Estrogen-containing Hormone Therapy, Selective Estrogen Receptor Modulators, and Alzheimer's Disease
Estrogen-containing Hormone Therapy, Selective Estrogen Receptor Modulators, and Alzheimer's Disease
US Neurological Disease 2006
Published: October 2008
Published: October 2008
Of all the problems that beset people during the aging process, dementia is perhaps the most feared. Alzheimer’s disease (AD) is the most common cause of dementia, accounting for an estimated 4.5 million cases in the US.1 Within the brain, AD is characterized by the presence of neuritic plaques in specific cortical areas and by neurofibrillary tangles within vulnerable neurons. Plaques often contain a central core of the ß- amyloid polypeptide. Episodic memory loss, manifest by the inability to learn new information or to recall recent events, is an early and consistent feature, and cognitive decline progresses inexorably over a period of years.
A number of genetic and non-genetic factors may influence the development of AD. Mutations in genes on chromosomes 14, 1, and 21, which increase ß- amyloid deposition and lead to dementia symptoms before the age of 60, are inherited in an autosomal dominant manner. 2 These relatively rare mutations do not contribute to late-onset dementia, where dementia risk is likely influenced by susceptibility genes, the best recognized of which encodes apolipoprotein E,2 a lipid transport protein involved in neuronal repair processes. Other factors linked to AD risk include head injury, depression, lower education, absence of physical exercise, and conditions associated with cardiovascular disease (CVD). Estrogen, as will now be described, has several effects on brain function that could influence AD; exposures to endogenous estrogens and to estrogencontaining hormone therapy (HT) are relevant to AD pathogenesis and treatment.
Menopause and Estrogen
Menopause represents the permanent cessation of menses due to the loss of ovarian follicular function,3 including the near-complete loss of estrogen production by the ovaries. Natural menopause, usually heralded by several years of menstrual cycle irregularity, occurs at an average age of 51 years. Approximately 40% of a woman’s adult life occurs after her final menstrual period.Two forms of estrogen receptors, which function as ligand-activated transcription factors, are expressed by neurons in the human brain.
Estrogen has been shown to promote neurite growth, modulate synaptic plasticity, and enhance long-term potentiation (a physiological process thought to underlie the formation of episodic memories).4 Estrogen protects neurons from oxidative stress, excitatory neurotoxicity, and ß-amyloid toxicity,5 reduces neuronal death from apoptosis,6 and diminishes ß-amyloid deposition in the brain.7
Cholinergic deficits are prominent in AD, and cholinergic neurons express receptors for estrogen.8 The effects of estrogen on noradrenalin and serotonin,9,10 two other neurotransmitters affected in AD, may be important to cognition and mood. The competing effects of estrogen on inflammation and coagulation have the potential for harm, and estrogen can increase the risk of ischemic stroke.11
References:
1. Hebert L E, Scherr P A, Bienias J L, et al., - Alzheimer disease in the US population: prevalence estimates using the 2000 census; , Arch Neurol (2003);60: pp. 1,119 1,122.
2. Bird T D, - Genetic factors in Alzheimer s disease; , N Engl J Med (2005);352: pp. 862 864.
3. North American Menopause Society, Menopause Practice: A Clinician s Guide, Cleveland, OH (2004).
4. Foy M R, Henderson V W, Berger T W,Thompson R F, - Estrogen and neural plasticity; , Curr Dir Psychol Sci (2000);9: pp. 148 152.
5. Goodman Y, Bruce A J, Cheng B, Mattson M P,- Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid ß-peptide toxicity in hippocampal neurons; , J Neurochem (1996);66: pp. 1,836 1,844.
6. Pike C J,- Estrogen modulates neuronal Bcl-xL expression and ß-amyloid-induced apoptosis: relevance to Alzheimer s disease; , J Neurochem (1999);72: pp. 1,552 1,563.
