AD/PD 2009: Experts Ponder Association Between Oophorectomy and Dementia

Pauline Anderson

March 26, 2009

March 26, 2009 (Prague, Czech Republic) — Researchers have already determined that removing a woman's ovaries before she reaches menopause puts her at increased risk for dementia. Now, they are trying to determine why that is.

Experts have come up with possible scenarios to explain this association between ovary removal and impaired cognition. Walter A. Rocca, MD, professor of epidemiology and neurology at the Mayo Clinic College of Medicine, in Rochester, Minnesota, discussed some of these hypotheses during a presentation here at AD/PD 2009: 9th International Conference of Alzheimer's and Parkinson's Diseases.

Perhaps top of the list of potential culprits is the abrupt decrease in circulating estrogen following the removal of the ovaries, said Dr. Rocca. Estrogen, he said, has a host of beneficial effects on the brain, including reducing oxidative stress and increasing cerebral blood flow. "When you divide women whose ovaries are removed into those who receive estrogen treatment through to age 50 and those who do not or whose hormone use is interrupted before age 50, all of the risk is among the women who did not get treated," he said.

The original study, called the Mayo Clinic Cohort Study of Oophorectomy and Aging, examined the incidence of dementia in women who underwent unilateral or bilateral oophorectomy before menopause. The study included women who had surgical removal of 1 or both ovaries during the preceding 40 years (1950 – 1987), as well as a reference group of women who did not undergo oophorectomy.

Twofold Increased Risk

The researchers, led by Dr. Rocca, found that women who underwent a bilateral oophorectomy before menopause had close to a 2-fold increased risk for not only dementia but also parkinsonism, compared with those who did not have the surgery. The risk was also greater among those who had their ovaries removed and who stopped taking estrogen therapy before the age of 50 years. Women who underwent the procedure but who received estrogen-replacement therapy (ERT) until at least the age of 50 years returned to normal risk (Rocca WA et al. Neurology. 2007;69:1074-1083).

Since then, they have further reported that women with bilateral oophorectomy in this study also had a greater risk for depressive or anxiety symptoms (Rocca WA et al. Menopause. 2008;15:1050-1059).

"For dementia, there is some serious evidence — although not definitive — that the mechanism may be mediated by estrogen, so my theory number 1 is that estrogen is probably important," said Dr. Rocca in an interview.

However, he did not want to say definitively that estrogen withdrawal is the sole mechanism causing the increased risk for dementia, stressing that medicine has a long history of making premature assumptions. "If you jump to conclusions, you may be wrong, and then the cure may be worse than the problem."

The role of estrogen is not clear, as the documented risks of estrogen-replacement therapy illustrate. The Women's Health Initiative (WHI) study, for example, found a link between ERT and increased risks for cardiovascular disease, breast and endometrial cancer, stroke, and dementia.

Estrogen Paradox

So while the Mayo Clinic study showed increased risk for dementia in relatively young women whose exposure to estrogen was interrupted, the WHI findings, for example, showed estrogen treatment initiated 10 to 15 years after menopause was associated with an increase in dementia risk. Dr. Rocca called it a "paradox" that while estrogen can be so seemingly neuroprotective at 1 point during a woman's life, it can be potentially toxic at another.

Alternatively, there could be other mechanisms at play. The ovary is the major endocrine organ for the production of not only estrogen, but also of progesterone and testosterone, and removing this organ likely has an impact on everything from the brain to the skin to the heart and other tissues, said Dr. Rocca. "When you remove the ovary early in life, you also remove progesterone and testosterone early on," he said. "Women must have the best possible balance."

Role of Genes

Genetic interactions may also factor into the equation. Genes may modulate the actions of estrogen or modify the hormonal effect of bilateral oophorectomy through simple or more complex interactions, said Dr. Rocca.

Excessive production of hormones released from the pituitary gland could be yet another important element, as could smoking status, obesity, and diet, he added.

So should women who have their ovaries removed before natural menopause take hormones, and if so, for how long? Dr. Rocca suggested that young women who need to have their ovaries removed because of ovarian diseases such as endometriosis or because they have a sister with ovarian cancer or are carriers of the BRCA1 or BRCA2 genetic variants that have been linked to breast and ovarian cancer should consider treatment with estrogen through the age of 50 years.

The type and timing of ovary removal and hormone replacement is a subject Dr. Rocca hopes will be more thoroughly researched in the future. He predicts that eventually women and their physicians will be able to make more informed decisions about the benefits and the risks of oophorectomy on a case-by-case basis.

Cognitive Impact in Men?

Dr. Rocca had some interesting opinions on the possible cognitive impact in men with prostatic hypertrophy or prostate cancer who are treated with drugs that oppose the effect of testosterone.

"I think that this treatment may be risky (in terms of increasing dementia risk), because it appears these sex hormones are important to development," he said. Removing testosterone could cause problems in men similar to removing ovaries in young women. "I predict that a major premature decline in testosterone among men will have an effect on bone, muscle, and probably the brain," he said.

Dr. Rocca and colleagues expand on some of these potential mechanisms in an article published earlier this year (Rocca WA et al. Women's Health. 2009;5:39-48).

AD/PD 2009: 9th International Conference on Alzheimer's and Parkinson's Diseases. Presented March 12, 2009.

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