Association of Premenopausal Bilateral Oophorectomy With Parkinsonism and Parkinson Disease

Walter A Rocca; Carin Y Smith; Liliana Gazzuola Rocca; Rodolfo Savica; Michelle M Mielke

doi:10.1001/jamanetworkopen.2022.38663

. 2022 Oct 26;5(10):e2238663. doi: 10.1001/jamanetworkopen.2022.38663

Association of Premenopausal Bilateral Oophorectomy With Parkinsonism and Parkinson Disease

Walter A Rocca ^1,^2,^3,^✉, Carin Y Smith ⁴, Liliana Gazzuola Rocca ¹, Rodolfo Savica ^1,², Michelle M Mielke ^1,^2,^3,⁵

¹Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota

²Department of Neurology, Mayo Clinic, Rochester, Minnesota

³Mayo Clinic Specialized Center of Research Excellence (SCORE) on Sex Differences, Mayo Clinic, Rochester, Minnesota

⁴Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota

⁵Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Accepted for Publication: September 11, 2022.

Published: October 26, 2022. doi:10.1001/jamanetworkopen.2022.38663

^✉

Corresponding Author: Walter A. Rocca, MD, MPH, Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, 200 First St, SW, Rochester, MN 55905 (rocca@mayo.edu).

Author Contributions: Dr Rocca and Ms Smith had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rocca.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Rocca.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Smith.

Obtained funding: Rocca.

Administrative, technical, or material support: Rocca.

Supervision: Rocca, Savica.

Conflict of Interest Disclosures: Dr Rocca reported receiving grants from the National Institute on Aging and a Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research endowment from the Mayo Clinic during the conduct of the study. Dr Mielke reported receiving grants from the National Institute on Aging (via Mayo Clinic) during the conduct of the study and serving as a consultant for Biogen, Eli Lilly and Company, Labcorp, and Merck outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grants U54 AG044170 and RF1 AG055151 from the National Institute on Aging, National Institutes of Health (Drs Rocca and Mielke). This study used the resources of the Rochester Epidemiology Project medical records–linkage system, which is supported by grant R33 AG058738 from the National Institute on Aging, the Mayo Clinic Research Committee, and annual fees from Rochester Epidemiology Project users.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content of this article is solely the responsibility of the authors and does not represent the official views of the Mayo Clinic or the National Institutes of Health.

^✉

Corresponding author.

PMCID: PMC9606839 PMID: 36287560

Key Points

Question

Is bilateral oophorectomy performed before spontaneous menopause associated with an increased risk of parkinsonism and Parkinson disease (PD)?

Findings

In this cohort study of 5499 women who did and did not undergo premenopausal bilateral oophorectomy, 978 women who underwent oophorectomy before age 43 years had a statistically significant higher risk of parkinsonism and PD compared with 978 women who did not undergo oophorectomy, with a number needed to harm of 27 women for parkinsonism and 48 women for PD. The risk increased with younger age at bilateral oophorectomy.

Meaning

These findings suggest that reducing the performance of prophylactic bilateral oophorectomy in premenopausal women with average risk of ovarian cancer may have a substantial impact in decreasing the risk of parkinsonism and PD.

Abstract

Importance

The association of premenopausal bilateral oophorectomy with parkinsonism and Parkinson disease (PD) remains controversial.

Objective

To assess whether women who underwent premenopausal bilateral oophorectomy were at increased risk of parkinsonism and PD and whether the associations varied by age at oophorectomy and by receipt of estrogen replacement therapy.

Design, Setting, and Participants

This cohort study used data from a combination of 2 independent cohort studies, the Mayo Clinic Cohort Study of Oophorectomy and Aging 1 and 2, which were based on the Rochester Epidemiology Project medical records–linkage system. A population-based sample of 5499 women from Olmsted County, Minnesota, were included; of those, 2750 women underwent bilateral oophorectomy for a benign indication before spontaneous menopause between January 1, 1950, and December 31, 2007 (oophorectomy cohort), and 2749 age-matched women who did not undergo bilateral oophorectomy were randomly sampled from the general population (reference cohort). Data were analyzed from March 1 to April 30, 2022. The date of oophorectomy was considered the index date for both groups.

Exposures

Medical record documentation of bilateral oophorectomy abstracted from a medical records–linkage system (Rochester Epidemiology Project).

Main Outcomes and Measures

Incidence and risk of parkinsonism or PD, with diagnoses confirmed by in-person examination or medical record review.

Results

Among 5499 participants (median [IQR] age, 45.0 [40.0-48.0] years; 5312 [96.6%] White), 2750 women (2679 White [97.4%]) underwent bilateral oophorectomy at a median age of 45.0 years (IQR, 40.0-48.0 years), and 2749 women (2633 White [95.8%]) with a median age of 45.0 years (IQR, 40.0-48.0 years) at the index date were included in the reference cohort. Bilateral oophorectomy was associated with an increased risk of parkinsonism overall (hazard ratio [HR], 1.59; 95% CI, 1.02-2.46) and in women younger than 43 years at oophorectomy (HR, 7.67; 95% CI, 1.77-33.27). There was a pattern of increasing risk with younger age at the time of oophorectomy using 4 age strata (≥50 years: HR, 1.43 [95% CI, 0.50-4.15]; 46-49 years: HR, 1.55 [95% CI, 0.79-3.07]; 40-45 years: HR, 1.36 [95% CI, 0.64-2.89]; <40 years: HR, 8.82 [95% CI, 1.08-72.00]; P = .02 for trend). The number needed to harm was 53 women overall and 27 women younger than 43 years at the time of oophorectomy. Bilateral oophorectomy was also associated with an increased risk of PD in women younger than 43 years at oophorectomy (HR, 5.00; 95% CI, 1.10-22.70), with a number needed to harm of 48 women. Among women who underwent oophorectomy at 45 years and younger, the risk was lower in women who received estrogen after the procedure and through age 50 years compared with women who did not. For parkinsonism, the HRs were 1.72 (95% CI, 0.54-5.53) vs 2.05 (95% CI, 0.80-5.23); for PD, the HRs were 1.53 (95% CI, 0.29-8.23) vs 2.75 (95% CI, 0.84-9.04). However, the differences were not significant.

Conclusions and Relevance

In this study, premenopausal women who underwent bilateral oophorectomy before age 43 years had an increased risk of parkinsonism and PD compared with women who did not undergo bilateral oophorectomy. These findings suggest that a reduction in the practice of prophylactic bilateral oophorectomy in premenopausal women at average risk of ovarian cancer may have substantial benefit for reducing the risk of parkinsonism and PD.

This cohort study uses data from the Mayo Clinic Cohort Study of Oophorectomy and Aging 1 and 2 to assess the association between premenopausal bilateral oophorectomy and the risk of parkinsonism and Parkinson disease in women.

Introduction

Age-specific incidence rates for Parkinson disease (PD) are higher in men than women across studies and populations.^1,2,3,4,5 Men and women also differ in their risk factors, clinical manifestations, and response to treatment for PD.^6,7,8 These differences have been explained in part by a possible neuroprotective benefit of estrogen for dopaminergic neurons.^8,9,10,11 Therefore, surgical removal of the ovaries in premenopausal women for the prevention of ovarian cancer provides a direct testing of this hypothesis. However, the results so far have been inconsistent, with 3 studies supporting the association and 2 not.^{12,13,14,15,16}

To address the uncertainty caused by the discrepancy across studies and by the limited statistical power of all existing studies, we further tested this association by combining data from 2 existing cohort studies, the Mayo Clinic Cohort Study of Oophorectomy and Aging 1 and 2 (MOA-1 and MOA-2),^12,17 which were based on the Rochester Epidemiology Project (REP) medical records–linkage system. In addition, we studied whether associations varied with age at bilateral oophorectomy and receipt of estrogen replacement therapy after the procedure.

