, diabetes mellitus, dyslipidemia, myocardial infarction, and stroke. Body mass index (BMI) was defined as weight in kilograms divided by height in meters squared.

2.5 Neuroimaging

All MRI scans were obtained on a 3T GE scanner with an eight-channel phase array coil (GE, Milwaukee, WI) between 2011 and 2020. DTI acquisition was performed using a single-shot echo-planar imaging sequence with an isotropic resolution of 2.7 mm. The DTI data consisted of 46 images for each set with 41 diffusion-encoding gradient directions (b = 1000 s/mm²) and five non-diffusion-weighted images (b = 0 s/mm²). The diffusion data were preprocessed using the in-house developed pipeline, as previously described.¹⁷ Advanced normalization tools–Symmetric Normalization (ANTS-SyN)¹⁸ was used to nonlinearly register FA image of the Johns Hopkins University “Eve” atlas to each participant's FA and MD images¹⁹ and the median values of FA and MD in each region were obtained. The left and right sides were averaged.

Both 3D MPRAGE and 2D FLAIR images were used to calculate WMH volume. The acquisition and analysis of the FLAIR images were described.²⁰ The possible WMH voxels on FLAIR images were identified through clustering via connected components, masked using white matter masks derived from 3D MPRAGE segmentation to exclude the false-positive WMH voxels, and edited by trained analysts to remove non-WMH voxels.

2.6 Statistical analyses

Data distributions across categorized ages at PBO (referents, PBO < 40, PBO 40-45, and PBO 46-49 years) were compared using chi-square/fisher exact tests for categorical variables, and Kruskal–Wallis tests for continuous variables. FA and MD imaging variables were within-sample z-scored among cognitively unimpaired participants. Associations between categorized age at PBO and z-scored FA and MD regions were analyzed using linear regression models, first unadjusted and then adjusted for age. In sensitivity analyses, we additionally adjusted for the presence of an APOE ɛ4 or for cardiovascular risk factors (i.e., hypertension, diabetes mellitus, dyslipidemia, myocardial infarction, and BMI). The age-adjusted results were visualized in forest plots. A 2-sided p-value < 0.05 was considered statistically significant. Given the exploratory nature of the analyses, we did not adjust for multiple comparisons.²¹ All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).

RESEARCH IN CONTEXT

Systematic review: We reviewed the literature using traditional search engines (e.g., PubMed and Google Scholar). Studies suggest that females with premenopausal bilateral oophorectomy (PBO) are at an increased risk of cognitive impairment and dementia. Few neuroimaging studies have been conducted to clarify the underlying pathogenesis. Long-term ovarian hormone deprivation in rats is associated with reduced white matter integrity. Among humans, females have lower white matter fractional anisotrophy (FA) compared to males across multiple brain regions, potentially reflecting differences in sex hormone exposure. Studies of females who underwent PBO have not comprehensively characterized brain white matter integrity in later-life.
Interpretation: Females who underwent PBO had worse white matter integrity in multiple brain regions, including the anterior corona radiata, genu of the corpus collosum, inferior fronto-occipital fasciculus, superior occipital, and superior temporal white matter. Findings were most pronounced for females who underwent PBO < 40 years. Adjusting for estrogen replacement therapy (ERT) use did not alter the findings.
Future directions: Our study suggests that females with PBO have worse brain white matter integrity in later-life. Future studies with larger sample sizes are needed to confirm the findings. In addition, females in this study used conjugated equine estrogens and it is not known whether other forms of ERT would be more beneficial in maintaining later-life brain white matter integrity.

3 RESULTS

The characteristics of the 1011 females at the first DTI scan after MCSA enrollment are shown in Table 1 by age at PBO or referent. There were no differences between the groups for age at neuroimaging, education, or vascular comorbidities. All females who underwent PBO were more likely to use ERT and for a longer duration compared to females who did not undergo PBO before age 50. Most women who underwent PBO had no ovarian indication. The mean (standard deviation) time between PBO and neuroimaging was 30.1 (11.7) years. Among referents, the average age at menopause was 47.7 years; 357 (39.4%) had a hysterectomy and 153 (16.9%) had a unilateral oophorectomy.

