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Women’s cognitive health: postmenopausal dementia and the women's health initiative memory study
Women’s Health Issues 14 (2004) 71–74
EDITORIAL
WOMEN’S COGNITIVE HEALTH: POSTMENOPAUSAL DEMENTIA AND THE WOMEN’S HEALTH INITIATIVE MEMORY STUDY Karen Potvin Klein, MAa* and Stephen R. Rapp, PhDb a
b
Women’s Health Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston-Salem, NC Received 2 February 2004; received in revised form 16 March 2004; accepted 4 May 2004
B
y 2050, it is estimated that 13 million Americans will have Alzheimer disease (AD) (Hebert, Scherr, Bienias, Bennett, & Evans, 2003). Milder cognitive impairment affects between one fifth and one third of older adults (Lopez, Jagust, DeKosky, et al., 2003) and predicts dementia and subsequent institutionalization (Fisk, Merry, & Rockwood, 2003). Medications have been developed specifically for the treatment of cognitive decline, but their benefit has been more modest than hoped for. A better understanding of risk factors for cognitive impairment, as well as treatments to ameliorate the condition, is an important public health priority. Postmenopausal women appear to have a greater risk of developing AD than men (Payami, Montee, Grimlid, Shattuc, & Kaye, 1996). One explanation relates to women’s lower endogenous estrogen levels after menopause (Paganini-Hill & Henderson, 1994). Initially, a positive association between exogenous estrogen and cognitive performance in nondemented older women was consistently reported (e.g., Kawas et al., 1997; Maki & Resnick, 2000; Phillips & Sherwin, 1991). In addition, meta-analyses of estrogen’s potential protective effects against dementia found risk reductions of 29% (Yaffe, Sawaya, Lieberburg, &
The Women’s Health Initiative Memory Study is funded in part by Wyeth Pharmaceuticals. The Women’s Health Initiative is funded by the National Heart, Lung and Blood Institute, National Institutes of Health. * Correspondence to: Karen Potvin Klein, MA, Women’s Health Center of Excellence, Wake Forest University School of Medicine, 2000 West First Street, Suite 101, Winston-Salem, North Carolina 27104. E-mail: [email protected]. Copyright © 2004 by the Jacobs Institute of Women’s Health. Published by Elsevier Inc.
Grady, 1998) and 34% (Nelson, Humphrey, Nygren, Teutsch, & Allen, 2002). Yet several prospective observational studies revealed no benefit of estrogen on either cognition or dementia (e.g., Barrett-Connor & Kritz-Silverstein, 1993) and clinical trials of unopposed estrogen in women with AD showed no benefit on cognitive performance (e.g., Mulnard et al., 2000). Lack of consensus and a paucity of large, controlled clinical trials left uncertain whether estrogen therapy had actual value in preventing cognitive decline and dementia in postmenopausal women.
