Ovary Removal Boosts Risks for Cognitive Impairment, Dementia, and Parkinsonism

Estrogen is neuroprotective, and estrogen replacement until age 50 should be considered as a way to protect the brain in women who require oophorectomy before menopause, according to Mayo Clinic researchers. In two recently published studies, Walter A. Rocca, MD, MPH, and colleagues found that women who had one or both ovaries removed before menopause were more likely to develop cognitive problems, dementia, or parkinsonism than were women who did not have oophorectomy.

“In general, women who underwent bilateral oophorectomy before menopause should consider initiating estrogen treatment after the surgery and continuing until at least age 50,” Dr. Rocca told Neurology Reviews. “However, there are possible contraindications, and the decision about treatment needs to be individualized.” Dr. Rocca is a Professor of Neurology and Epidemiology at the Mayo Clinic in Rochester, Minnesota.

Both studies included women who underwent unilateral or bilateral oophorectomy for a noncancer indication and before the onset of menopause while residing in Olmsted County, Minnesota, from 1950 through 1987. Each member of the oophorectomy cohort was matched by age to a woman from the same population who had not undergone oophorectomy. Follow-up data were collected from the participants or their family members, as well as medical records and neurologic examinations. The participants who died before the study or who were incapacitated were assessed via an interview of a proxy informant.

The parkinsonism analysis, which was reported online in the August 29 Neurology included 1,252 women with unilateral oophorectomy, 1,075 women with bilateral oophorectomy, and 2,368 referent women. Parkinson’s disease was diagnosed based on screening interviews and direct examinations, on review of medical records, on previous diagnosis as reported by the subject or by the proxy at interview, or on information from death certificates.

Dr. Rocca found that women who had either unilateral or bilateral ooph-orectomy before the onset of menopause were significantly more likely to develop parkinsonism (hazard ratio [HR], 1.68). The risk increased with younger age at oophorectomy. Furthermore, risk for Parkinson’s disease in women who retained one ovary was as high as for those who had both ovaries removed. “Our findings add new evidence for different risk and protective factors for parkinsonism in men and women,” said Dr. Rocca. “The role of estrogen in the etiology of parkinsonism remains controversial, and our study is an important contribution.”

The analysis of cognitive impairment and dementia, which was reported in the September 14 Neurology, included 813 women with unilateral oophorectomy, 676 women with bilateral oophorectomy, and 1,472 referent women. The subjects were followed up with the Telephone Interview for Cognitive Status-modified questionnaire (TICS-m). For women who died or became incapacitated, the researchers identified a proxy informant who was surveyed with a brief dementia questionnaire. Women were considered affected by cognitive impairment or dementia if they met one of three criteria: score of 27 or less on the TICS-m; a diagnosis of dementia, senility, or Alzheimer’s disease (reported by a proxy); or an impairment in activities of daily living due to cognitive problems (reported by a proxy).

Women who had either unilateral or bilateral oophorectomy before menopause had a significantly increased risk of cognitive impairment or dementia compared with women who had not had their ovaries removed (HR, 1.46). As in the parkinsonism study, risk increased with younger age at oophorectomy and was elevated for both unilateral and bilateral oophorectomy.

The investigators suggested that the trends of increased risk with younger age at oophorectomy indicate that the neuroprotective effects of estrogen may be age-dependent and have a critical age window. “We have previously reported from this same cohort study an age-dependent effect of estrogen on overall mortality and on mortality specific for neurologic and psychiatric disorders,” they wrote. “In addition, we have reported an age-dependent effect of estrogen on the incidence of cognitive impairment or dementia and on the incidence of parkinsonism. Unfortunately, our study did not address the possible biologic mechanisms linking estrogen deficiency with an increased risk of these neurologic diseases.”

Dr. Rocca said that the researchers were surprised that women who had only one ovary removed were also at increased risk of dementia or parkinsonism. “This was contrary to common belief that one ovary is sufficient to produce adequate amounts of estrogen. More research on long-term sequelae of unilateral oophorectomy is needed,” he told Neurology Reviews. He said that some data suggest that removal of the uterus or of only one ovary may compromise the blood supply to the remaining ovary, but he noted that mechanisms other than blood supply are also possible.

“Our study is one of the first to investigate estrogen deficiency before age 50,” said Dr. Rocca. “Because the majority of women reach natural menopause around age 50, only women who underwent oophorectomy and were minimally treated can answer that question. Our findings need to be replicated; however, a clinical trial is not practical. The number of years between estrogen deficiency and neurologic outcomes (eg, parkinsonism and dementia) may be too long for a trial follow-up. In addition, there may be ethical concerns about randomizing young women to estrogen treatment or placebo after oophorectomy. Therefore, we envision that new observational studies would provide more evidence in this age window (before age 50).”

“In view of this new information, careful individualized counseling is necessary to help women make informed decisions. When oophorectomy is indicated in a young woman, it is important to carefully educate that patient regarding estrogen replacement. Unless clear contraindications are present, most women should be advised to take estrogen therapy until approximately age 50,” Dr. Gostout said.            

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