7. Zheng H, Xu H, Uljon S N, et al., - Modulation of Aß peptides by estrogen in mouse models; , J Neurochem (2002);80: pp. 191 196.
8. Shughrue P J, Scrimo P J, Merchenthaler I, - Estrogen binding and estrogen receptor characterization (ERa and ERß) in the cholinergic neurons of the rat basal forebrain; , Neuroscience (2000);96: pp. 41 49.
9. Herbison A E, Simonian S X,Thanky N R, Bicknell R J,- Oestrogen modulation of noradrenaline neurotransmission; ,Novartis Found Symp (2000);230: pp. 74 85.
10. Bethea C L, Lu N Z, Gundlah C, Streicher J M, - Diverse actions of ovarian steroids in the serotonin neural system; , Front Neuroendocrinol (2002);23: pp. 41 100.
11. Anderson G L, Limacher M, Assaf A R, et al., - Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women s Health Initiative randomized controlled trial; , JAMA (2004);291: pp. 1,701 1,712.
12. Shaywitz S E, Naftolin F, Zelterman D, et al., - Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen; , Menopause (2003);10: pp. 420 426.
13. Phillips S M, Sherwin B B, - Effects of estrogen on memory function in surgically menopausal women; , Psychoneuroendocrinology (1992);17: pp. 485 495.
14. Henderson V W, Dudley E C, Guthrie J R, Burger H G, Dennerstein L, - Estrogen exposures and memory at midlife: a population-based study of women; , Neurology (2003);60: pp. 1,369 1,371.
15. Fuh J L,Wang S J, Lee S J, Lu S R, Juang K D, - A longitudinal study of cognition change during early menopausal transition in a rural community; , Maturitas (2005 [E-pub ahead of print]).
16. Meyer P M, Powell L H,Wilson R S, et al., - A population-based longitudinal study of cognitive functioning in the menopausal transition; , Neurology (2003);61: pp. 801 806.
17. Kang J H,Weuve J, Grodstein F, - Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women; , Neurology (2004);63: pp. 101 107.
18. Carlson M C, Zandi P P, Plassman B L, et al., - Hormone replacement therapy and reduced cognitive decline in older women: the Cache County study; , Neurology (2001);57: pp. 2,210 2,216.
19. Grady D, Yaffe K, Kristof M, et al., - Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study; , Am J Med (2002);113: pp. 543 548.
20. Viscoli C M, Brass L M, Kernan W N, et al.,- Estrogen therapy and risk of cognitive decline: results from the Women s Estrogen for Stroke Trial (WEST); , Am J Obstet Gynecol (2005);192: pp. 387 393.
21. Rapp S R, Espeland M A, Shumaker S A, et al.,- The effect of estrogen with progestin treatment on global cognitive function in postmenopausal women: results from the Women s Health Initiative Memory Study; , JAMA (2003);289: pp. 2,663 2,672.
22. Espeland M A, Rapp S R, Shumaker S A, et al.,- Conjugated equine estrogens and global cognitive function in postmenopausal women:Women s Health Initiative Memory Study; , JAMA (2004);291: pp. 2,959 2,968.
23. Paganini-Hill A, Henderson V W, - Estrogen replacement therapy and risk of Alzheimer s disease; , Arch Intern Med(1996);156: pp. 2,213 2,217.
24. Tang M X, Jacobs D, Stern Y, et al.,- Effect of oestrogen during menopause on risk and age at onset of Alzheimer s disease; , Lancet (1996);348: pp. 429 432.
25. Kawas C, Resnick S, Morrison A, et al., - A prospective study of estrogen replacement therapy and the risk of developing Alzheimer s disease: the Baltimore Longitudinal Study of Aging; , Neurology (1997);48: pp. 1,517 1,521.
26. Zandi P P, Carlson M C, Plassman B L, et al., - Hormone replacement therapy and incidence of Alzheimer s disease on older women: the Cache County study; , JAMA (2002);288: pp. 2,123 2,129.