TABLE 1. Participant characteristics, by age at premenopausal bilateral oophorectomy (PBO), at first study visit with diffusion tensor imaging.

Characteristic	Referent: No PBO < 50 N = 907 Median (IQR)/N(%)	PBO < 40 N = 22 Median (IQR)/N(%)	PBO 40-44 N = 43 Median (IQR)/N(%)	PBO 45-49 N = 39 Median (IQR)/N(%)	Total N = 1011 Median (IQR)/N(%)	p-value
Age at imaging	72.07 (63.95, 77.37)	75.41 (64.62, 78.99)	73.00 (63.40, 82.13)	72.61 (66.44, 78.28)	72.15 (64.08, 77.70)	0.45^a
Years from PBO to imaging	–	39.35 (30.62, 44.55)	29.78 (20.08, 38.68)	25.40 (18.44, 30.54)	28.91 (21.59, 38.66)	<0.001^a
BMI, n = 1004	27.37 (24.35, 31.73)	27.48 (22.72, 30.26)	28.43 (26.28, 33.57)	28.25 (25.04, 31.65)	27.44 (24.37, 31.61)	0.33^a
Education, n = 1010	14 (12, 16)	13 (12, 15)	14 (12, 16)	14 (12, 16)	14 (12, 16)	0.35^a
Diabetes	172 (19.0%)	5 (22.7%)	10 (23.3%)	9 (23.1%)	196 (19.4%)	0.80^b
Hypertension	542 (59.8%)	16 (72.7%)	26 (60.5%)	23 (59.0%)	607 (60.0%)	0.68^b
Any APOE E4 allele	272 (30.0%)	6 (27.3%)	12 (27.9%)	13 (33.3%)	303 (30.0%)	0.95^b
Ever use of ERT	508 (56.0%)	18 (81.8%)	38 (88.4%)	34 (87.2%)	598 (59.1%)	<0.001^c
Years of ERT	7.29 (3.89, 12.48)	16.16 (7.69, 24.21)	8.68 (4.48, 14.31)	12.07 (6.15, 16.42)	7.69 (3.98, 13.00)	<0.001^a
Indication						0.10^c
Cancer	–	1 (4.5%)	3 (7.0%)	0 (0.0%)	4 (3.8%)
Non-cancer	–	6 (27.3%)	9 (20.9%)	3 (7.7%)	18 (17.3%)
No ovarian condition	–	15 (68.2%)	31 (72.1%)	36 (92.3%)	82 (78.8%)

Abbreviations: BMI, body mass index; ERT, estrogen replacement therapy; IQR, interquartile range; PBO, premenopausal bilateral oophorectomy.
^a Kruskal–Wallis.
^b Chi-squared.
^c Fisher exact test.

Females with PBO < 40 years, compared to referent females, had significantly lower FA in the anterior corona radiata (b = −0.39, p = 0.02), genu of the corpus collosum (b = −0.37, p = 0.05), inferior fronto-occipital fasciculus (b = −0.60, p = 0.005), inferior frontal white matter (b = −0.48, p = 0.007), superior occipital (b = −0.41, p = 0.04), and superior temporal white matter (b = −0.48, p = 0.02) (Figure 1). Consistently, females with PBO < 40 years also had higher MD in the corona radiata, genu of the corpus collosum, inferior fronto-occipital fasciculus, posterior thalamic radiation, superior occipital, and superior temporal white matter (Figure 2). There were no differences in FA or MD white matter integrity for females who underwent PBO between 40 and 44 compared to referent females. However, females who underwent PBO aged 45-49 years had lower FA in the interior occipital (b = −0.43, p = 0.006), middle frontal (b = -0.35, p = 0.02), posterior thalamic radiation (b = −0.31, p = 0.04), supramarginal (b = -0.33, p = 0.03), superior occipital (b = −0.31, p = 0.04) white matter regions compared to referents. Similarly, females who underwent PBO aged 45-49 years had higher MD in middle frontal (b = 0.28, p = 0.045), retrolenticular part of the internal capsule (b = 0.35, p = 0.02), superior occipital (b = 0.41, p = 0.007), and superior temporal (b = 0.29, p = 0.047) white matter regions. There was a trend for an association between PBO < 40 and higher WMH volume (Table 2).

