Confirmed: Surgical Menopause Linked to Cognitive Decline

Pauline Anderson

December 18, 2013

The earlier the age of surgical menopause, the faster the decline in cognition, particularly in areas of episodic and semantic memory, and the more Alzheimer disease (AD) neuropathology, new results suggest.

The study confirms previous research showing that abrupt hormonal changes in midlife have a negative effect on cognition in women.

While other studies have looked at the relationship between surgical menopause and cognition, this study was unique in that it included information on AD pathology obtained from autopsies, said lead author Riley Bove, MD, instructor, neurology, Harvard Medical School, and associate neurologist, Brigham and Women's Hospital, Boston, Massachusetts.

The findings were published online December 11 in Neurology.

More Rapid Rate of Cognitive Decline

The study included women from 2 longitudinal studies of cognitive decline: the Religious Orders Study of older Catholic priests, nuns, and brothers that was started in 1994 and the Rush Memory and Aging Project that began enrolling residents of the Chicago area in 1997. All participants were free of known dementia at the time of enrollment.

The current analysis included 1884 women, mean age 78 years at enrollment, who completed the baseline evaluation between January 1994 and August 2012 and for whom reproductive data were available. A third (n = 607) reported having undergone surgical menopause.

A clinical evaluation was repeated annually for up to 18 years. Cognitive function was evaluated using a global cognitive score, with tests categorized into 5 domains: episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability.

Dr. Riley Bove

The investigators found that women who had undergone surgical menopause had a younger mean menopausal age (42 vs 49 years) and were more likely to use hormone replacement therapy (HRT) (53% vs 27%) compared with women who went through natural menopause.

Of the HRT users (n = 632), 71% reported use within 5 years of menopause, with a mean duration of over 13 years.

The results also showed that the earlier age at surgical menopause, the steeper the slope of global cognitive decline (P = .0007). Each year of earlier surgical menopause was similar to the cognitive effects associated with 6 months of aging. Age at time of surgical menopause, divided by quartiles (under 38, 38 to 43, 43 to 49, and over 49 years), was also significant (P = .0008).

"Women who were younger at the time of surgical menopause have a more rapid rate (steeper slope) of cognitive decline than women who were older at the time of surgery or than women undergoing natural menopause," the authors write.

As for the type of cognition affected, earlier age at surgical menopause was associated with a steeper slope of decline in episodic memory (P = .0003) and semantic memory (P = .002).

Window of Opportunity

"One of the hypotheses behind the epidemiologic association between surgical menopause and cognitive decline is that the abruptness of withdrawal of ovarian sources of estradiol may play a role, and also the earlier timing of this withdrawal," said Dr. Bove.

The researchers also had access to brain autopsies for 600 women. They found that earlier age at surgical menopause was associated with a higher burden of the global measure of AD neuropathology (P = .038).

Of the 3 individual markers of AD pathology — neuritic amyloid plaques, neurofibrillary tangles, and diffuse amyloid plaques — the strongest association was with neuritic plaques (P = .013).

"The finding of an association between age at surgical menopause and AD neuropathology is something that is quite unique to our study," said Dr. Bove.

When investigating the role of HRT, the researchers found that HRT use, initiated within 5 years of surgical menopause and continued for at least 10 years, was associated with a decreased slope of decline in global cognition (P = .023) and in less decline in episodic memory, semantic memory, and visuospatial ability.

Duration of HRT use was associated with "more gentle slopes" of decline in episodic memory, visuospatial memory, and perceptual speed, the authors note.

Researchers have long hypothesized that there's about a 5-year perimenopausal "window of opportunity" during which HRT may be protective against cognitive decline, "but if initiated outside that window, there's a risk that HRT may be neutral or even harmful," said Dr. Bove.

"There may be downregulation of estrogen receptors in the brain once there's no longer a continuous major ovarian source of estradiol production."

HRT Protective?

These results should not automatically open the door for women to take HRT to protect their memory because the researchers looked at only 1 aspect of health over the lifespan, said Dr. Bove.

"Perhaps in terms of individuals at risk of cognitive decline, HRT might offer some protection, but the decision of whether or not to start HRT depends on a host of other risk factors, and balancing the pros and cons," one of which is a possible increased risk for breast cancer.

The protective effect was not observed with AD neuropathology, which suggests that the study was underpowered to assess this effect or that HRT's protective effects occur independently of neuropathologic changes, the authors note.

None of the associations observed between early surgical menopause and cognition or AD pathology were observed in women who had natural menopause.

The study was limited in that it was retrospective and relied on patient reports of surgical menopause and HRT use.

In addition, its category of surgical menopause included all gynecologic surgeries, which could be important because only bilateral oophorectomy is associated with abrupt cessation of all ovarian estrogenic production.

"We included women who might have had a hysterectomy and had preserved ovaries and therefore ongoing ovarian production of estradiol, so we believe this may have actually led us to underappreciate the effect of surgical menopause," said Dr. Bove.

Confirms, Extends Earlier Findings

In an accompanying editorial, Walter A. Rocca, MD, Mayo Clinic, Rochester, Minnesota, and Victor W. Henderson, MD, from Stanford University in California, said the study is the first to "confirm and extend" the findings of the 2007 Mayo Clinic Cohort Study of Oophorectomy and Aging.

They also noted that "surgical menopause" in this new study included women who had a preserved ovary.

"Only the women who underwent bilateral oophorectomy are believed to experience an abrupt decline in circulating estrogens and progesterone," they write.

"The effects of removing only the uterus on the remaining ovaries, or the effects of removing one ovary on the other ovary, remain largely unknown," they add.

They pointed out that an oophorectomy done before the onset of natural menopause has more extreme endocrine consequences than when done after the onset of menopause.

Considering the risks and protective factors of dementia in women separately from men will "accelerate the progress of discovery and translation" in AD, the burden of which is particularly great in women.

The study authors, Dr. Rocca, and Dr. Henderson have disclosed no relevant financial relationships.

Neurology. Published online December 11, 2013. Abstract Editorial

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