The Women’s Health Initiative Memory Study The accumulated evidence summarized above formed the basis for the design and rationale for the two Women’s Health Initiative (WHI) clinical trials of hormone therapy, which employed conjugated equine estrogen alone (E-Alone) or combined with medroxyprogesterone acetate (E⫹P), each versus matched placebos. As an ancillary study to WHI, The Women’s Health Initiative Memory Study (WHIMS) sought to determine whether these regimens would reduce the incidence of all-cause dementia and mild cognitive impairment in healthy women 65 years and older enrolled in the WHI hormone therapy trials. The WHI E⫹P trial was discontinued early because 1) treatment was associated with increased risk of heart disease, stroke, pulmonary embolism, and breast cancer; and 2) the risks of treatment outweighed the benefits for colon cancer and osteoporotic fractures (Writing Group for the Women’s Health Initiative Investigators, 2002). Subsequent analysis of the WHIMS data from the E⫹P trial showed an increased risk for probable dementia 1049-3867/04 $-See front matter. doi:10.1016/j.whi.2004.05.001
72
K. P. Klein and S. R. Rapp / Women’s Health Issues 14 (2004) 71–74
(Shumaker et al., 2003) and a small increase in risk for global cognitive decline associated with E⫹P treatment (Rapp et al., 2003). Thus, WHIMS demonstrated that contrary to earlier research suggesting a protective effect of estrogen on the brain, E⫹P had the opposite effect—the risk of dementia and of global cognitive deterioration increased with E⫹P compared to placebo among these older postmenopausal women. Recently, the E-Alone WHI trial was also halted early because of an increased risk of stroke and a lack of benefit on coronary heart disease endpoints versus placebo (Women’s Health Initiative Steering Committee, 2004). WHIMS data for the E-Alone trial are being analyzed and will be published soon. In that analysis, the investigators will examine E-Alone versus placebo, and both E-Alone and E⫹P combined versus placebo, to answer the main question asked in WHIMS, namely, does the risk of dementia and mild cognitive impairment increase after older postmenopausal women begin hormone therapy? The findings from WHI and WHIMS have challenged widely and long-held assumptions of benefits for women taking postmenopausal hormone therapy. Consequently, they have caused scientists and clinicians to pause and reflect on the implications for clinical care of peri- and postmenopausal women. The surprising results from WHI, the largest-ever randomized clinical trial of women, suggest that still more questions need to be asked about why some studies before WHI found benefit, not harm, from hormone therapy—and how to continue to safeguard postmenopausal women’s health. Some of those questions are discussed here.
Is the Drug Regimen the Key? Regimen refers to the particular composition of the drug and dosage in which it is used. The most widely used form of hormone therapy in the United States is conjugated equine estrogen (CEE), the same drug tested in the E-Alone WHI and WHIMS trials. For decades, estrogen was given to women to manage menopausal symptoms, and because it was believed to benefit a woman’s health and well-being. When it was realized that estrogen given alone increased the risk of endometrial cancer among women with a uterus (see Grady, Gebretsadik, Kerlikowske, Ernster & Petitti, 1995 for a meta-analysis), a new compound was created by adding medroxyprogesterone acetate (MPA), a drug that inhibits endometrial growth, to CEE. This compound soon became widely prescribed for women with a uterus (women who had never had a hysterectomy). Today, the most widely used form of hormone therapy is CEE ⫹ MPA—the compound used in WHI and WHIMS. A question that remains, then, is whether all regi-
mens of hormone therapy will produce the same increased risk of dementia, or whether different compounds will have different effects. Before WHIMS, studies of hormone therapy for the prevention of dementia often did not distinguish between regimens of estrogen alone versus estrogen plus progestin. It is possible that addition of a progestin, most frequently MPA, might somehow counteract the beneficial neurobiological or vascular effects of estrogen, underlining the importance of conducting studies like WHIMS that compare different regimens. Estrogen actually describes a class of compounds consisting of various subtypes of estrogens. Thus, different types of estrogen might have somewhat different effects on the brain. Carefully conducted clinical trials are needed to test this hypothesis. But what might be should not outweigh what we have learned from WHI and WHIMS already. Thus, until definitively established, prudence suggests that the WHI and WHIMS data would generalize to all estrogens (see the current Food and Drug Administration guidelines at http://www. fda.gov/bbs/topics/NEWS/2004/NEW01022.html).
