Interrogating the effects of surgical menopause on the brain using precision MRI: Implications for women’s health

Authors & Affiliations

Elle M. Murata [1], Emily G. Jacobs [1,2]

[1] Department of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA

[2] Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA

Abstract

Although the mechanisms underlying menopause-related neural changes are well-characterized

in animal studies, there is a limited understanding of how the loss of ovarian hormones

associated with menopause influences the human brain. Surgical menopause, which is

associated with an abrupt loss of ovarian hormones, is an operation undergone by hundreds of

thousands of women in the U.S. to treat cancer, endometriosis, fibroids, and other disorders.

Most existing studies on surgical menopause are cross-sectional or only capture a few

timepoints before and after hormone loss, which fails to capture the brain’s response to dynamic

changes in hormone production. Here, I will leverage a dense-sampling, precision imaging

approach to MRI to a clinical setting that is grossly understudied: surgical menopause. In this

longitudinal study, the timeline is designed to capture how the brain changes as it transitions

into a state of chronic hormone loss.

Introduction

Motivation

Despite epidemiological reports that ~60% of women experience menopause-related cognitive

changes (1), cognitive neuroscience studies have historically overlooked the neural effects of

the loss of ovarian hormones associated with menopause. Decades of animal research has

established the neuroprotective effects of ovarian hormones in brain regions that support

memory and cognition and are densely populated with sex steroid hormone receptors, including

the hippocampus and prefrontal cortex (2-3). Although the neural underpinnings of menopause-

related cognitive changes are increasingly well-characterized in animal studies (4), there is a

limited understanding of how menopause influences the brain in humans. This proposal will

leverage a longitudinal design to understand how the immediate loss of estrogen and

progesterone with surgical menopause shapes brain structure, function, and cognition.

Impact/Significance

Each year in the United States, an estimated 300,000 prophylactic oophorectomies are

performed to prevent or alleviate cancer, endometriosis, and other disorders (5). Surgical

menopause has been linked to short-term and long-term health consequences, including

vasomotor symptoms, risk of cardiovascular disease, and neurocognitive changes (6). Rocca

and colleagues (2009) reported that premenopausal bilateral salpingo-oophorectomy (BSO)

was associated with an increased risk of cognitive dysfunction, medial temporal lobe (MTL)

thinning, and dementia (7). A nested case-control study found that premenopausal women who

underwent BSO demonstrated MTL degeneration compared to control women (8). While these

studies indicate that the sudden loss of ovarian hormones impact brain structure and cognition,

cross-sectional and sparse sampling methods limit our understanding of these effects. How

quickly might these changes unfold in individuals? Applying dense-sampling methods to answer

this question will allow us to characterize the timeline and extent to which surgical menopause

impacts brain morphology.

One of the strengths of our lab is our ability to use dense-sampling ‘precision imaging’

designs to understand the brain’s response to dynamic changes in hormone production.

For example, tracking individuals every 12-24 hours for 30 days, the lab discovered that large-scale

brain networks are reorganized in response to diurnal changes in hormone production and

across the menstrual cycle (9-10). Sex hormones also exert a powerful role on brain morphology.

Endogenous fluctuations in progesterone are associated with dynamic volumetric changes in

the MTL. The changes that occur across the menstrual cycle are abolished by chronic hormone

suppression, revealing progesterone’s ability to rapidly modulate neural structures underlying

cognition (11).The immediate loss of estrogen and progesterone associated with BSO may

negatively impact the brain and behavior yet strikingly little is known about how surgical

menopause shapes the brain.

Hypotheses/Aims

Aim 1. Assess the effect of surgical menopause on regional brain morphology.

I will measure gray matter volume and cortical thickness changes to understand whether the

loss of hormones impacts brain structure.

Hypothesis: I predict that surgical menopause will result in decreased gray matter volume and

cortical thickness in the prefrontal cortex and medial temporal lobe regions.

Aim 2. Determine how the sudden loss of ovarian hormones is related to changes in

resting-state functional connectivity.

I will leverage a network-level approach to understand whether surgical menopause impacts

functional connectivity in regions densely packed with ovarian hormone receptors.

Hypothesis: I expect that the rapid decrease in ovarian hormones after surgery will be linked to

decreased coherence in hormone receptor-rich brain networks such as the Default Mode and

Dorsal Attention Networks.

