Basic science research has demonstrated that estrogen positively affects neuronal structure and function and has receptors in areas of the brain especially involved in memory processes (Asthana1; Garcia-Segura et al.2). Although the biology of estrogen appears to support the benefits of this hormone for enhancing cognitive function, the results of human studies are conflicting (Herlitz & Yonker3; LeBlanc et al.9; Yaffe et al.8). A major potential reason for the controversy is poor methodology in clinical studies that fail to distinguish different types of estrogen and use poor, global, neuropsychological measures incapable of targeting specific cognitive domains (Asthana). Estrogen receptors are distributed in several areas of the brain, many of which are instrumental to the memory process, including: the cerebral cortex, hypothalamus, pituitary, amygdala, and hippocampus.1,2 Estrogen affects cognition by binding to its specific receptors within brain cells, thus influencing brain function in the area in which the receptors reside.3 Estrogen hormones affect more than just reproductive organs and female characteristics-research shows that estradiol plays a role in the cognitive function of women. In a series of studies, Hampson4 found that women scored higher on verbal production and fine motor tasks during the high-estrogen phase of their menstrual cycle. In addition, results showed that women performed significantly better on tests of manual and articulatory speed and accuracy and more poorly on tests of visuospatial ability when their estrogen levels were higher.4 Hampson’s study indicates that monthly hormonal fluctuations affect specific aspects of female cognition, such that high estrogen levels tend to improve verbal production, fine motor tasks, visual memory, and articulatory speed and accuracy. 4 A similar association between estrogen levels and cognition has been researched in menopausal women. Menopause is characterized by a decline in hormonal levels especially estrogen and progesterone. In fact, men have three times the levels of estradiol as postmenopausal women of the same age.5 About two-thirds of women also report poor memory during perimenopause, the years preceding menopause,6 and later, as estrogen levels continue to decline.7 In a review by Yaffe et al.8, 27 studies were considered, 13 addressing the effect of estrogen use on cognitive function, 10 examining estrogen’s impact on the risk for developing Alzheimer’s Disease (AD) or other dementia, and 4 exploring the effect of Estrogen Replacement Therapy (ERT) in women already diagnosed with AD. The conclusion of the review was that ERT seems to improve cognition in recently menopausal women with substantial symptoms.8 Other studies have demonstrated similar benefits of ERT on menopausal women, such as improved verbal memory, vigilance, reasoning, and motor speed.9 Research using both behavioural and physiological measures, involving healthy older women, has shown positive results as well. Schmidt et al.10 conducted a combination neuropsychological and brain MRI study on 210 women that were part of a large-scale stroke prevention initiative. The study revealed an association between ERT and improved cognitive functioning in addition to a lower rate of clinically unsuspected ischemic brain damage. The results suggest that estrogen has a positive influence on language and memory by affecting functional brain organization. In her studies of surgically menopausal women, Sherwin11 also found that oophorectomized women who received a placebo, compared to estrogen alone, estrogen-androgen, or androgen alone, had lower scores on four measures of cognitive functioning, correlating with significantly lower concentrations of estrogen and testosterone. A clear division exists between studies using synthetic conjugated equine estrogens (CEE), primarily Premarin™, and 17 b-estradiol. The most commonly used drug in ERT, Premarin™ is derived from pregnant mares’ urine, a substance foreign to the human body. A plant-based derivative, biologically identical estradiol is converted in a laboratory into a more potent hormone whose molecular structure is the same as that produced naturally in the human body Asthana1 has noted that the biologically less estrogenic CEE is a mix of various estrogens and androgens, many of which are unidentified and whose neurobiology is essentially unknown. In addition, CEE is generally administered orally, resulting in lower and less stable plasma levels of estradiol than when estrogen is delivered transdermally. The Women’s Health Initiative Memory Study (WHIMS)13 employed an oral tablet of CEE or a placebo. In results that made major headlines, WHIMS concluded, that hormone therapy actually had an adverse effect on cognition among women aged 65 to 79 years, with the effects greater among women with lower cognitive function before treatment. The researchers acknowledged that the study tested only CEE and that outcomes might differ with “other doses, formulations, or routes of delivery.”13 This dichotomy also is apparent in the National Institute on Aging’s Alzheimer’s Disease Cooperative Study14 where research showed that oral administration of Premarin did not slow disease progression or improve cognitive function in AD patients. In contrast, Asthana et al.1 treated mild-to-moderate AD women with 17 b-estradiol, which appeared to enhance selective attention and verbal memory. A key issue often overlooked is the timing of ERT. Citing a study by Matthews et al. (1999), Birge6 suggests that estrogen’s effects on brain aging depend on beginning hormone therapy at the time of menopause, a critical window of opportunity that may be limited to this transitional period from the reproductive state to the estrogen deficiency state. In a study by Zandi et al.,12 women who initiated ERT around the time of menopause had between a 40% and 80% reduction in the incidence of AD, compared to a twofold greater incidence of AD in women who began HRT after age 60, as opposed to nonusers of ERT. Of special interest is an AD study by Asthana et al.,1 in which participants ranging from 66-89 years old, with existing probable AD, appeared to improve on cognitive measures after ERT treatment. Birge6 estimates that for every 1,000 women who begin ERT at the time of menopause, there will be 240 fewer women who will develop AD during their lifetime. 1Asthana, S. (2003). Estrogen and cognition: The story so far. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 58, M322-M323. 2Garcia-Segura, L. M., Azcoitia, I., & DonCarlos, L. L. (2001). Neuroprotection by estradiol. Progress in Neurobiology, 63, 29-60. 3Herlitz, A., & Yonker, J. (2004). Hormonal effects on cognition in adults. In R. A. Dixon, L. Bäckman, & L-G. Nilsson (Eds.), New frontiers in cognitive aging (pp. 253-277). New York: Oxford University Press. 4Hampson, E., &Kimura, D. (1994). Cognitive pattern in men and women is influenced by fluctuations in sex hormones. Current Directions in Psychological Science, 3, 57-61. 5Meisler, J. G. (2002). Toward optimal health: The experts discuss cognitive function and memory changes. Journal of Women’s Health, 11, 683-689. 6ABirge, S. J. (1996). Is there a role for estrogen replacement therapy in the prevention and treatment of dementia? Journal of the American Geriatrics Society, 44, 865-870 6BBirge, S. J. (2004). The WHI and the brain: What have we learned? 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A., Mayer, L. S., Steffens, D.C., Breitner, J. C. S. (2003). Hormone replacement therapy and incidence of Alzheimer’s disease in older women: The Cache County Study. Journal of the American Medical Association, 288, 2123-2129. 13Espeland, M. A., Rapp, S. R., Shumaker, S. A., Brunner, R., Manson, J. E., Sherwin, B. B., Hsia, J., Margolis, K. L., Hogan, P. E., Wallace, R., Dailey, M., Freeman, R., Hays, J. (2004). Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. Journal of the American Medical Association, 291, 2959-2968. 14Mulnard, R. A., Cotman, C. W., Kawas, C., van Dyck, C. H., Sano, M., Doody, R., Koss, E., Pfeiffer, E., Jin, S., Gamst, A., Grundman, M., Thomas, R., & Thal, L. J. (2000). Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. Journal of the American Medical Association, 283, 1007-1015.