Or Is It Timing? Secondary prevention clinical trials have not demonstrated benefit of hormone therapy in slowing the progression of dementia (Hogervorst, Yaffe, Richards, & Huppert, 2002; Yaffe, Sawaya, Lieberburg, & Grady 1998). Most of the research examining the effects of estrogen on cognition in demented persons has studied dementia of the Alzheimer type. The characteristic brain pathologies in AD are the gradual and insidious accumulation of neuritic plaques and neurofibrillary tangles in the brain. Failure of hormone therapy to lessen the impact of AD may mean that once it has begun, hormone therapy cannot arrest or reverse these neuropathologies. It is noteworthy, however, that the WHIMS E⫹P trial demonstrated not only lack of protection against developing dementia, but increased risk associated with treatment. Therefore, dementia prevention trials in older women may not represent primary prevention of the underlying neuropathologic processes. An alternative hypothesis is that increased risk of dementia among women in the early stages of AD occurs when estrogen creates neurovascular disease (e.g., small strokes), a second pathology in the brain, that leads to cognitive decline and ultimately dementia ( Iadecola & Gorelick, 2003; Neuropathology Group of the Medical Research Council Cognitive Function and Aging Study, 2001; Snowdon et al., 1997). Identification of such individuals before initiating hormone therapy is highly desirable. Epidemiologic studies have suggested that there is a window of biological opportunity for receiving benefit to the brain from estrogen (Zandi et al., 2002). Women
K. P. Klein and S. R. Rapp / Women’s Health Issues 14 (2004) 71–74
who report taking hormone therapy during the perimenopausal and early postmenopausal periods have better global cognitive scores and a lower incidence of dementia than those who have never taken hormone therapy, or who started well beyond the menopausal transition. Although these data are suggestive, there are limitations to this type of study that restrict confidence in the suggestion that taking hormone therapy early is beneficial.
What Work Remains? The data from the E-Alone WHIMS trial will provide further evidence regarding whether differences in risk of cognitive decline are observed between the two regimens and compared to placebo. These data will also add to the information on all-cause dementia obtained from the E⫹P WHIMS trial. But because the WHI and WHIMS protocols included only two regimens of hormone therapy, WHIMS cannot answer the question of whether different regimens could provide protection against dementia. Nor can WHIMS tell us whether taking hormone therapy around the time of menopausal transition is protective against dementia or mild cognitive impairment. Until other studies can provide answers to these issues, it makes the most sense to assume that the WHIMS findings apply to other regimens and schedules of hormone therapy. The field would be advanced significantly by studies that reveal the neurologic mechanisms associated with the effects of hormone therapy. Lacking, for example, are large-scale studies employing stateof-the-art neuroimaging technologies that would allow examination of functional brain changes in women taking hormone therapy. In a planned supplemental study, WHIMS will collect magnetic resonance images of the brains of a subset of participants and analyze these data in conjunction with clinical and cognitive assessments to provide a much more complete picture. WHIMS has provided scientists and clinicians important new information to aid them in understanding the effects of hormone therapy on the brain. Questions remain unanswered, but the picture is clearer than before WHIMS. Hopefully, new studies will address the regimen and timing questions. Women and their doctors need to know how to estimate their risk of dementia before taking hormone therapy. What we do know is that use of hormone therapy remains a complex decision that must be carefully considered by each individual woman and her health care provider.