Methods

This cohort study included a population-based sample of 5499 women from Olmsted County, Minnesota, who either underwent bilateral oophorectomy for a benign indication before spontaneous menopause between January 1, 1950, and December 31, 2007 (oophorectomy cohort), or did not undergo bilateral oophorectomy and were randomly selected from the general population and matched by age with women in the oophorectomy cohort (reference cohort). Data were analyzed from March 1 to April 30, 2022. Race and ethnicity data were abstracted from medical records (some electronic and some paper); they were used for balancing the 2 cohorts at index date. We included race in our balancing characteristics because there is a known association between race and PD. All research activities were approved by the institutional review boards of the Mayo Clinic and the Olmsted Medical Center. Written informed consent was obtained from all participants who were contacted in person as part of the original MOA-1 study. However, women were only followed up passively through a medical records–linkage system in the extended MOA-1 study and the MOA-2 study; therefore, informed consent was waived. Women were excluded from the study if they did not authorize the use of their medical records for research (2.5% of 78 448 women in Olmsted County).¹⁸ This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline for cohort studies.

Methods of the MOA-1 Study

The methods of the MOA-1 have been extensively reported elsewhere.^12,19 In brief, we included all premenopausal women residing in Olmsted County who underwent bilateral oophorectomy for a benign indication from January 1, 1950, through December 31, 1987. For women who did not have clear documentation of age at spontaneous menopause, we included those who had bilateral oophorectomy up to age 55 years and were presumed to be premenopausal. Each member of the oophorectomy cohort was matched by age (birth year) to a woman residing in the same county who had not undergone bilateral or unilateral oophorectomy.

For this combined study, we included in the analyses only 1 woman in the reference cohort for each woman in the oophorectomy cohort, and we extended the follow-up from the original MOA-1 study through the last contact with the REP or through December 31, 2020. In total, we included 1097 women who underwent bilateral oophorectomy and 1097 women in the population-based reference cohort. We identified all women who developed parkinsonism during the extended follow-up and added them to the women who had developed parkinsonism in the original MOA-1 study.¹²

Methods of the MOA-2 Study

Details about the MOA-2 study were reported elsewhere.^17,20,21,22 In brief, the MOA-2 included all of the premenopausal women residing in Olmsted County who underwent bilateral oophorectomy for a benign indication between January 1, 1988, and December 31, 2007. However, in contrast to the MOA-1, only women who underwent bilateral oophorectomy before spontaneous menopause and before age 50 years were included. Each woman was randomly matched by age (plus or minus 1 year) to a woman residing in the same county who had not undergone bilateral oophorectomy before the index date (population-based reference cohort). In contrast to the MOA-1, women in the reference cohort who underwent unilateral oophorectomy or hysterectomy with at least 1 ovary conserved were not excluded.

Assessment of Bilateral Oophorectomy

All data were obtained using the medical records–linkage system of the REP, which includes complete records (inpatient and outpatient) from all major medical care facilities in Olmsted County, Minnesota, as described in detail elsewhere.^18,23,24 Demographic and clinical characteristics as well as surgical indications were collected via abstraction of medical records.^12,17,20

Assessment of Parkinsonism and PD

In the original MOA-1 study, women who developed parkinsonism were identified using a combination of direct or proxy interviews, neurological examinations, medical records in a records-linkage system, and death certificates.¹² For the extension of the MOA-1 and for the MOA-2, we searched the electronic indexes of the REP for a series of diagnostic codes for parkinsonism (eTable 1 in the Supplement). Complete medical records in the records-linkage system for women with at least 1 code were reviewed extensively by a nurse abstractor or a physician (L.G.R.) using a structured data entry system. We used diagnostic criteria for parkinsonism and PD that have been reported in detail elsewhere.⁵ However, we excluded women with drug-induced parkinsonism to focus on neurodegenerative types of parkinsonism. The onset of disease for primary analyses was considered the date of first diagnosis.

Statistical Analysis

The index date for each pair was the date of oophorectomy. Women were followed up from their index date until the date of diagnosis of parkinsonism, death, last visit with a REP health care facility, or the end of the study (December 31, 2020). The 2 combined cohorts from the MOA-1 and MOA-2 were balanced at baseline by age at index date, calendar year, race (ie, White vs the combined group of Asian, Black, and other races, given the small percentages in the latter 3 categories), and years of education (≤12 years, 13-16 years, >16 years, and unknown) using inverse probability weights. Other variables at baseline were not available for the MOA-1 cohorts. The inverse probability weights were calculated separately within each stratum to maximize the balance of the variables. After balancing, the standardized differences for all of the characteristics considered were at or lower than the recommended threshold of 0.10 (ie, negligible imbalance between the 2 cohorts) (eFigure 1 in the Supplement).

Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs using age as the time scale. The Cox models used robust sandwich covariance estimates to account for the use of estimated weights and the inclusion of women in both cohorts (women in the reference cohort who underwent subsequent bilateral oophorectomy). Cumulative incidence curves were estimated using the cumulative incidence function; these curves included inverse probability weighting and accounted for the competing risk of death. Differences between the oophorectomy and reference cohorts were also measured using the absolute risk increase or reduction (calculated by subtracting the 2 absolute risks at 50 years after the index date) and the number needed to harm (NNH; calculated as the inverse of the absolute risk increase).

Analyses were performed for all women combined (overall analyses) and separately within strata by age at oophorectomy, surgical indication, and calendar year of surgery (1950-1969, 1970-1989, and 1990-2007). To maximize statistical power within strata, our primary analyses considered age at oophorectomy in tertiles (with tertile 1 indicating age <43 years; tertile 2, age 43-46 years; and tertile 3, age ≥47 years). However, secondary analyses considered age using more conventional cutoffs (<40 years, 40-45 years, 46-49 years, and ≥50 years).²⁵ We also conducted tests for linear trends of the HRs by age of bilateral oophorectomy. Analyses by receipt of estrogen replacement therapy through age 50 years were also stratified by age (≤45 years and 46-49 years). The stratum of 45 years and younger corresponded to the definition of premature or early menopause.²⁵

We performed 4 sets of sensitivity analyses: (1) using age at onset of symptoms of parkinsonism and PD, (2) censoring women in the reference cohort at the time of bilateral oophorectomy if the procedure was performed after the index date, (3) removing from both cohorts women who had undergone hysterectomy, unilateral oophorectomy, or both procedures before the index date, and (4) considering the MOA-1 and MOA-2 studies separately. The balancing variables for the MOA-1 study were the same as those in the combined sample (the list is available in eFigure 1 and eTable 2, footnote c, in the Supplement). However, for the MOA-2 study, we balanced more baseline characteristics (the list is available in eFigure 1 and eTable 3, footnote c, in the Supplement). All tests were conducted with a significance level of 2-tailed α = .05. Analyses were performed using R software, version 4.1.2 (R Foundation for Statistical Computing), and SAS software, version 9.4 (SAS Institute Inc).