27. Hogervorst E,Williams J, Budge M, Riedel W, Jolles J, - The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis; , Neuroscience (2000);101: pp. 485 512.
28. Shumaker S A, Legault C, Kuller L, et al., - Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women:Women s Health Initiative Memory Study; , JAMA (2004);291: pp. 2,947 2,958.
29. Matthews K A, Kuller L H,Wing R R, et al.,- Prior to use of estrogen replacement therapy, are users healthier than non-users?; , Am J Epidemiol (1996);143: pp. 971 978.
30. Henderson V W, - Estrogen-containing hormone therapy and Alzheimer s disease risk: understanding discrepant inferences from observational and experimental research; , Neuroscience (2005 [e-published ahead of print]).
31. Henderson V W, Benke K S, Green R C, et al.,- Postmenopausal hormone therapy and Alzheimer s disease risk: interaction with age; , J Neurol Neurosurg Psychiatry (2005);76: pp. 103 105.
32. Torgerson D J, Bell-Syer S E, - Hormone replacement therapy and prevention of non-vertebral fractures: a meta-analysis of randomized trials; , JAMA (2001);285: pp. 2,891 2,289.
33. Mack W J, Slater C C, Xiang M, et al.,- Elevated subclinical atherosclerosis associated with oophorectomy is related to time since menopause rather than type of menopause; , Fertil Steril (2004);82: pp. 391 397.
34. Henderson V W, Paganini-Hill A, Miller B L, et al., - Estrogen for Alzheimer s disease in women: randomized, double-blind, placebo-controlled trial; , Neurology (2000);54: pp. 295 301.
35. Mulnard R A, Cotman C W, Kawas C, et al.,- Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial; , JAMA (2000);283: pp. 1,007 1,015.
36. Rigaud A S, Andre G,Vellas B,Touchon J, Pere J J, - No additional benefit of HRT on response to rivastigmine in menopausal women with AD; , Neurology (2003);60: pp. 148 149.
37. Asthana S, Baker L D, Craft S, et al., - High-dose estradiol improves cognition for women with AD: results of a randomized study; , Neurology (2001);57: pp. 605 612.
38. McDonnell D P, - The molecular pharmacology of SERMs; , Trends Endocrinol Metab (1999);10: pp. 301 311.
39. Zhou W, Koldzic-Zivanovic N, Clarke C H, et al., - Selective estrogen receptor modulator effects in the rat brain; , Neuroendocrinology (2002);75: pp. 24 33.
40. Yaffe K, Krueger K, Sarkar S, et al., - Cognitive function in postmenopausal women treated with raloxifene; , N Engl J Med (2001);344: pp. 1,207 1,213.
41. Yaffe K, Krueger K, Cummings S R, et al., - Effect of raloxifene on the prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial; , Am J Psychiatry (2005);162: pp. 680 693.
42. Paganini-Hill A, Clark L J,- Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen; , Breast Cancer Res Treat (2000);64: pp. 165 176.
43. Hersh A L, Stefanick M L, Stafford R S,- National use of postmenopausal hormone therapy: annual trends and response to recent evidence; , JAMA (2004);291: pp. 47 53.
2. Bird T D, - Genetic factors in Alzheimer s disease; , N Engl J Med (2005);352: pp. 862 864.
3. North American Menopause Society, Menopause Practice: A Clinician s Guide, Cleveland, OH (2004).
4. Foy M R, Henderson V W, Berger T W,Thompson R F, - Estrogen and neural plasticity; , Curr Dir Psychol Sci (2000);9: pp. 148 152.
5. Goodman Y, Bruce A J, Cheng B, Mattson M P,- Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid ß-peptide toxicity in hippocampal neurons; , J Neurochem (1996);66: pp. 1,836 1,844.
6. Pike C J,- Estrogen modulates neuronal Bcl-xL expression and ß-amyloid-induced apoptosis: relevance to Alzheimer s disease; , J Neurochem (1999);72: pp. 1,552 1,563.