73
References Barrett-Connor, E., & Kritz-Silverstein, D. (1993). Estrogen replacement therapy and cognitive function in older women. Journal of the American Medical Association, 269, 2637–2641. Fisk, J. D., Merry, H. R., & Rockwood, K. (2003). Variations in case definition affect prevalence but not outcomes of mild cognitive impairment. Neurology, 61, 1179 –1184. Grady, D., Gebretsadik, T., Kerlikowske, K., Ernster, V., & Petitti, D. (1995). Hormone replacement therapy and endometrial cancer risk: A meta-analysis. Obstetrics and Gynecology, 85, 304 –313. Hebert, L. E., Scherr, P. A., Bienias, J. L., Bennett, D. A., & Evans, D. A. (2003). Alzheimer disease in the US population: Prevalence estimates using the 2000 census. Archives of Neurology, 60, 1119 – 1122. Hogervorst, E., Yaffe, K., Richards, M., & Huppert, F. (2002). Hormone replacement therapy for cognitive function in postmenopausal women. The Cochrane Database of Systematic Reviews. Oxford, England: Update Software. Iadecola, C., & Gorelick, P. B. (2003). Converging pathogenic mechanisms in vascular and neurodegenerative dementia. Stroke, 34, 335–337. Kawas, C., Resnick, S. M., Morrison, A., Brookmeyer, R., Corrada, M., Zonderman, A., et al (1997). A prospective study of estrogen replacement therapy and the risk of developing Alzheimer disease: The Baltimore Longitudinal Study on Aging. Neurology, 48, 1517–1521. Lopez, O. L., Jagust, W. J., DeKosky, S. T., Becker, J. T., Fitzpatrick, A., Dulberg, C., et al (2003). Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study: Part 1. Archives of Neurology, 60, 1385–1389. Maki, P. M., & Resnick, S. M. (2000). Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition. Neurobiology of Aging, 21, 373–383. Mulnard, R. A., Cotman, C. W., Kawas, C., van Dyxk, C. H., Sano, M., Doody, R., et al (2000). Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. Journal of the American Medical Association, 283, 1007–1015. Nelson, H. D., Humphrey, L. L., Nygren, P., Teutsch, S. M., & Allan, J. D. (2002). Postmenopausal hormone replacement: Scientific review. Journal of the American Medical Association, 288, 872– 881. Neuropathology Group of the Medical Research Council Cognitive Function and Aging Study (MRC CFAS) (2001). Pathological correlates of late-onset dementia in a multicentre community-based population in England and Wales. Lancet, 347, 169 –175. Paganini-Hill, A., & Henderson, V. W. (1994). Estrogen deficiency and risk of Alzheimer disease in women. American Journal of Epidemiology, 140, 256 –261. Payami, H., Montee, K., Grimslid, H., Shattuc, S., & Kaye, J. (1996). Increased risk of familial late-onset Alzheimer’s disease in women. Neurology, 46, 126 –129. Phillips, S., & Sherwin, B. B. (1991). Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology, 17, 485– 495. Rapp, S., Espeland, M. A., Shumaker, S. A., Henderson, V. W., Brunner, R. L., Manson, J. E., et al (2003). The effect of estrogen with progestin treatment on global cognitive function in postmenopausal women: Results from the Women’s Health Initiative Memory Study. Journal of the American Medical Association, 289, 2663–2672. Shumaker, S. A., Legault, C., Rapp, S. R., Thal, L., Wallace, R. B., Ockene, J. K., et al (2003). Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study: A randomized controlled trial. Journal of the American Medical Association, 289, 2651–2662. Snowdon, D. A., Greiner, L. H., Mortimer, J. A., Riley, K. P., Greiner, P. A., & Markesbery, W. R. (1997). Brain infarction and the
74
K. P. Klein and S. R. Rapp / Women’s Health Issues 14 (2004) 71–74
clinical expression of Alzheimer disease: The Nun Study. Journal of the American Medical Association, 277, 813– 817. Women’s Health Initiative Steering Committee (2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association, 291, 1701–1712. Writing Group for the Women’s Health Initiative Investigators (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association, 288, 321–333. Yaffe, K., Sawaya, G., Lieberburg, I., & Grady, D. (1998). Estrogen therapy in postmenopausal women: Effects on cognitive function and dementia. Journal of the American Medical Association, 279, 688 – 695. Zandi, P. P., Carlson, M. C., Plassman, B. L., Welsh-Bohmer, K. A., Mayer, L. S., Steffens, D. C., & Breitner, J. C. (2002). Hormone
replacement therapy and the incidence of Alzheimer disease in older women: The Cache County Study. Journal of the American Medical Association, 288, 2123–2129.
Author Descriptions Ms. Klein is a Research Associate in the Department of Public Health Sciences and the Women’s Health Center of Excellence at Wake Forest University School of Medicine (WFUSM), Winston-Salem, North Carolina. Dr. Rapp is a Professor in the Department of Psychiatry and Behavioral Medicine at WFUSM and CoPrincipal Investigator of the Women’s Health Initiative Memory Study (WHIMS).
