Cognitive Decline Detected in Early Perimenopause

Pauline Anderson

January 10, 2013

A new study using updated reproductive staging and sensitive cognitive testing found subtle declines in verbal learning, verbal memory, and fine motor skills in the first year after the final menstrual period.

The cognitive effects were not due to menopausal symptoms, such as hot flashes, or to sleep issues, depression, or anxiety. And although the study did not find that estrogen levels were associated with cognitive declines, hormonal fluctuations probably do play a role, according to the authors.

Their result "adds to the body of understanding of what happens with cognition in transition," said lead author Miriam T. Weber, PhD, assistant professor, Department of Neurology, University of Rochester New York.

Their findings are similar to those of another recent study, the Study of Women's Health Across the Nation (SWAN), "that had a beautiful, very representative sample," Dr. Weber notes. "Their cognitive tests perhaps weren't as comprehensive and as sensitive as ours but we generally have the same findings."

The study was published online January 3 in Menopause: The Journal of the North American Menopause Society.

Cognitive Battery

The analysis included 117 women aged 40 to 60 years (mean age, 48.7 years; 91% white) who had an intact uterus and reported changes in menstrual cycles and at least 1 menstrual period in the prior 12 months.

Researchers administered a battery of tests to assess 6 cognitive domains:

  1. Basic attention using the Digit Span subtest of the Wechsler Adult Intelligence Scale III

  2. Working memory using the Letter-Number Sequencing subtest of the Wechsler Adult Intelligence Scale III

  3. Verbal fluency using the Controlled Oral Word Association

  4. Motor skills and dexterity using the Grooved Pegboard Test

  5. Visuospatial skills using the Hooper Visual Organization Test

  6. Verbal encoding and retention using the Rey Auditory Verbal Learning Test

According to Dr. Weber, this cognitive battery lasted longer and was more comprehensive than that used in earlier research. As well, the tests had a "high ceiling," which made it easier to detect subtle differences.

On the day of cognitive testing, researchers collected serum estradiol (E2) and follicle-stimulating hormone (FSH) levels. Study participants completed questionnaires assessing depression, anxiety, general health, quality of life, and memory function, and they used calendars to track menstrual cycles.

Reproductive Stages

The study examined cognitive performance as a function of 4 reproductive aging stages instead of just the 2 or 3 used in previous research. This updated approach allowed researchers to investigate women experiencing the earliest changes in menstrual cycles and to evaluate finer differences in the early postmenopausal period.

The 4 stages of reproductive aging were:

  1. Late reproductive: subtle changes in menstrual flow and/or cycle length

  2. Early menopausal transition: persistent cycle irregularity, defined as a difference in the length of consecutive cycles of 7 days or more on at least 2 occasions in the prior 10 cycles

  3. Late menopausal transition: interval of amenorrhea of 60 days or more

  4. Early postmenopause: the first 12 months after the final menstrual period)

The results showed that women in early postmenopause performed worse than women in the late reproductive stage on the verbal learning (P = .02), verbal memory (P = .02), and fine motor skills (P = .03) composite scores. There was a trend for women in early postmenopause to perform worse than women in the late reproductive stage on the attention/working memory composite score, but this did not reach statistical significance (P = .08).

In addition, women in early postmenopause performed worse than women in the late menopausal transition stage on verbal learning (P < .01), verbal memory (P = .01), fine motor skills (P = .03), and attention/working memory (P = .04).

For verbal memory, the study found a failure to improve during repeated administration of the same task rather than a decline from prior performance.

Depression, anxiety, sleep disturbance, and vasomotor symptoms were not significant predictors of any cognitive composite measure.

Hormone Measures

Generally, neither FSH nor E2 related to cognitive function. The exception was that higher E2 levels were associated with better performance on the fine motor skills composite (P = .02), although E2 was not a significant predictor of any other cognitive composite measure. Higher FSH levels were marginally associated with better performance on the fine motor skills composite.

Although the data do not show a strong relationship between cognitive performance and hormone levels taken at 1 period of time, Dr. Weber and her colleagues still believe that cognitive declines are due to dramatic hormonal fluctuations occurring during the perimenopause.

"We assume that it's something physiological related to the transition. We know hormones influence behavior and cognition and we think it's still hormonally related although the data don't say that."

Dr. Weber noted that the attention/working memory and verbal learning domains that were affected by reproductive stages are those supported by the hippocampus and the prefrontal cortex (PFC), regions that are "rich in estrogen receptors."

"The hippocampus plays a critical role in verbal episodic memory, including memory encoding and storage," the authors write. "The PFC also plays a critical role in early memory processing and is consistently activated on tasks of memory encoding, and working memory."

Sample Not Representative

Dr. Weber cautioned that her study cohort, which included high-functioning, predominantly white women, is not a representative sample. SWAN, on the other hand, included more than 2000 women, was multiethnic, and showed similar cognitive declines although it had less sensitive cognitive tests and more limited reproductive staging.

These data are "good preliminary data, but it's not necessarily generalizable to the population at large," Dr. Weber said. "We see this finding and we think it's real, but clearly we need to look at it at a much larger much more representative cohort."

Dr. Weber's research team will follow the cohort for 5 years. Their continuing work should shed more light on what happens to cognition following the 2-year period after the final menstrual period during which hormone levels continue to change. There is some suggestion that cognitive declines may "rebound" in time, said Dr. Weber.

This study was supported, in part, by the National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health. One coauthor has received consultant fees from Noven Pharmaceuticals.

Menopause. Published online January 3, 2013. Abstract

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