Results

Characteristics at Index Date

Among 5499 total participants (median [IQR] age, 45.0 [40.0-48.0] years; 5312 [96.6%] White), 2750 underwent bilateral oophorectomy, and 2749 did not. The oophorectomy cohort included 2750 women who underwent bilateral oophorectomy at a median age of 45.0 years (IQR, 40.0-48.0 years); the median follow-up was 23.9 years (IQR, 17.6-33.1 years; range 0-61.9 years). Of those, 34 women (1.2%) were Asian, 19 (0.7%) were Black, 2679 (97.4%) were White, and 18 (0.7%) were of other races (including American Indian or Alaska Native, Native Hawaiian or Pacific Islander, multiple races, and unknown); 36 women (1.3%) were of Hispanic ethnicity. The reference cohort included 2749 women who did not undergo bilateral oophorectomy, with a median age at index date of 45.0 years (IQR, 40.0-48.0 years); the median follow-up time was 23.8 years (IQR, 17.4-32.8 years; range 0-67.2 years). Of those, 71 women (2.6%) were Asian, 31 (1.1%) were Black, 2633 (95.8%) were White, and 14 (0.5%) were of other races (including American Indian or Alaska Native, Native Hawaiian or Pacific Islander, multiple races, and unknown); 35 women (1.3%) were of Hispanic ethnicity. One woman in the reference cohort was excluded because she developed parkinsonism before the index date. Detailed flowcharts for the combined sample are shown in eFigure 2 in the Supplement, and baseline characteristics of the women included in the combined cohorts are shown in Table 1. Women who underwent bilateral oophorectomy were more commonly White and had fewer years of education (eg, >16 years: 344 women [12.5%] in the oophorectomy cohort vs 395 women [14.4%] in the reference cohort).

Table 1. Baseline Characteristics of Women With and Without Bilateral Oophorectomy.

Characteristic	Participants, No. (%)		P value
Characteristic	With bilateral oophorectomy (n = 2750)	Without bilateral oophorectomy (n = 2749)^a	P value
Age tertile at index date, y^b
<43	978 (35.6)	978 (35.6)	NA
43-46	836 (30.4)	836 (30.4)
≥47	936 (34.0)	935 (34.0)
Age group at index date, y^b
<40	582 (21.2)	582 (21.2)	NA
40-45	1002 (36.4)	1002 (36.4)
46-49	917 (33.3)	917 (33.4)
≥50	249 (9.1)	248 (9.0)
Age at index date, median (IQR), y^b	45.0 (40.0-48.0)	45.0 (40.0-48.0)	NA
Index year^b
1950-1959	145 (5.3)	145 (5.3)	NA
1960-1969	189 (6.9)	189 (6.9)
1970-1979	384 (14.0)	383 (13.9)
1980-1989	481 (17.5)	481 (17.5)
1990-1999	831 (30.2)	831 (30.2)
2000-2007	720 (26.2)	720 (26.2)
Race
Asian	34 (1.2)	71 (2.6)	<.001
Black	19 (0.7)	31 (1.1)
White	2679 (97.4)	2633 (95.8)
Other^c	18 (0.7)	14 (0.5)
Hispanic ethnicity	36 (1.3)	35 (1.3)	.91
Years of education
≤12	983 (35.7)	957 (34.8)	.002
13-16	1267 (46.1)	1186 (43.1)
>16	344 (12.5)	395 (14.4)
Unknown	156 (5.7)	211 (7.7)
Hysterectomy status
None	52 (1.9)	2469 (89.8)	<.001
Before index date^b	191 (6.9)	280 (10.2)
Concurrent	2507 (91.2)	NA
Previous unilateral oophorectomy^d	228 (8.3)	52 (1.9)	<.001
Ovarian indication^e
None	1518 (55.2)	NA	NA
Benign	1232 (44.8)	NA	NA

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Abbreviation: NA, not applicable.

^{^a}

One matched woman in the reference cohort was excluded because she had developed parkinsonism before the index date (eFigure 2 in the Supplement).

^{^b}

The index date (or year) for each pair was the date (or year) of oophorectomy.

^{^c}

Other races included American Indian or Alaska Native, Native Hawaiian or Pacific Islander, multiple races, or unknown.

^{^d}

Of the 228 women who underwent unilateral oophorectomy before bilateral oophorectomy, 61 also underwent hysterectomy. Therefore, the total count of women who had hysterectomy, unilateral oophorectomy, or both procedures before the bilateral oophorectomy was 358. Similarly, of the 52 referent women who underwent unilateral oophorectomy before the index date, 33 also underwent hysterectomy. Therefore, the total count of women who had hysterectomy, unilateral oophorectomy, or both procedures was 299.

^{^e}

The indication was listed by the gynecologist in the medical record at the time of oophorectomy. Benign ovarian conditions included benign tumor, cyst, or endometriosis in either ovary. No ovarian indication included women without a benign ovarian condition in either ovary. Historically, the terms prophylactic, elective, or incidental oophorectomy were used; however, those terms were not used in the present study.

Risk of Parkinsonism and PD

Among 5499 women, 82 (1.5%) developed parkinsonism (50 in the oophorectomy cohort and 32 in the reference cohort), and 53 (1.0%) developed PD (32 in the oophorectomy cohort and 21 in the reference cohort). In the oophorectomy cohort, the median age at symptom onset was 72.0 years (IQR, 66.0-78.0 years), and the median age at diagnosis was 72.5 years (IQR, 66.0-79.0 years), with a median of 26.5 years (IQR, 18.2-36.0 years) between index date and diagnosis. In the reference cohort, the median age at symptom onset was 74.0 years (IQR, 66.5-80.5 years), and the median age at diagnosis was 75.5 years (IQR, 68.5-82.0 years), with a median of 28.2 years (IQR, 21.6-31.7 years) between index date and diagnosis. Among 82 women with parkinsonism, most cases were identified through diagnostic code only (34 women [41.5%]) or direct interview (31 women [37.8%]), with most diagnoses confirmed through medical record review (69 women [84.1%]). Additional characteristics of women who developed parkinsonism during the study follow-up period, details about the types of parkinsonism, and sources of clinical information are shown in Table 2.

Table 2. Characteristics of Women Who Developed De Novo Parkinsonism During Follow-up.

Characteristic	Participants, No. (%)		P value
Characteristic	With bilateral oophorectomy (n = 50)	Without bilateral oophorectomy (n = 32)	P value
Age tertile at index date, y^a
<43	12 (24.0)	2 (6.3)	.03
43-46	12 (24.0)	15 (46.9)
≥47	26 (52.0)	15 (46.9)
Age group at index date, y^a
<40	6 (12.0)	1 (3.1)	.58
40-45	16 (32.0)	12 (37.5)
46-49	20 (40.0)	13 (40.6)
≥50	8 (16.0)	6 (18.8)
Age at index date, median (IQR), y^a	47.0 (43.0-49.0)	46.0 (44.0-49.0)	.77
Index year^a
1950-1959	7 (14.0)	3 (9.4)	.37
1960-1969	7 (14.0)	5 (15.6)
1970-1979	18 (36.0)	7 (21.9)
1980-1989	9 (18.0)	11 (34.4)
1990-1999	9 (18.0)	5 (15.6)
2000-2007	0	1 (3.1)
Race
Asian	0	0	>.99
Black	0	0
White	49 (98.0)	32 (100)
Unknown	1 (2.0)	0
Hispanic ethnicity	0	1 (3.1)	.39
Years of education
≤12	24 (48.0)	17 (53.1)	.89
13-16	15 (30.0)	7 (21.9)
>16	9 (18.0)	7 (21.9)
Unknown	2 (4.0)	1 (3.1)
Hysterectomy status
None	2 (4.0)	24 (75.0)	<.001
Before index date^a	3 (6.0)	8 (25.0)
Concurrent	45 (90.0)	NA
Previous unilateral oophorectomy^b	5 (10.0)	2 (6.3)	.70
Ovarian indication^c
None	28 (56.0)	NA	NA
Benign	22 (44.0)	NA	NA
Type of parkinsonism
Parkinson disease	32 (64.0)	21 (65.6)	.77
Parkinsonism with dementia^d	11 (22.0)	9 (28.1)
Multiple system atrophy	1 (2.0)	0
Progressive supranuclear palsy	2 (4.0)	0
Unspecified	4 (8.0)	2 (6.3)
Source of parkinsonism screening^e
Direct interview	18 (36.0)	13 (40.6)	.90
Proxy interview	11 (22.0)	6 (18.8)
Diagnostic code only	21 (42.0)	13 (40.6)
Source of parkinsonism confirmation^e
Direct examination	8 (16.0)	4 (12.5)	.85
Medical record review	41 (82.0)	28 (87.5)
Direct interview	0	0
Proxy interview	1 (2.0)	0
Age, median (IQR), y
At onset of symptoms	72.0 (66.0-78.0)	74.0 (66.5-80.5)	.52
At diagnosis	72.5 (66.0-79.0)	75.5 (68.5-82.0)	.55
Years between onset of symptoms and diagnosis, median (IQR)	0.5 (0-1.6)	0.7 (0.3-1.6)	.48
Years between index date and diagnosis, median (IQR)^a	26.5 (18.2-36.0)	28.2 (21.6-31.7)	.63
Age tertile at index date
1 (<43 y)	34.2 (21.6-39.9)	49.7 (47.0-52.4)	.04
2 (43-46 y)	33.7 (28.3-37.1)	28.1 (23.3-32.8)	.16
3 (≥47 y)	21.4 (15.7-27.0)	25.1 (20.5-30.4)	.29