EDITORIAL
WOMEN’S COGNITIVE HEALTH: POSTMENOPAUSAL DEMENTIA AND THE WOMEN’S HEALTH INITIATIVE MEMORY STUDY Karen Potvin Klein, MAa* and Stephen R. Rapp, PhDb a
b
Women’s Health Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston-Salem, NC Received 2 February 2004; received in revised form 16 March 2004; accepted 4 May 2004
B
y 2050, it is estimated that 13 million Americans will have Alzheimer disease (AD) (Hebert, Scherr, Bienias, Bennett, & Evans, 2003). Milder cognitive impairment affects between one fifth and one third of older adults (Lopez, Jagust, DeKosky, et al., 2003) and predicts dementia and subsequent institutionalization (Fisk, Merry, & Rockwood, 2003). Medications have been developed specifically for the treatment of cognitive decline, but their benefit has been more modest than hoped for. A better understanding of risk factors for cognitive impairment, as well as treatments to ameliorate the condition, is an important public health priority. Postmenopausal women appear to have a greater risk of developing AD than men (Payami, Montee, Grimlid, Shattuc, & Kaye, 1996). One explanation relates to women’s lower endogenous estrogen levels after menopause (Paganini-Hill & Henderson, 1994). Initially, a positive association between exogenous estrogen and cognitive performance in nondemented older women was consistently reported (e.g., Kawas et al., 1997; Maki & Resnick, 2000; Phillips & Sherwin, 1991). In addition, meta-analyses of estrogen’s potential protective effects against dementia found risk reductions of 29% (Yaffe, Sawaya, Lieberburg, &
The Women’s Health Initiative Memory Study is funded in part by Wyeth Pharmaceuticals. The Women’s Health Initiative is funded by the National Heart, Lung and Blood Institute, National Institutes of Health. * Correspondence to: Karen Potvin Klein, MA, Women’s Health Center of Excellence, Wake Forest University School of Medicine, 2000 West First Street, Suite 101, Winston-Salem, North Carolina 27104. E-mail: [email protected]. Copyright © 2004 by the Jacobs Institute of Women’s Health. Published by Elsevier Inc.
Grady, 1998) and 34% (Nelson, Humphrey, Nygren, Teutsch, & Allen, 2002). Yet several prospective observational studies revealed no benefit of estrogen on either cognition or dementia (e.g., Barrett-Connor & Kritz-Silverstein, 1993) and clinical trials of unopposed estrogen in women with AD showed no benefit on cognitive performance (e.g., Mulnard et al., 2000). Lack of consensus and a paucity of large, controlled clinical trials left uncertain whether estrogen therapy had actual value in preventing cognitive decline and dementia in postmenopausal women.
