ARTICLE IN BRIEF
Investigators found early age at menopause was associated with a faster decline in semantic, long-term, and episodic memory, as well as global cognition. The data will be described later this month at the AAN annual meeting.
Is earlier age at menopause associated with faster cognitive decline? Is hormone replacement therapy (HRT) use harmful or neuroprotective? These questions have informed an ongoing debate about the association between age at menopause and HRT and cognition for more than a decade.
Now, a new study has again found that an earlier age at surgical menopause may be associated with an increased risk of memory decline and cognitive impairment. More complete data will be presented to scientific peers at the AAN annual meeting in San Diego later this month.
“The results suggested that younger age at surgical menopause is associated with a steeper slope of long-term cognitive decline as well as with increased neuritic plaques, all of which have been associated with Alzheimer's disease,” study author Riley Bove, MD, instructor in neurology at Harvard Medical School and an associate neurologist at the Brigham and Women's Hospital in Boston, MA, told Neurology Today.
Also, “we saw an association between longer duration of HRT and slower rate of cognitive decline — only in women undergoing surgical menopause,” she added.
“We conducted an observational study that examined 1837 women, 33 percent of whom had undergone surgical menopause. We examined performance on cognitive tests, as well as their pathologic outcomes and clinical diagnoses,” said Dr. Bove.
The women were between the ages of 53 and 100, and participating in the Religious Orders Study and Memory and Aging Project at Rush University Medical Center. Follow-up, on average, was about seven to eight years. The study found that early age at menopause was associated with faster decline in semantic memory, or long-term memory concerned with ideas, meanings, and concepts, (p=0.002); episodic memory (events of personal importance) and global cognition (ps<0.001). Age at menopause and neuropathologic measures, such as neuritic plaques (p=0.01) and global pathology score (p=0.04) also showed a significant association. There was no significant association with incident Alzheimer's disease (p=0.093). Duration of HRT was associated with slower decline in global cognition (p=0.037). These associations were only seen in women who had undergone surgical menopause.
These are very preliminary data, Dr. Bove said, but they replicate the findings of a 2007 Neurology study by Walter A. Rocca, MD, MPH, and colleagues. At this time, she added, “these findings do not warrant any medical advice” about discontinuing HRT use.
This study was supported by grants from the National Institutes of Health. [The Religious Orders Study was initially funded in 1993, with clinical evaluations beginning in 1994.]
Dr. Rocca, the Ralph S. and Beverley E. Caulkins professor of neurodegenerative diseases research, professor of epidemiology and neurology at Mayo Clinic in Rochester, MN, said this study is the first to replicate the findings from the Mayo Clinic Cohort Study of Oophorectomy and Aging in a North American population.
“In 2007, we first reported evidence from the Mayo Clinic study suggesting that women who undergo bilateral oophorectomy before the onset of menopause have a long-term increased risk of cognitive impairment or dementia. The risk increased with younger age at oophorectomy, did not vary by indication for the oophorectomy, and was eliminated by estrogen treatment after the surgery and up to age 50 years or longer,” he said.
He added that the findings were first replicated by a Danish study in 2010, but not by any groups in the US. So, he said, “the study by Bove and colleagues is an exciting surprise coming six years later.”
One limitation of the study, Dr. Rocca added, is the use of the term “surgical menopause.” Surgical menopause is an ambiguous term, he said, which includes “several distinct endocrine situations. It is important to separate the group of women who had hysterectomy with one or both ovaries preserved from those women who had both ovaries removed (with or without hysterectomy). Only the women who underwent bilateral oophorectomy are believed to experience an abrupt decline in circulating estrogen and other ovarian hormones.”
This study is another piece of the puzzle, said Kristine Yaffe, MD, professor of psychiatry, neurology, and epidemiology and biostatistics, and associate chair of clinical and translational research in the department of psychiatry at the University of California, San Francisco. “What they are doing is looking at oophorectomy or surgical menopause as a proxy for earlier menopause. They're showing that the earlier the menopause — that is, the less estrogen or other hormone exposure during that period — the greater the risk of dementia.”
Dr. Yaffe added, after reviewing the abstract for the paper, that “there are still a lot of remaining questions. Although the investigators adjusted for age, education, and smoking; there are other things that they didn't adjust for that I really want to see that could explain this association.” For example, she said, race and socioeconomic status. We know that women with lower socioeconomic status often have greater rates of surgical menopause, she said, “and there may be significant ethnic and race differences, which happen to have big effects on dementia.”
Francine Grodstein, an associate professor in the department of epidemiology at Harvard School of Public Health, whose work is focused primarily on healthy aging in women, said that the preliminary data looks promising. “I know this group does very good work. The only thing you cannot tell from the abstract is how they defined the reference group, which clearly is important.” In addition, Dr. Grodstein pointed out, “in public health terms, surgical menopause is less common now than at the time this study was done.”
Dr. Rocca hopes this study will stimulate other investigators “to further explore the link between menopause, oophorectomy, estrogen treatment, and cognitive aging. We also hope that this study will prompt new funding from NIH for studies exploring risk and protective factors for cognitive decline or dementia that are related to sex and hormonal differences in men and women.”
The study of these risks and protective factors “in men and women separately may accelerate the progress of discovery in the area of brain aging. The differences between men and women can be partly biological (e.g., chromosomal sex and hormones) and partly social and cultural (gender),” Dr. Rocca said.
Further research needs to be conducted to evaluate the potential neuroprotective effects of HRT after surgical menopause, Dr. Bove told Neurology Today. “We are planning a more detailed analysis into the various types of HRT use, as well as the timing of HRT start relative to start of menopause.”