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Abbreviation: NA, not applicable.

^{^a}

The index date (or year) for each pair was the date (or year) of oophorectomy.

^{^b}

Of the 5 women who underwent unilateral oophorectomy before bilateral oophorectomy, 0 also underwent hysterectomy. Therefore, the total count of women who had hysterectomy, unilateral oophorectomy, or both procedures before the bilateral oophorectomy was 8. Similarly, of the 2 women in the reference cohort who underwent unilateral oophorectomy before the index date, 1 also underwent hysterectomy. Therefore, the total count of women who had hysterectomy, unilateral oophorectomy, or both procedures was 9.

^{^c}

The indication was listed by the gynecologist in the medical record at the time of oophorectomy. Benign ovarian conditions included benign tumors, cyst, or endometriosis in either ovary. No ovarian indication included women without a benign ovarian condition in either ovary. Historically, the terms prophylactic, elective, or incidental oophorectomy were used; however, those terms were not used in the present study.

^{^d}

Parkinsonism with dementia included women with evidence of dementia before or after the onset of parkinsonism symptoms. Because of the small number of women, the conditions of dementia with Lewy bodies (for dementia that occurred before or within the first year of onset of parkinsonism) and Parkinson disease dementia (for dementia that occurred >1 year after onset of symptoms) were combined.

^{^e}

In the Mayo Clinic Cohort Study of Oophorectomy and Aging (MOA) 1, women who had a positive screening result for parkinsonism via direct or proxy interview were offered an examination by a movement disorders specialist. In addition, and independent from the direct contact, all women in both the MOA-1 and MOA-2 received screening for 1 or more diagnostic codes for parkinsonism. Among the 48 women who had a direct or proxy interview, 46 also had parkinsonism diagnostic codes (17 had a direct interview and 10 had a proxy interview among women who underwent bilateral oophorectomy, and 13 had a direct interview and 6 had a proxy interview among women in the reference cohort). Therefore, only 2 of 82 women would have been missed using only the medical records–linkage system. For women who had positive screening results, complete medical records were reviewed to confirm the diagnosis and type of parkinsonism.

The results of cohort analyses for the combined sample are shown in Table 3, Figure 1, and eFigure 3 in the Supplement. Bilateral oophorectomy was associated with an increased risk of parkinsonism overall (HR, 1.59; 95% CI, 1.02-2.46; NNH, 53 women) (Figure 1A) and in women younger than 43 years at oophorectomy (first tertile; HR, 7.67; 95% CI, 1.77-33.27; NNH, 27 women) (eFigure 3A in the Supplement). There was a statistically significant pattern of increasing risk with younger age at oophorectomy using 4 age strata (≥50 years: HR, 1.43 [95% CI, 0.50-4.15]; 46-49 years: HR, 1.55 [95% CI, 0.79-3.07]; 40-45 years: HR, 1.36 [95% CI, 0.64-2.89]; <40 years: HR, 8.82 [95% CI, 1.08-72.00]; P = .02 for trend) (Figure 1C).

Table 3. Association of Bilateral Oophorectomy With Incident Parkinsonism.