The Women’s Health Initiative Memory Study The accumulated evidence summarized above formed the basis for the design and rationale for the two Women’s Health Initiative (WHI) clinical trials of hormone therapy, which employed conjugated equine estrogen alone (E-Alone) or combined with medroxyprogesterone acetate (E⫹P), each versus matched placebos. As an ancillary study to WHI, The Women’s Health Initiative Memory Study (WHIMS) sought to determine whether these regimens would reduce the incidence of all-cause dementia and mild cognitive impairment in healthy women 65 years and older enrolled in the WHI hormone therapy trials. The WHI E⫹P trial was discontinued early because 1) treatment was associated with increased risk of heart disease, stroke, pulmonary embolism, and breast cancer; and 2) the risks of treatment outweighed the benefits for colon cancer and osteoporotic fractures (Writing Group for the Women’s Health Initiative Investigators, 2002). Subsequent analysis of the WHIMS data from the E⫹P trial showed an increased risk for probable dementia 1049-3867/04 $-See front matter. doi:10.1016/j.whi.2004.05.001
72
K. P. Klein and S. R. Rapp / Women’s Health Issues 14 (2004) 71–74
(Shumaker et al., 2003) and a small increase in risk for global cognitive decline associated with E⫹P treatment (Rapp et al., 2003). Thus, WHIMS demonstrated that contrary to earlier research suggesting a protective effect of estrogen on the brain, E⫹P had the opposite effect—the risk of dementia and of global cognitive deterioration increased with E⫹P compared to placebo among these older postmenopausal women. Recently, the E-Alone WHI trial was also halted early because of an increased risk of stroke and a lack of benefit on coronary heart disease endpoints versus placebo (Women’s Health Initiative Steering Committee, 2004). WHIMS data for the E-Alone trial are being analyzed and will be published soon. In that analysis, the investigators will examine E-Alone versus placebo, and both E-Alone and E⫹P combined versus placebo, to answer the main question asked in WHIMS, namely, does the risk of dementia and mild cognitive impairment increase after older postmenopausal women begin hormone therapy? The findings from WHI and WHIMS have challenged widely and long-held assumptions of benefits for women taking postmenopausal hormone therapy. Consequently, they have caused scientists and clinicians to pause and reflect on the implications for clinical care of peri- and postmenopausal women. The surprising results from WHI, the largest-ever randomized clinical trial of women, suggest that still more questions need to be asked about why some studies before WHI found benefit, not harm, from hormone therapy—and how to continue to safeguard postmenopausal women’s health. Some of those questions are discussed here.
Is the Drug Regimen the Key? Regimen refers to the particular composition of the drug and dosage in which it is used. The most widely used form of hormone therapy in the United States is conjugated equine estrogen (CEE), the same drug tested in the E-Alone WHI and WHIMS trials. For decades, estrogen was given to women to manage menopausal symptoms, and because it was believed to benefit a woman’s health and well-being. When it was realized that estrogen given alone increased the risk of endometrial cancer among women with a uterus (see Grady, Gebretsadik, Kerlikowske, Ernster & Petitti, 1995 for a meta-analysis), a new compound was created by adding medroxyprogesterone acetate (MPA), a drug that inhibits endometrial growth, to CEE. This compound soon became widely prescribed for women with a uterus (women who had never had a hysterectomy). Today, the most widely used form of hormone therapy is CEE ⫹ MPA—the compound used in WHI and WHIMS. A question that remains, then, is whether all regi-
mens of hormone therapy will produce the same increased risk of dementia, or whether different compounds will have different effects. Before WHIMS, studies of hormone therapy for the prevention of dementia often did not distinguish between regimens of estrogen alone versus estrogen plus progestin. It is possible that addition of a progestin, most frequently MPA, might somehow counteract the beneficial neurobiological or vascular effects of estrogen, underlining the importance of conducting studies like WHIMS that compare different regimens. Estrogen actually describes a class of compounds consisting of various subtypes of estrogens. Thus, different types of estrogen might have somewhat different effects on the brain. Carefully conducted clinical trials are needed to test this hypothesis. But what might be should not outweigh what we have learned from WHI and WHIMS already. Thus, until definitively established, prudence suggests that the WHI and WHIMS data would generalize to all estrogens (see the current Food and Drug Administration guidelines at http://www. fda.gov/bbs/topics/NEWS/2004/NEW01022.html).