Details are in the caption following the image — **FIGURE 1**
Open in figure viewer

Associations of age at premenopausal bilateral oophorectomy (PBO) and white matter integrity fractional anisotropy assessed using diffusion tensor imaging. Females without a history of PBO before the age of 50 are referents. Models adjust for age. WM, white matter.

TABLE 2. Associations of age at premenopausal bilateral oophorectomy (PBO) and percent brain white matter hyperintensity volume.

Outcome	Mean estimate (95% CI)	p	Mean estimate (95% CI)	p	Mean estimate (95% CI)	p	Mean estimate (95% CI)	p
	Unadjusted		Age adjusted		Age+APOE adjusted		Age+APOE+ERT adjusted
No PBO < 50	ref	–	ref	–	ref	–	ref	–
PBO < 40	0.41 (−0.02, 0.84)	0.06	0.28 (−0.10, 0.65)	0.15	0.28 (−0.10, 0.65)	0.15	0.31 (−0.07, 0.69)	0.11
PBO 40-44	0.22 (−0.09, 0.54)	0.16	0.18 (−0.09, 0.45)	0.20	0.18 (−0.10, 0.45)	0.20	0.23 (−0.05, 0.51)	0.11
PBO 45-49	0.27 (−0.06, 0.60)	0.11	0.16 (−0.12, 0.45)	0.27	0.16 (−0.13, 0.45)	0.27	0.21 (−0.09, 0.50)	0.17

Abbreviations: APOE, apolipoprotein E; CI, confidence interval; PBO, premenopausal bilateral oophorectomy.

In additional analyses, adjustment for APOE ɛ4 status did not change the results, and presence of an APOE ɛ4 allele did not modify the association between PBO and DTI regions. Results also did not differ after additional adjustment for cardiovascular risk factors, ERT use, number of pregnancies, or use of hormonal contraception. Excluding referent women who underwent premature menopause did not alter the associations.

4 DISCUSSION

Although PBO has been associated with an increased risk of cognitive impairment and dementia,^1-4 few studies have examined the impact of PBO on brain structure to understand potential mechanisms. In this study, females who underwent PBO, especially before the age of 40 years, had worse white matter integrity in multiple brain regions, including the anterior corona radiata, genu of the corpus collosum, inferior fronto-occipital fasciculus, superior occipital, and superior temporal white matter.

Across the lifespan from birth up to 80 years old, males have greater white matter volume than females and the sex differences are consistent both before and after menopause.²² The sex differences in the brain's microstructure have been hypothesized to be due to sex hormones (gonadally mediated) rather than sex chromosomes (non-gonadally mediated). Female-to-male transexuals have larger white matter volumes across multiple regions compared with cis-female age-matched controls,^{23, 24} and white matter FA values increase in congruence with increasing testosterone levels via hormone treatment among these individuals.^{23, 24} In addition, females with complete androgen insensitivity syndrome in the presence of a 46,XY karyotype have lower FA across all brain regions compared to 46,XY males, and similar to 46,XX females.¹³ Thus, increasing testosterone and androgenization is associated with higher FA values. The current results suggest that women who undergo PBO, compared to women who do not, have worse white matter integrity across multiple brain regions. Notably, the ovaries are important endocrine organs that secrete hormones both before (primarily estrogen, progesterone, and testosterone) and after menopause (primarily testosterone and androstenedione). Thus, PBO results in abrupt decreases in both estrogen and testosterone in women. Given the effects of testosterone on brain white matter, and the result in our study that most women who underwent PBO used ERT but still have reduced white matter integrity, it may be hypothesized that the explanation for our results is in part due to loss of testosterone. Additional studies to replicate this finding are clearly needed.