Characteristic	Women with bilateral oophorectomy				Women without bilateral oophorectomy				Unweighted models^a		Weighted models^b
Characteristic	No. at risk	Person-years	Events, No.	Cumulative incidence at age 50 y, % (95% CI)^c	No. at risk	Person-years	Events, No.	Cumulative incidence at age 50 y, % (95% CI)^c	HR (95% CI)	P value	HR (95% CI)	P value
Parkinsonism
Overall parkinsonism	2750	68 572	50	4.5 (3.3-6.2)^d	2749	68 334	32	2.6 (1.8-3.9)^d	1.60 (1.03-2.47)	.04	1.59 (1.02-2.46)	.04
Age tertile, y^e
<43	978	25 320	12	4.3 (2.3-8.0)^f	978	24 615	2	0.6 (0.1-4.4)^f	6.20 (1.45-26.58)	.01	7.67 (1.77-33.27)	.006
43-46	836	19 947	12	5.3 (2.9-9.6)	836	20 088	15	5.1 (3.0-8.7)	0.82 (0.38-1.75)	.60	0.80 (0.38-1.72)	.58
≥47	936	23 305	26	4.7 (3.0-7.2)	935	23 631	15	2.8 (1.7-4.7)	1.76 (0.95-3.27)	.07	1.72 (0.92-3.19)	.09
Age group, y^e
<40	582	15 498	6	3.2 (1.3-8.2)	582	14 790	1	1.0 (0.1-6.7)	5.98 (0.74-48.23)	.09	8.82 (1.08-72.00)	.04
40-45	1002	24 488	16	5.7 (3.4-9.6)	1002	24 490	12	3.3 (1.8-6.2)	1.36 (0.64-2.89)	.42	1.36 (0.64-2.89)	.42
46-49	917	21 377	20	5.6 (3.3-9.4)	917	21 862	13	2.9 (1.6-5.2)	1.60 (0.81-3.16)	.17	1.55 (0.79-3.07)	.21
≥50	249	7209	8	3.4 (1.7-6.7)	248	7192	6	2.5 (1.1-5.4)	1.33 (0.46-3.83)	.60	1.43 (0.50-4.15)	.51
Estrogen therapy within age group^g
≤45 y
Received therapy	629	10 855	9	8.8 (4.1-18.5)	565	9511	4	3.6 (1.1-11.8)	1.74 (0.54-5.58)	.35	1.72 (0.54-5.53)	.36
Did not receive therapy	769	14 447	12	4.4 (2.4-8.0)	658	13 697	7	2.8 (1.3-6.3)	1.77 (0.70-4.46)	.23	2.05 (0.80-5.23)	.13
46-49 y
Received therapy	568	11 956	12	9.4 (4.1-21.2)	547	11 628	7	3.0 (1.3-7.0)	1.69 (0.66-4.32)	.27	1.69 (0.66-4.37)	.28
Did not receive therapy	325	7482	8	4.7 (2.3-9.6)	319	7764	5	2.8 (1.2-6.7)	1.67 (0.55-5.07)	.36	1.64 (0.54-4.98)	.38
Ovarian indication
Benign^h	1232	32 331	22	4.2 (2.7-6.6)	1232	31 902	11	2.3 (1.2-4.4)	2.05 (1.02-4.11)	.04	2.07 (1.03-4.18)	.04
Noneⁱ	1518	36 242	28	4.8 (3.1-7.4)	1517	36 432	21	2.8 (1.8-4.4)	1.37 (0.78-2.40)	.28	1.34 (0.76-2.36)	.31
Index year^j
1950-1969	334	11 616	14	4.6 (2.7-7.7)	334	11 602	8	2.2 (1.1-4.7)	1.78 (0.75-4.26)	.19	1.86 (0.78-4.45)	.16
1970-1989	865	27 150	27	4.4 (3.0-6.7)	864	27 368	18	2.6 (1.6-4.3)	1.54 (0.85-2.78)	.16	1.56 (0.86-2.83)	.14
1990-2007	1551	29 807	9	NA	1551	29 364	6	NA	1.50 (0.57-3.91)	.41	1.45 (0.55-3.78)	.45
Parkinson disease
Overall Parkinson disease	2750	68 658	32	2.6 (1.8-3.9)	2749	68 378	21	1.7 (1.0-2.7)	1.55 (0.89-2.68)	.12	1.54 (0.89-2.67)	.12
Age tertile, y^e
<43	978	25 344	8	2.7 (1.3-6.0)^k	978	24 615	2	0.6 (0.1-4.4)^k	4.16 (0.93-18.66)	.06	5.00 (1.10-22.70)	.04
43-46	836	19 964	7	2.5 (1.1-5.7)	836	20 123	8	2.4 (1.2-5.0)	0.89 (0.32-2.44)	.82	0.88 (0.32-2.42)	.80
≥47	936	23 350	17	2.8 (1.7-4.8)	935	23 640	11	2.0 (1.1-3.6)	1.56 (0.73-3.33)	.25	1.54 (0.72-3.28)	.27
Age group, y^e
<40	582	15 509	4	1.7 (0.5-5.6)	582	14 790	1	1.0 (0.1-6.7)	3.99 (0.46-34.40)	.21	4.93 (0.57-42.55)	.15
40-45	1002	24 515	10	3.3 (1.7-6.6)	1002	24 518	7	1.6 (0.7-3.6)	1.44 (0.55-3.81)	.46	1.47 (0.56-3.89)	.44
46-49	917	21 406	13	3.2 (1.7-6.1)	917	21 876	8	1.7 (0.8-3.7)	1.69 (0.70-4.08)	.25	1.64 (0.68-3.98)	.27
≥50	249	7228	5	2.1 (0.9-5.1)	248	7193	5	2.0 (0.8-4.8)	0.99 (0.29-3.41)	.99	1.10 (0.32-3.76)	.88
Estrogen therapy within age group^g
≤45 y
Received therapy	629	10 874	4	2.0 (0.6-6.6)	565	9518	2	0.9 (0.2-3.8)	1.65 (0.31-8.84)	.56	1.53 (0.29-8.23)	.62
Did not receive therapy	769	14 466	9	3.5 (1.7-7.0)	658	13 718	4	1.7 (0.6-5.1)	2.35 (0.73-7.57)	.15	2.75 (0.84-9.04)	.09
46-49 y
Received therapy	568	11 971	8	5.7 (2.0-15.7)	547	11 635	4	1.0 (0.4-2.7)	1.96 (0.59-6.52)	.27	2.03 (0.60-6.86)	.25
Did not receive therapy	325	7497	5	2.5 (1.0-6.2)	319	7772	3	1.8 (0.6-5.6)	1.78 (0.43-7.42)	.43	1.74 (0.42-7.24)	.45
Ovarian indication
Benign^h	1232	32 378	13	2.4 (1.4-4.4)	1232	31 926	5	1.2 (0.5-3.0)	2.64 (0.95-7.38)	.06	2.70 (0.97-7.54)	.06
Noneⁱ	1518	36 280	19	2.7 (1.6-4.7)	1517	36 452	16	2.0 (1.2-3.4)	1.21 (0.62-2.34)	.58	1.19 (0.62-2.32)	.60
Index year^j
1950-1969	334	11 638	9	3.0 (1.6-5.7)	334	11 619	7	1.9 (0.9-4.3)	1.30 (0.48-3.48)	.61	1.37 (0.51-3.67)	.54
1970-1989	865	27 208	16	2.6 (1.5-4.4)	864	27 385	11	1.5 (0.8-2.7)	1.47 (0.69-3.17)	.32	1.50 (0.70-3.23)	.30
1990-2007	1551	29 812	7	NA	1551	29 373	3	NA	2.32 (0.60-8.96)	.22	2.29 (0.59-8.84)	.23

Open in a new tab

Abbreviation: HR, hazard ratio; NA, not applicable.

^{^a}

HRs were calculated using Cox proportional hazards models with age as the time scale.

^{^b}

HRs were calculated using Cox proportional hazards models with age as the time scale and including inverse probability weights derived from a logistic regression model. The inverse probability weights were calculated separately within each stratum to maximize the balance of the variables. After balancing the 2 cohorts using inverse probability weights, the standardized differences for all of the conditions or characteristics considered were below the recommended threshold of 0.10 (ie, negligible imbalance between the 2 cohorts) (eFigure 1 in the Supplement). Interactions by age, receipt of estrogen replacement therapy, ovarian indication, and calendar year were assessed using stratified analyses. No significant overall interactions were found.

^{^c}

Cumulative risk of parkinsonism at age 50 years after bilateral oophorectomy (or index date) was calculated using the cumulative incidence function and accounting for the competing risk of death. The models included inverse probability weights derived from a logistic regression model.

^{^d}

The overall absolute risk increase for parkinsonism was 1.9% (calculated as 4.5% minus 2.6%), and the number needed to harm was 53 women (calculated as 1 divided by 1.9%).

^{^e}

Linear patterns by age tertile and by conventional age group were assessed using separate models comparing age at oophorectomy strata with all women in the reference cohort combined and including inverse probability weights. The linear pattern for parkinsonism was not significant by age tertile (P = .07) but was significant by age group (P = .02). No significant linear patterns were found for Parkinson disease by age tertile (P = .21) or by age group (P = .11).

^{^f}

Among women younger than 43 years at oophorectomy, the absolute risk increase for parkinsonism was 3.7% (calculated as 4.3% minus 0.6%), and the number needed to harm was 27 women (calculated as 1 divided by 3.7%).

^{^g}

Women who were receiving systemic estrogen replacement therapy (only oral or transdermal) at age 50 years after bilateral oophorectomy. Women who died or were unavailable for follow-up before age 50 years or had not reached age 50 years as of December 31, 2020, were not included in these analyses. Follow-up for these analyses began when women reached age 50 years.

^{^h}

The benign condition (eg, benign tumor, cyst, or endometriosis) was listed by the gynecologist in the medical record at the time of bilateral oophorectomy but may not have been the sole ovarian indication for the procedure.

^ⁱ

Includes women without an ovarian condition. Historically, the terms prophylactic, elective, or incidental bilateral oophorectomy were used; however, those terms were not used in the present study.

^{^j}

The index year for each pair was the year of oophorectomy.

^{^k}

Among women younger than 43 years at oophorectomy, the absolute risk increase for Parkinson disease was 2.1% (calculated as 2.7% minus 0.6%), and the number needed to harm was 48 women (calculated as 1 divided by 2.1%).

The results for PD considered alone were similar in extent and pattern to the results for parkinsonism; however, because of the smaller number of cases, the 95% CIs were broader (Figure 1B). Bilateral oophorectomy was associated with an increased risk of PD in women younger than 43 at oophorectomy (HR, 5.00; 95% CI, 1.10-22.70; NNH, 48 women) (eFigure 3D in the Supplement). However, bilateral oophorectomy was not associated with a significantly higher risk of PD overall (HR, 1.54; 95% CI, 0.89-2.67).