Or Is It Timing? Secondary prevention clinical trials have not demonstrated benefit of hormone therapy in slowing the progression of dementia (Hogervorst, Yaffe, Richards, & Huppert, 2002; Yaffe, Sawaya, Lieberburg, & Grady 1998). Most of the research examining the effects of estrogen on cognition in demented persons has studied dementia of the Alzheimer type. The characteristic brain pathologies in AD are the gradual and insidious accumulation of neuritic plaques and neurofibrillary tangles in the brain. Failure of hormone therapy to lessen the impact of AD may mean that once it has begun, hormone therapy cannot arrest or reverse these neuropathologies. It is noteworthy, however, that the WHIMS E⫹P trial demonstrated not only lack of protection against developing dementia, but increased risk associated with treatment. Therefore, dementia prevention trials in older women may not represent primary prevention of the underlying neuropathologic processes. An alternative hypothesis is that increased risk of dementia among women in the early stages of AD occurs when estrogen creates neurovascular disease (e.g., small strokes), a second pathology in the brain, that leads to cognitive decline and ultimately dementia ( Iadecola & Gorelick, 2003; Neuropathology Group of the Medical Research Council Cognitive Function and Aging Study, 2001; Snowdon et al., 1997). Identification of such individuals before initiating hormone therapy is highly desirable. Epidemiologic studies have suggested that there is a window of biological opportunity for receiving benefit to the brain from estrogen (Zandi et al., 2002). Women
K. P. Klein and S. R. Rapp / Women’s Health Issues 14 (2004) 71–74
who report taking hormone therapy during the perimenopausal and early postmenopausal periods have better global cognitive scores and a lower incidence of dementia than those who have never taken hormone therapy, or who started well beyond the menopausal transition. Although these data are suggestive, there are limitations to this type of study that restrict confidence in the suggestion that taking hormone therapy early is beneficial.
What Work Remains? The data from the E-Alone WHIMS trial will provide further evidence regarding whether differences in risk of cognitive decline are observed between the two regimens and compared to placebo. These data will also add to the information on all-cause dementia obtained from the E⫹P WHIMS trial. But because the WHI and WHIMS protocols included only two regimens of hormone therapy, WHIMS cannot answer the question of whether different regimens could provide protection against dementia. Nor can WHIMS tell us whether taking hormone therapy around the time of menopausal transition is protective against dementia or mild cognitive impairment. Until other studies can provide answers to these issues, it makes the most sense to assume that the WHIMS findings apply to other regimens and schedules of hormone therapy. The field would be advanced significantly by studies that reveal the neurologic mechanisms associated with the effects of hormone therapy. Lacking, for example, are large-scale studies employing stateof-the-art neuroimaging technologies that would allow examination of functional brain changes in women taking hormone therapy. In a planned supplemental study, WHIMS will collect magnetic resonance images of the brains of a subset of participants and analyze these data in conjunction with clinical and cognitive assessments to provide a much more complete picture. WHIMS has provided scientists and clinicians important new information to aid them in understanding the effects of hormone therapy on the brain. Questions remain unanswered, but the picture is clearer than before WHIMS. Hopefully, new studies will address the regimen and timing questions. Women and their doctors need to know how to estimate their risk of dementia before taking hormone therapy. What we do know is that use of hormone therapy remains a complex decision that must be carefully considered by each individual woman and her health care provider.
73