Aim 3. Characterize the effect of surgical menopause on cognition.

Finally, I will test whether cognition is impacted by BSO and the sudden loss of ovarian

hormones.

Hypothesis: I hypothesize that BSO will alter cognitive processes dependent on underlying

medial temporal-prefrontal cortex circuitry, such as associative memory performance.

Materials/Methods

Design: Participants will include three premenopausal women ages 25-45 who undergo bilateral

oophorectomy surgery. Participants will undergo venipuncture and brain imaging prior to

bilateral oophorectomy and after surgery. Individuals will be scanned at two baseline sessions

before surgery, and five sessions after surgery. These visits will be scheduled at 1 month and 1

week pre-surgery and at 1 week, 1 month, 6 months, 8 months, and 1 year post-surgery. Each

visit will include a blood draw, MRI scan, and questionnaires to assess menopause symptoms,

stress, mood, and sleep.

Questionnaires: A short ~10-minute questionnaire including the Perceived Stress Scale,

Pittsburgh Sleep Quality Index, State-Trait Anxiety Inventory, Menopause-Specific Quality of Life,

and medication adherence measures, will be completed within 24 hours of each visit.

Cognitive Tasks: To understand how hormone suppression impacts cognition and memory,

participants will perform an executive function battery validated for longitudinal testing via the

Adaptive Cognitive Evaluation Explorer mobile tool. Tasks include assessments of selective and

sustained attention, inhibitory control, and working memory capacity.

Multimodal Neuroimaging Protocol: To assess the effect of ovarian hormone depletion on large-

scale brain networks, each scanning session includes a 10-minute resting-state paradigm. High-

resolution T1 and T2-weighted anatomical scans will be collected to quantify structural changes.

Finally, diffusion spectrum imaging will allow assessment of potential changes in white matter

integrity in response to decreased hormones. All neuroimaging data will be collected on UC Santa

Barbara’s research-dedicated Siemens Prisma 3T MRI scanner equipped with multiband echo

planar imaging sequences and a 64-channel head coil.

Serological Hormone Assessments: Blood samples will be obtained at each study visit. Endocrine

assessments include gonadal steroid hormones (estradiol, progesterone, testosterone) and

gonadotropins (Luteinizing Hormone, Follicle-Stimulating Hormone).

Budget

This grant would support serological hormone assessments and blood shipping and supply fees

for the proposed project. Estrogen (27 @ $52 per sample = $1,404), progesterone (27 @ $44

per sample = $1,188), follicle-stimulating hormone (27 @ $28 per sample = $756), and

luteinizing hormone samples (27 @ $20 per sample = $540) sum to $3,888. Blood supplies and

shipping cost approximately $1200. The total comes out to $5,088.

References

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perceived memory changes: observations from the Seattle Midlife Women's Health

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https://doi.org/10.1089/152460901750269670.

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in the female rat hippocampus. Hormones and behavior, 34(2), 140–148.

https://doi.org/10.1006/hbeh.1998.1466

3. Taxier, L.R., Gross, K.S. & Frick, K.M. Oestradiol as a neuromodulator of learning and

memory. Nat Rev Neurosci 21, 535–550 (2020).

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9. Grotzinger, H., Pritschet, L., Shapturenka, P., Santander, T., Murata, E.M., & Jacobs,

E.G. (In Press). Diurnal fluctuations in steroid hormones tied to variation in intrinsic

functional connectivity in a densely sampled male. The Journal of Neuroscience.

10. Pritschet, L., Santander, T., Taylor, C. M., Layher, E., Yu, S., Miller, M. B., Grafton, S. T.,

& Jacobs, E. G. (2020). Functional reorganization of brain networks across the human

menstrual cycle. NeuroImage, 220, 117091.

https://doi.org/10.1016/j.neuroimage.2020.117091.

11. Taylor, C. M., Pritschet, L., Olsen, R. K., Layher, E., Santander, T., Grafton, S. T., &

Jacobs, E. G. (2020). Progesterone shapes medial temporal lobe volume across the

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https://doi.org/10.1016/j.neuroimage.2020.117125.

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Interrogating the effects of surgical menopause on the brain using precision MRI: Implications for women’s health

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