The results of stratified analyses were similar for parkinsonism and PD. For example, the patterns by age at oophorectomy were similar (Figure 1C and D). Women with a benign ovarian indication had a higher risk of parkinsonism (HR, 2.07; 95% CI, 1.03-4.18) and PD (HR, 2.70; 95% CI, 0.97-7.54) compared with women without a benign indication (parkinsonism: HR, 1.34 [95% CI, 0.76-2.36]; PD: HR, 1.19 [95% CI, 0.62-2.32]); however, the differences were not significant. Similarly, women undergoing bilateral oophorectomy at 45 years and younger who did not receive estrogen replacement therapy through age 50 years had a higher risk of parkinsonism (HR, 2.05; 95% CI, 0.80-5.23) and PD (HR, 2.75; 95% CI, 0.84-9.04) than those 45 years and younger who received estrogen replacement therapy (parkinsonism: HR, 1.72 [95% CI, 0.54-5.53]; PD: HR, 1.53 [95% CI, 0.29-8.23]); however, the differences were not significant. Analyses stratified by 3 calendar epochs did not reveal significant differences over time for either the risk of parkinsonism (1950-1969: HR, 1.86 [95% CI, 0.78-4.45]; 1970-1989: HR, 1.56 [95% CI, 0.86-2.83]; 1990-2007: HR, 1.45 [95% CI, 0.55-3.78]) or the risk of PD (1950-1969: HR, 1.37 [95% CI, 0.51-3.67]; 1970-1989: HR, 1.50 [95% CI, 0.70-3.23]; 1990-2007: HR, 2.29 [95% CI, 0.59-8.84]) (Table 3). Figure 2 shows 3 diagrams to illustrate the hypothetical explanations for the association between oophorectomy and parkinsonism or PD.

Figure 2. — In panels A and C, the term gynecologic condition or symptom includes benign ovarian conditions (eg, benign tumor, cyst, or endometriosis), benign uterine conditions (eg, fibroma or adenomyosis), or gynecologic symptoms (eg, chronic pelvic pain or excessive bleeding) that may have prompted the bilateral oophorectomy (indication for the procedure).

Sensitivity Analyses

The results from sensitivity analyses using age at onset of symptoms rather than age at diagnosis of parkinsonism or PD were almost identical to those of the primary analyses (data not shown). Similarly, analyses excluding 256 women in the reference cohort who underwent bilateral oophorectomy after the index date and were censored at the time of oophorectomy and analyses excluding 657 women who underwent hysterectomy, unilateral oophorectomy, or both procedures before the index date yielded similar results (data not shown). Analyses restricted to the MOA-1 study, which included fewer balancing variables, were similar to the analyses restricted to the MOA-2 study, which included additional balancing variables (eTable 2 and eTable 3 in the Supplement). Analyses stratified by smoking in the MOA-2 did not reveal an interaction between oophorectomy and smoking (eTable 3 in the Supplement).

Discussion

Principal Findings

In this population-based cohort study, bilateral oophorectomy was associated with an increased risk of parkinsonism overall and in women who were younger than 43 years at surgery, and there was a significant linear pattern of increasing risk with younger age at oophorectomy. The results for PD considered alone were similar in extent and pattern to the results for parkinsonism; however, the numbers were smaller. We confirmed the importance of age at oophorectomy; however, our sample size was inadequate to detect a significant reduction in risk for women who received estrogen replacement therapy after the oophorectomy.

Historical Comparison With Other Studies

A 2001 case-control study²⁶ reported an association between hysterectomy performed before spontaneous menopause and the risk of PD in a population from the US Midwest. The authors hypothesized that hysterectomy was associated with premature or early ovarian insufficiency. However, a 2003 cohort study²⁷ from the Nurses’ Health Study (NHS) conducted in 11 US states and a 2004 case-control study²⁸ from Sicily, Italy, did not confirm the association. These 3 initial studies^26,27,28 were not specifically designed to assess the association with bilateral oophorectomy .

The 2008 MOA-1 study,¹² which was specifically designed to test this hypothesis in a population from the US Midwest, reported an HR of 1.78 for parkinsonism and a significant pattern of higher risk with younger age at oophorectomy. The results were consistent for PD alone, but they were not statistically significant (likely due to limited statistical power). The authors hypothesized that the harmful consequences of estrogen deprivation for the striatonigral pathway were dependent on age at oophorectomy.^12,29

A first attempt to replicate or refute the MOA-1 findings and to test the age at oophorectomy hypothesis was a 2009 cohort study from the NHS conducted in 11 US states. The NHS analyses did not confirm the association.¹⁵ Important differences between the 2 cohort studies included the restriction of the NHS to volunteer nurses (health care professionals), the self-reporting of gynecologic procedures, the small number of women with PD, and the mean lag time of 5 years between the time of oophorectomy and the time of recruitment into the NHS. The NHS authors reported some important interactions of estrogen with caffeine and smoking.^15,28 However, we did not confirm an interaction of oophorectomy with smoking in our MOA-2 analyses.

The age at oophorectomy hypothesis was further tested in 2 studies^13,14 published in 2014. One case-control study¹³ involving a US population (6 states and 2 metropolitan areas) confirmed the initial hypothesis; however, another case-control study¹⁶ from Denmark found an association in the opposite direction (reduced risk of PD after bilateral oophorectomy). A 2021 French case-control study¹⁴ confirmed an association between bilateral oophorectomy before menopause and an increased risk of PD. A clear explanation of the conflicting results across the 8 studies has not yet been offered. Although there were important methodological differences in the design of the studies (eg, case-control vs cohort studies) and the quality of the data (eg, ascertainment of exposures or outcomes), some differences may be genuine and may be explained by contextual settings (eg, different surgical and medical practices or different smoking habits in different countries or over time).²⁹

Interpretation

Previous publications^12,30,31 have discussed several possible mechanisms to explain the association between bilateral oophorectomy and parkinsonism or PD and have included several diagrams to illustrate the potential mechanisms. Additional diagrams are shown in Figure 2. With some simplification, we propose 3 possible explanations for the association between bilateral oophorectomy and parkinsonism or PD.

First, the association may be explained by a major confounding effect of genetic variants or behavioral and environmental risk factors that may independently increase the risk of both parkinsonism (or PD) and gynecologic conditions or symptoms leading to bilateral oophorectomy (Figure 2A).²² Under this hypothesis, a change in surgical practice to discontinue bilateral oophorectomy for the prevention of ovarian cancer would not modify the risk of parkinsonism or PD. The MOA-1 and MOA-2^12,17 studies did not collect genetic information; however, in sensitivity analyses restricted to the MOA-2, we were able to balance the 2 cohorts at the index date for 18 chronic conditions, years of education, household income, race, body mass index, cigarette smoking, age, and calendar year (using inverse probability weights). These variables could either be direct confounders or could be associated with other confounders that were not observed. The extent of the HRs was not reduced.

Second, bilateral oophorectomy may be associated with brain aging and the risk of parkinsonism or PD (Figure 2B). The association may be mediated by the abrupt and complete deprivation of estrogen or of some other ovarian hormone, producing an acceleration of biological aging of the entire body or, more specifically, of the brain only. Under this hypothesis, a change in surgical practice would have more complete benefits in reducing risk. We estimated that among every 53 women who underwent bilateral oophorectomy, 1 woman would develop parkinsonism within 50 years (NNH, 53 women). In this scenario, genetic variants or behavioral and environmental risk factors may be modifiers rather than confounders. In support of a direct adverse physiological effect of bilateral oophorectomy are reports of accelerated aging after the procedure, measured using either the accumulation of multimorbidity or a methylation clock.^21,22,32,33 A possible adverse effect specific to the brain is also supported by the parallel associations of bilateral oophorectomy with cognitive decline or dementia and with restless legs syndrome.^34,35 Our sample size was inadequate to detect a significant reduction in risk for women who received estrogen replacement therapy after the procedure and through age 50 years.

