Increased Risk of Cognitive Impairment or Dementia in Women Who Underwent Oophorectomy before Menopause

Abstract & Commentary

By Sarah L. Berga, MD, James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, is Associate Editor for OB/GYN Clinical Alert.

Dr. Berga reports no financial relationship to this field of study.

Synopsis: Both unilateral and bilateral oophorectomy preceding the onset of menopause increased the risk of cognitive impairment and dementia. Younger age at time of oophorectomy and lack of hormone use after premenopausal oophorectomy were associated with a greater risk of dementia.

Source: Rocca WA, et al. Neurology. [Epub ahead of print] 2007;69:1074-1083.

The present study indirectly tested the hypothesis that estrogen exposure is neuroprotective by studying the risk of dementia in women who underwent oophorectomy premenopausally. All women residing in Olmstead, MN, from 1950 to 1987 who underwent unilateral or bilateral oophorectomy were followed through death or end of study (staggered from 2001 to 2006). There were 813 women who had unilateral oophorectomy and 676 with bilateral oophorectomy. The referent group was 1472 women residing in the same county who were of comparable age. The RR for cognitive impairment or dementia after premenopausal oophorectomy was 1.46 (confidence interval 1.13-1.90), p < 0.0001. The younger the age of the woman at the time of oophorectomy, the greater was the risk of cognitive impairment or dementia. However, use of hormones up to age 50 after the oophorectomy was associated with a risk of cognitive impairment or dementia comparable to that of the referent (intact) group.

Commentary

The data come from the Mayo Clinic Cohort Study of Oophorectomy and Aging. Using this same cohort, the investigators previously reported that women who underwent prophylactic bilateral oophorectomy before age 45 years and who did not use replacement hormone therapy experienced an increased risk of all cause mortality. Other studies have shown that premenopausal oophorectomy increased the risk of osteoporosis and cardiovascular disease. The investigators interpreted the prior and current studies as evidence for a critical age window of exposure to gonadal steroids. Further, they suggest that the current study results help to reconcile the finding of the Women's Health Initiative Memory (WHIM) study, which showed an increased risk of mild cognitive impairment and dementia in women who took hormones after menopause. Indeed, several lines of evidence support the notion that estrogen is neuroprotective, including the findings that: (1) estrogen improves synapse formation in the hippocampus, a key memory center; (2) estrogen improves cerebral blood flow and glucose metabolism; (3) estrogen increases choline acetyltransferase activity in basal forebrain and hippocampus; (4) estrogen reduces the deposition of beta-amyloid in the brain; and (5) estrogen prevents beta-amyloid from causing mitochondrial damage. There are other data as well, including neuroimaging data in humans that show better reading performance and increased blood flow to regions activated during cognitive tasks in postmenopausal women taking hormones (Shaywitz S, et al. Menopause. 2003; 10:420). No one study alone is conclusive or convincing, but when considered in aggregate, it would appear that estrogen exposure is especially important for women who undergo oophorectomy before menopause. The WHIM trial could be interpreted as suggesting that estrogen loses its neuroprotective actions as women age. Alternatively, it could be that a hiatus in estrogen exposure is the critical insult from which complete recovery is not possible with subsequent estrogen use. Clearly it matters to understand which of these potential interpretations is most likely, as clinical intervention strategies would need to be revised if a hiatus were the factor most likely to accelerate brain aging. It may seem curious that both unilateral and bilateral oophorectomy done before menopause increase the risk of cognitive impairment and dementia. The authors suggest that unilateral oophorectomy or concurrent hysterectomy contribute to premature ovarian failure by interfering with blood supply to the remaining ovary.