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Menopause Matters

Memory Complaints

Victor W. Henderson, MD, MS

Memory and other cognitive abilities change throughout life, and with advancing age, there is a trend toward decline in some cognitive skills. The brain is an important target for estrogen, and animal models and laboratory research suggest that the postmenopausal loss of ovarian estradiol production could adversely affect cognition or contribute to dementia. However, findings from human studies are only beginning to address this controversial issue.

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By contrast, physicians and psychologists view memory more restrictively. Particularly important in the clinical arena is the ability to learn new information and then consciously recall this information at some later time. Such –episodic” memory plays a special role in evaluating cognitive decline. In older persons, episodic memory loss (defined by poor scores on tests that assess delayed recall) can be an early predictor of Alzheimer disease (AD)—even when other aspects of cognition are still normal. Frequently forgetting appointments may reflect a problem with episodic memory, whereas failure to recall a personês name does not.

Few studies provide objective measures of cognition during perimenopause or early postmenopause, but findings on natural menopause are reassuring. Cross-sectional data from an Australian cohort1 revealed no differences in episodic memory scores among middle-aged women analyzed by reproductive stage (perimenopause, early post-menopause, late postmeno-pause), serum estradiol levels, or use of estrogen-containing hormone therapy (HT). In a large US study that assessed perceptual speed and the ability to manipulate information,2 no decline was found during the menopausal transition.

While little is known concerning memory after premature ovarian failure, research has been performed in women who underwent bilateral oophorectomy and experienced abrupt curtailment of ovarian hormone production. In these women, limited short-term clinical trial evidence indicates that estrogen therapy benefits episodic memory, at least with regard to memory for verbally encoded information.

Limited evidence from observational studies and small clinical trials raises the possibility that HT may enhance aspects of cognitive performance in middle-aged women, but findings are inconclusive. The evidence is clearer for older postmenopausal women; several large, randomized clinical trials have shown that HT provides no benefit for memory or other cognitive skills, and that initiation of HT after age 64 years actually increases dementia risk.3-5

Long-term cognitive effects of relatively short-term HT use during midlife are unknown, but the available evidence does not point to substantial risk. A follow-up study of participants in clinical trials who used HT for osteoporosis prevention6 reported that middle-aged postmenopausal women who used HT for 2 to 3 years had a lower risk of cognitive impairment 10 years later than women assigned to placebo. Results from a number of observational studies also indicate a protective association between HT, often used at a relatively young age, and AD risk. However, such studies may be biased by a tendency for healthier women to use HT in the first place, suggesting the need for caution in drawing clinical inferences, particularly in view of adverse findings regarding HT initiated by older women.5

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MANAGEMENT

Many women complain of poor memory during perimenopause and early postmenopause. The incidence of dementia is very low during midlife, however, and cognitive symptoms are seldom accompanied by objective evidence of cognitive impairment. Thus, the clinician can provide reassurance that such symptoms are common, usually self-limiting, and not linked to AD risk. Screening instruments such as the Mini-Mental State Examination7 are insensitive to mild cognitive deficits, but they are a useful adjunct if dementia is suspected. For the middle-aged woman, questions of clinically important cognitive changes can be evaluated through formal neuropsychological assessment, but this is unnecessary in most instances.

Contributing factors should be evaluated. Vasomotor instability, sleep disturbances, fatigue, family/ employment stressors, and depression are all potential causes of memory complaints and, possibly, reduced performance on cognitive tasks. Also, some prescription and nonprescription medications have cognitive side effects.

Estrogen-containing HT has been approved by the US Food and Drug Administration for short-term treatment of moderate to severe vasomotor symptoms, and some evidence indicates that estrogen improves mood. Studies of HT and depression are limited, however. Indeed, HT is not approved for treatment of depression, and it does not replace standard approaches to depression management.

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CONCLUSION

Memory complaints are common during midlife, and encompass a variety of symptoms. Contributing factors can often be identified. However, the menopausal transition per se is not associated with objective cognitive decline. Limited evidence suggests that HT immediately after surgical menopause has a short-term benefit for verbal episodic memory. With respect to HT and memory after natural menopause, though, data from the early postmenopause are too limited for even tentative conclusions. Long-term cognitive consequences of HT used in midlife are largely unknown. Initiation of HT by older women does not improve memory, and it increases risk of dementia.

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Victor W. Henderson, MD, MS, is professor of health research and policy (epidemiology) and of neurology and neurological sciences, Stanford University, Stanford, Calif; and member, 2004-2005 Board of Trustees, The North American Menopause Society.

References

1. Henderson VW, Guthrie JR, Dudley EC, Burger HG, Dennerstein L. Estrogen exposures and memory at midlife: a population-based study of women. Neurology. 2003;60(8): 1369-1371.
2. Meyer PM, Powell LH, Wilson RS, et al. A population-based longitudinal study of cognitive functioning in the menopausal transition. Neurology. 2003;61(6):801-806.
3. Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E. Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Am J Med. 2002;113(7):543-548.
4. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women. Womenês Health Initiative Memory Study. JAMA. 2004;291(24):2959-2968.
5. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Womenês Health Initiative Memory Study. JAMA. 2004;291(24):2947-2958.
6. Bagger YZ, Tanko LB, Alexandersen P, Qin G, Christiansen C; PERF Study Group. Early postmenopausal hormone replacement therapy may prevent cognitive impairment later in life. Menopause. 2005;12(1):12-17.
7. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State Examination (MMSE) [Psychological Assessment Resources Web site]. Available at: http://www3.parinc.com/products/product.aspx?Productid=MMSE. Accessed June 14, 2005.

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