In addition, our findings supported the hypothesis that age at oophorectomy was associated with parkinsonism. Therefore, previous studies that did not consider age at bilateral oophorectomy or did not include an adequate number of premature (age <40 years) or early (age 40-45 years) procedures may not have properly assessed the association. In addition, the findings of this cohort study provided additional evidence for the adverse effects of estrogen deprivation (or deprivation of other ovarian hormones) for brain aging.³¹ Similar associations have been reported for cognitive decline, dementia, and restless legs syndrome.^34,35

Third, there may be both a confounding effect and an adverse effect of bilateral oophorectomy for the risk of parkinsonism or PD (Figure 2C). Under this more complex hypothesis, bilateral oophorectomy may be partly involved in a chain of adverse events, and a change in surgical practice may have a partial beneficial outcome.

Strengths and Limitations

This study has several strengths. In particular, the 2 oophorectomy cohorts and the 2 reference cohorts were representative of a defined population of the upper Midwest (from population-based studies^12,17). Second, the study did not involve self-reporting of bilateral oophorectomy, thus limiting recall bias. Third, the follow-up period was long (overall median, 23.9 years; IQR, 17.5-33.0 years; range 0-67.2 years).

This study also has limitations. First, our detection of women who developed parkinsonism was imperfect, and we may have missed some women who were not diagnosed or who received an incorrect diagnostic code. However, of the 82 women who developed parkinsonism during follow-up, only 2 did not have any diagnostic code for parkinsonism in the medical records–linkage system and were detected only via direct contact during the original MOA-1 study. Therefore, the possible underascertainment of women with parkinsonism should be small and nondifferential. Second, some of the women with parkinsonism may have been misclassified by type of parkinsonism. Again, the misclassification should be small and nondifferential.

Third, the association between oophorectomy and parkinsonism may be confounded by socioeconomic status. However, analyses balanced for years of education yielded consistent associations in both the MOA-1 and MOA-2 cohorts and in the combined sample. In addition, the results remained consistent in the MOA-2 study after balancing for several potential confounders, including income (eTable 3 in the Supplement). Fourth, our findings may be explained by a surveillance bias favoring the diagnosis of parkinsonism through the records-linkage system in women who underwent oophorectomy. However, the lag time between oophorectomy (or index date) and diagnosis of parkinsonism was long (median, 26.5 years among women in the oophorectomy cohort and 28.2 years among women in the reference cohort).

Fifth, the oophorectomies included in our historical cohorts were performed over 58 years, from 1950 through 2007, and surgical practices and estrogen use changed over time and differed from current standards. However, we did not observe any significant differences over 3 calendar year epochs. Sixth, the population of Olmsted County is primarily White with European ancestry, and our findings may not be generalizable to other populations with a different racial or ethnic composition. Seventh, although our study had adequate power for overall analyses, some of the stratified analyses for age patterns and for the association of estrogen replacement therapy were based on small numbers (ie, limited power). Similarly, the women who developed parkinsonism were too few to group their disease into synucleinopathies and tauopathies.⁵

Conclusions

This population-based cohort study provided stronger evidence in support of an association between premenopausal bilateral oophorectomy and an increased risk of parkinsonism and, among women younger than 43 years at oophorectomy, an increased risk of PD. The findings confirmed the hypothesis that age at oophorectomy was associated with parkinsonism and PD and provided some explanation for the conflicting results from previous studies. The NNHs found in this study suggested that a reduction in the practice of prophylactic bilateral oophorectomy in premenopausal women at average risk of ovarian cancer may have a substantial impact in reducing the risk of parkinsonism and PD.

Supplement.

eTable 1. Diagnostic Codes for Parkinsonism Used to Screen Medical Records

eTable 2. Associations of Bilateral Oophorectomy Performed in 1950-1987 With Incident Parkinsonism (MOA-1 Study)

eTable 3. Associations of Bilateral Oophorectomy Performed in 1988-2007 With Incident Parkinsonism (MOA-2 Study)

eFigure 1. Balance of Characteristics at Baseline Obtained Using Inverse Probability Weights

eFigure 2. Flowchart of the Study Groups

eFigure 3. Cumulative Incidence of Parkinsonism and Parkinson Disease by Age at Oophorectomy in Tertiles

Click here for additional data file.^{(241.8KB, pdf)}

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17.Rocca WA, Gazzuola Rocca L, Smith CY, et al. Cohort profile: the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) in Olmsted County, Minnesota (USA). BMJ Open. 2017;7(11):e018861. doi: 10.1136/bmjopen-2017-018861 [DOI] [PMC free article] [PubMed] [Google Scholar]
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20.Rocca WA, Gazzuola Rocca L, Smith CY, et al. Personal, reproductive, and familial characteristics associated with bilateral oophorectomy in premenopausal women: a population-based case-control study. Maturitas. 2018;117:64-77. doi: 10.1016/j.maturitas.2018.09.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Rocca WA, Gazzuola-Rocca L, Smith CY, et al. Accelerated accumulation of multimorbidity after bilateral oophorectomy: a population-based cohort study. Mayo Clin Proc. 2016;91(11):1577-1589. doi: 10.1016/j.mayocp.2016.08.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Rocca WA, Gazzuola Rocca L, Smith CY, et al. Bilateral oophorectomy and accelerated aging: cause or effect? J Gerontol A Biol Sci Med Sci. 2017;72(9):1213-1217. doi: 10.1093/gerona/glx026 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Rocca WA, Yawn BP, St Sauver JL, Grossardt BR, Melton LJ III. History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population. Mayo Clin Proc. 2012;87(12):1202-1213. doi: 10.1016/j.mayocp.2012.08.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
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25.Rocca WA, Mielke MM, Gazzuola Rocca L, Stewart EA. Premature or early bilateral oophorectomy: a 2021 update. Climacteric. 2021;24(5):466-473. doi: 10.1080/13697137.2021.1893686 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Benedetti MD, Maraganore DM, Bower JH, et al. Hysterectomy, menopause, and estrogen use preceding Parkinson’s disease: an exploratory case-control study. Mov Disord. 2001;16(5):830-837. doi: 10.1002/mds.1170 [DOI] [PubMed] [Google Scholar]
27.Ragonese P, D’Amelio M, Salemi G, et al. Risk of Parkinson disease in women: effect of reproductive characteristics. Neurology. 2004;62(11):2010-2014. doi: 10.1212/WNL.62.11.2010 [DOI] [PubMed] [Google Scholar]
28.Ascherio A, Chen H, Schwarzschild MA, Zhang SM, Colditz GA, Speizer FE. Caffeine, postmenopausal estrogen, and risk of Parkinson’s disease. Neurology. 2003;60(5):790-795. doi: 10.1212/01.WNL.0000046523.05125.87 [DOI] [PubMed] [Google Scholar]
29.Marras C, Saunders-Pullman R. The complexities of hormonal influences and risk of Parkinson’s disease. Mov Disord. 2014;29(7):845-848. doi: 10.1002/mds.25891 [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Rocca WA, Shuster LT, Grossardt BR, et al. Long-term effects of bilateral oophorectomy on brain aging: unanswered questions from the Mayo Clinic Cohort Study of Oophorectomy and Aging. Womens Health (Lond). 2009;5(1):39-48. doi: 10.2217/17455057.5.1.39 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Rocca WA, Gazzuola Rocca L, Smith CY, et al. Loss of ovarian hormones and accelerated somatic and mental aging. Physiology (Bethesda). 2018;33(6):374-383. doi: 10.1152/physiol.00024.2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Levine ME, Lu AT, Chen BH, et al. Menopause accelerates biological aging. Proc Natl Acad Sci U S A. 2016;113(33):9327-9332. doi: 10.1073/pnas.1604558113 [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Lu S, Xu F, Hu W, et al. SCD1 methylation in subcutaneous adipose tissue associated with menopausal age. Climacteric. 2019;22(4):395-402. doi: 10.1080/13697137.2019.1571028 [DOI] [PubMed] [Google Scholar]
34.Rocca WA, Lohse CM, Smith CY, Fields JA, Machulda MM, Mielke MM. Association of premenopausal bilateral oophorectomy with cognitive performance and risk of mild cognitive impairment. JAMA Netw Open. 2021;4(11):e2131448. doi: 10.1001/jamanetworkopen.2021.31448 [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Huo N, Smith CY, Gazzuola Rocca L, Rocca WA, Mielke MM. Association of premenopausal bilateral oophorectomy with restless legs syndrome. JAMA Netw Open. 2021;4(2):e2036058. doi: 10.1001/jamanetworkopen.2020.36058 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eTable 1. Diagnostic Codes for Parkinsonism Used to Screen Medical Records