The regions in which the white matter changes were observed, such as the genu of the corpus callosum and inferior frontal white matter, are more consistent with the typical distribution of vascular brain pathology rather than the typical distribution of core Alzheimer's disease (AD) pathologies including amyloid and tau in early AD. However, it is possible that AD pathology could be contributing because we identified some white matter changes in the temporal lobes. The median age of the participants was only 72 years; therefore, we might expect white matter changes due to Alzheimer's pathology to further emerge with increasing age. Notably, brain vascular changes often accompany AD pathology and may be important factors in AD-related cognitive decline.²⁵ In addition, brain vascular changes are early, preclinical features of AD pathology; decreases in cortical blood flow impact amyloid clearance.^{26, 27}

It is interesting that females who underwent PBO between the ages of 45-49 years, but not 40-44 years, also had reduced FA and elevated MD in the same regions. Reasons for this observation are not clear because the characteristics (e.g., comorbidities, education, BMI) at the time of the neuroimaging visit are similar. Further, more than 80% of females who underwent PBO at all ages used ERT; adjusting for ERT use did not affect the associations. Notably, the females in the current cohort would have been prescribed conjugated equine estrogens based on the years of PBO and transition through menopause for referents. It is not known whether other hormone regimens such as transdermal 17β-estradiol would have affected white matter integrity differently.

A strength of the study is the abstraction of medical records to confirm PBO prior to spontaneous menopause and to record ERT use. However, limitations warrant acknowledgment. First, PBO has been associated with an increased risk of cardiovascular disease and other chronic conditions, as well as increased mortality. Thus, females with PBO may have died before the study began or were less likely to participate in the MCSA study or to have a DTI scan. Indeed, compared to women who participated in imaging, women who did not were older and had a higher prevalence of myocardial infarction and chronic kidney disease, all of which contribute to lower white matter integrity. This bias could have led to more conservative results. Second, the participants in the study were predominantly white. Therefore, the results may not be generalizable to more ethnically diverse populations. Third, because this study was exploratory, we did not adjust for multiple comparisons. Future studies are needed to validate the results in larger datasets. Fourth, women who had conditions that led to PBO as an elective surgery may have had a different hormone exposure prior to surgery which impacted the desire to operate and could not be accounted for in the current study. Fifth, menopause-associated hot flashes have been found to influence white matter integrity²⁸ but information regarding hot flashes was not often reported in the medical records. Last, over 80% of the females who underwent PBO used ERT. Therefore, we had limited power to assess whether an interaction existed between PBO and ERT use on brain white matter. However, adjusting for ERT use did not change the results.

Abrupt sex hormone changes due to PBO, especially < 40 years, are associated with lower white matter integrity in later-life. A larger cohort with longer follow-up is essential to further characterize the white matter changes and to establish the relationship between these changes and cognitive impairment.

ACKNOWLEDGMENTS

The authors have nothing to report. Funding for this study was provided by grants from the NIH (U01 AG006786, RF1 AG055151, U54 AG044170) and the GHR Foundation. This study used the resources of the Rochester Epidemiology Project (REP) medical records-linkage system, which is supported by the National Institute on Aging (R33 AG058738), by the Mayo Clinic Research Committee, and by fees paid annually by REP users. However, the content of this article is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health (NIH) or the Mayo Clinic. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.

CONFLICT OF INTEREST STATEMENT

Dr. Mielke has served on scientific advisory boards and/or has consulted for Biogen, Eisai, LabCorp, Lilly, Merck, Roche, Siemens Healthineers, and Sunbird Bio and receives grant support from the National Institute of Health, Department of Defense, and Alzheimer's Association. Dr. Fields serves on the OSMB for the SWAN-aging study. All other authors report no conflicts. Author disclosures are available in the supporting information.

Supporting Information

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Volume20, Issue7

July 2024

Pages 5054-5061

Premenopausal bilateral oophorectomy and brain white matter brain integrity in later-life