References Barrett-Connor, E., & Kritz-Silverstein, D. (1993). Estrogen replacement therapy and cognitive function in older women. Journal of the American Medical Association, 269, 2637–2641. Fisk, J. D., Merry, H. R., & Rockwood, K. (2003). Variations in case definition affect prevalence but not outcomes of mild cognitive impairment. Neurology, 61, 1179 –1184. Grady, D., Gebretsadik, T., Kerlikowske, K., Ernster, V., & Petitti, D. (1995). Hormone replacement therapy and endometrial cancer risk: A meta-analysis. Obstetrics and Gynecology, 85, 304 –313. Hebert, L. E., Scherr, P. A., Bienias, J. L., Bennett, D. A., & Evans, D. A. (2003). Alzheimer disease in the US population: Prevalence estimates using the 2000 census. Archives of Neurology, 60, 1119 – 1122. Hogervorst, E., Yaffe, K., Richards, M., & Huppert, F. (2002). Hormone replacement therapy for cognitive function in postmenopausal women. The Cochrane Database of Systematic Reviews. Oxford, England: Update Software. Iadecola, C., & Gorelick, P. B. (2003). Converging pathogenic mechanisms in vascular and neurodegenerative dementia. Stroke, 34, 335–337. Kawas, C., Resnick, S. M., Morrison, A., Brookmeyer, R., Corrada, M., Zonderman, A., et al (1997). A prospective study of estrogen replacement therapy and the risk of developing Alzheimer disease: The Baltimore Longitudinal Study on Aging. Neurology, 48, 1517–1521. Lopez, O. L., Jagust, W. J., DeKosky, S. T., Becker, J. T., Fitzpatrick, A., Dulberg, C., et al (2003). Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study: Part 1. Archives of Neurology, 60, 1385–1389. Maki, P. M., & Resnick, S. M. (2000). Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition. Neurobiology of Aging, 21, 373–383. Mulnard, R. A., Cotman, C. W., Kawas, C., van Dyxk, C. H., Sano, M., Doody, R., et al (2000). Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. Journal of the American Medical Association, 283, 1007–1015. Nelson, H. D., Humphrey, L. L., Nygren, P., Teutsch, S. M., & Allan, J. D. (2002). Postmenopausal hormone replacement: Scientific review. Journal of the American Medical Association, 288, 872– 881. Neuropathology Group of the Medical Research Council Cognitive Function and Aging Study (MRC CFAS) (2001). Pathological correlates of late-onset dementia in a multicentre community-based population in England and Wales. Lancet, 347, 169 –175. Paganini-Hill, A., & Henderson, V. W. (1994). Estrogen deficiency and risk of Alzheimer disease in women. American Journal of Epidemiology, 140, 256 –261. Payami, H., Montee, K., Grimslid, H., Shattuc, S., & Kaye, J. (1996). Increased risk of familial late-onset Alzheimer’s disease in women. Neurology, 46, 126 –129. Phillips, S., & Sherwin, B. B. (1991). Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology, 17, 485– 495. Rapp, S., Espeland, M. A., Shumaker, S. A., Henderson, V. W., Brunner, R. L., Manson, J. E., et al (2003). The effect of estrogen with progestin treatment on global cognitive function in postmenopausal women: Results from the Women’s Health Initiative Memory Study. Journal of the American Medical Association, 289, 2663–2672. Shumaker, S. A., Legault, C., Rapp, S. R., Thal, L., Wallace, R. B., Ockene, J. K., et al (2003). Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study: A randomized controlled trial. Journal of the American Medical Association, 289, 2651–2662. Snowdon, D. A., Greiner, L. H., Mortimer, J. A., Riley, K. P., Greiner, P. A., & Markesbery, W. R. (1997). Brain infarction and the
74
K. P. Klein and S. R. Rapp / Women’s Health Issues 14 (2004) 71–74
clinical expression of Alzheimer disease: The Nun Study. Journal of the American Medical Association, 277, 813– 817. Women’s Health Initiative Steering Committee (2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association, 291, 1701–1712. Writing Group for the Women’s Health Initiative Investigators (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association, 288, 321–333. Yaffe, K., Sawaya, G., Lieberburg, I., & Grady, D. (1998). Estrogen therapy in postmenopausal women: Effects on cognitive function and dementia. Journal of the American Medical Association, 279, 688 – 695. Zandi, P. P., Carlson, M. C., Plassman, B. L., Welsh-Bohmer, K. A., Mayer, L. S., Steffens, D. C., & Breitner, J. C. (2002). Hormone
replacement therapy and the incidence of Alzheimer disease in older women: The Cache County Study. Journal of the American Medical Association, 288, 2123–2129.
Author Descriptions Ms. Klein is a Research Associate in the Department of Public Health Sciences and the Women’s Health Center of Excellence at Wake Forest University School of Medicine (WFUSM), Winston-Salem, North Carolina. Dr. Rapp is a Professor in the Department of Psychiatry and Behavioral Medicine at WFUSM and CoPrincipal Investigator of the Women’s Health Initiative Memory Study (WHIMS).