eTable 2. Associations of Bilateral Oophorectomy Performed in 1950-1987 With Incident Parkinsonism (MOA-1 Study)

eTable 3. Associations of Bilateral Oophorectomy Performed in 1988-2007 With Incident Parkinsonism (MOA-2 Study)

eFigure 1. Balance of Characteristics at Baseline Obtained Using Inverse Probability Weights

eFigure 2. Flowchart of the Study Groups

eFigure 3. Cumulative Incidence of Parkinsonism and Parkinson Disease by Age at Oophorectomy in Tertiles

Click here for additional data file.^{(241.8KB, pdf)}

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[zoi221096r19] 19.Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ III. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol. 2006;7(10):821-828. doi: 10.1016/S1470-2045(06)70869-5 [DOI] [PubMed] [Google Scholar]

[zoi221096r20] 20.Rocca WA, Gazzuola Rocca L, Smith CY, et al. Personal, reproductive, and familial characteristics associated with bilateral oophorectomy in premenopausal women: a population-based case-control study. Maturitas. 2018;117:64-77. doi: 10.1016/j.maturitas.2018.09.002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r21] 21.Rocca WA, Gazzuola-Rocca L, Smith CY, et al. Accelerated accumulation of multimorbidity after bilateral oophorectomy: a population-based cohort study. Mayo Clin Proc. 2016;91(11):1577-1589. doi: 10.1016/j.mayocp.2016.08.002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r22] 22.Rocca WA, Gazzuola Rocca L, Smith CY, et al. Bilateral oophorectomy and accelerated aging: cause or effect? J Gerontol A Biol Sci Med Sci. 2017;72(9):1213-1217. doi: 10.1093/gerona/glx026 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r23] 23.Rocca WA, Yawn BP, St Sauver JL, Grossardt BR, Melton LJ III. History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population. Mayo Clin Proc. 2012;87(12):1202-1213. doi: 10.1016/j.mayocp.2012.08.012 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r24] 24.Rocca WA, Grossardt BR, Brue SM, et al. Data resource profile: expansion of the Rochester Epidemiology Project medical records–linkage system (E-REP). Int J Epidemiol. 2018;47(2):368-368j. doi: 10.1093/ije/dyx268 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r25] 25.Rocca WA, Mielke MM, Gazzuola Rocca L, Stewart EA. Premature or early bilateral oophorectomy: a 2021 update. Climacteric. 2021;24(5):466-473. doi: 10.1080/13697137.2021.1893686 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r26] 26.Benedetti MD, Maraganore DM, Bower JH, et al. Hysterectomy, menopause, and estrogen use preceding Parkinson’s disease: an exploratory case-control study. Mov Disord. 2001;16(5):830-837. doi: 10.1002/mds.1170 [DOI] [PubMed] [Google Scholar]

[zoi221096r27] 27.Ragonese P, D’Amelio M, Salemi G, et al. Risk of Parkinson disease in women: effect of reproductive characteristics. Neurology. 2004;62(11):2010-2014. doi: 10.1212/WNL.62.11.2010 [DOI] [PubMed] [Google Scholar]

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[zoi221096r29] 29.Marras C, Saunders-Pullman R. The complexities of hormonal influences and risk of Parkinson’s disease. Mov Disord. 2014;29(7):845-848. doi: 10.1002/mds.25891 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r30] 30.Rocca WA, Shuster LT, Grossardt BR, et al. Long-term effects of bilateral oophorectomy on brain aging: unanswered questions from the Mayo Clinic Cohort Study of Oophorectomy and Aging. Womens Health (Lond). 2009;5(1):39-48. doi: 10.2217/17455057.5.1.39 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r31] 31.Rocca WA, Gazzuola Rocca L, Smith CY, et al. Loss of ovarian hormones and accelerated somatic and mental aging. Physiology (Bethesda). 2018;33(6):374-383. doi: 10.1152/physiol.00024.2018 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r32] 32.Levine ME, Lu AT, Chen BH, et al. Menopause accelerates biological aging. Proc Natl Acad Sci U S A. 2016;113(33):9327-9332. doi: 10.1073/pnas.1604558113 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r33] 33.Lu S, Xu F, Hu W, et al. SCD1 methylation in subcutaneous adipose tissue associated with menopausal age. Climacteric. 2019;22(4):395-402. doi: 10.1080/13697137.2019.1571028 [DOI] [PubMed] [Google Scholar]

[zoi221096r34] 34.Rocca WA, Lohse CM, Smith CY, Fields JA, Machulda MM, Mielke MM. Association of premenopausal bilateral oophorectomy with cognitive performance and risk of mild cognitive impairment. JAMA Netw Open. 2021;4(11):e2131448. doi: 10.1001/jamanetworkopen.2021.31448 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi221096r35] 35.Huo N, Smith CY, Gazzuola Rocca L, Rocca WA, Mielke MM. Association of premenopausal bilateral oophorectomy with restless legs syndrome. JAMA Netw Open. 2021;4(2):e2036058. doi: 10.1001/jamanetworkopen.2020.36058 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Association of Premenopausal Bilateral Oophorectomy With Parkinsonism and Parkinson Disease

Walter A Rocca, MD, MPH

Carin Y Smith, BS

Liliana Gazzuola Rocca, MD

Rodolfo Savica, MD, PhD

Michelle M Mielke, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Methods of the MOA-1 Study

Methods of the MOA-2 Study

Assessment of Bilateral Oophorectomy

Assessment of Parkinsonism and PD

Statistical Analysis

Results

Characteristics at Index Date

Table 1. Baseline Characteristics of Women With and Without Bilateral Oophorectomy.

Risk of Parkinsonism and PD

Table 2. Characteristics of Women Who Developed De Novo Parkinsonism During Follow-up.

Table 3. Association of Bilateral Oophorectomy With Incident Parkinsonism.

Figure 1. Cumulative Incidence and Risk of Parkinsonism and Parkinson Disease.

Figure 2. Hypothetical Explanations for the Association of Bilateral Oophorectomy With Parkinsonism and Parkinson Disease.

Sensitivity Analyses

Discussion

Principal Findings

Historical Comparison With Other Studies

Interpretation

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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