7. Zheng H, Xu H, Uljon S N, et al., - Modulation of Aß peptides by estrogen in mouse models; , J Neurochem (2002);80: pp. 191 196.
8. Shughrue P J, Scrimo P J, Merchenthaler I, - Estrogen binding and estrogen receptor characterization (ERa and ERß) in the cholinergic neurons of the rat basal forebrain; , Neuroscience (2000);96: pp. 41 49.
9. Herbison A E, Simonian S X,Thanky N R, Bicknell R J,- Oestrogen modulation of noradrenaline neurotransmission; ,Novartis Found Symp (2000);230: pp. 74 85.
10. Bethea C L, Lu N Z, Gundlah C, Streicher J M, - Diverse actions of ovarian steroids in the serotonin neural system; , Front Neuroendocrinol (2002);23: pp. 41 100.
11. Anderson G L, Limacher M, Assaf A R, et al., - Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women s Health Initiative randomized controlled trial; , JAMA (2004);291: pp. 1,701 1,712.
12. Shaywitz S E, Naftolin F, Zelterman D, et al., - Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen; , Menopause (2003);10: pp. 420 426.
13. Phillips S M, Sherwin B B, - Effects of estrogen on memory function in surgically menopausal women; , Psychoneuroendocrinology (1992);17: pp. 485 495.
14. Henderson V W, Dudley E C, Guthrie J R, Burger H G, Dennerstein L, - Estrogen exposures and memory at midlife: a population-based study of women; , Neurology (2003);60: pp. 1,369 1,371.
15. Fuh J L,Wang S J, Lee S J, Lu S R, Juang K D, - A longitudinal study of cognition change during early menopausal transition in a rural community; , Maturitas (2005 [E-pub ahead of print]).
16. Meyer P M, Powell L H,Wilson R S, et al., - A population-based longitudinal study of cognitive functioning in the menopausal transition; , Neurology (2003);61: pp. 801 806.
17. Kang J H,Weuve J, Grodstein F, - Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women; , Neurology (2004);63: pp. 101 107.
18. Carlson M C, Zandi P P, Plassman B L, et al., - Hormone replacement therapy and reduced cognitive decline in older women: the Cache County study; , Neurology (2001);57: pp. 2,210 2,216.
19. Grady D, Yaffe K, Kristof M, et al., - Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study; , Am J Med (2002);113: pp. 543 548.
20. Viscoli C M, Brass L M, Kernan W N, et al.,- Estrogen therapy and risk of cognitive decline: results from the Women s Estrogen for Stroke Trial (WEST); , Am J Obstet Gynecol (2005);192: pp. 387 393.
21. Rapp S R, Espeland M A, Shumaker S A, et al.,- The effect of estrogen with progestin treatment on global cognitive function in postmenopausal women: results from the Women s Health Initiative Memory Study; , JAMA (2003);289: pp. 2,663 2,672.
22. Espeland M A, Rapp S R, Shumaker S A, et al.,- Conjugated equine estrogens and global cognitive function in postmenopausal women:Women s Health Initiative Memory Study; , JAMA (2004);291: pp. 2,959 2,968.
23. Paganini-Hill A, Henderson V W, - Estrogen replacement therapy and risk of Alzheimer s disease; , Arch Intern Med(1996);156: pp. 2,213 2,217.
24. Tang M X, Jacobs D, Stern Y, et al.,- Effect of oestrogen during menopause on risk and age at onset of Alzheimer s disease; , Lancet (1996);348: pp. 429 432.
25. Kawas C, Resnick S, Morrison A, et al., - A prospective study of estrogen replacement therapy and the risk of developing Alzheimer s disease: the Baltimore Longitudinal Study of Aging; , Neurology (1997);48: pp. 1,517 1,521.
26. Zandi P P, Carlson M C, Plassman B L, et al., - Hormone replacement therapy and incidence of Alzheimer s disease on older women: the Cache County study; , JAMA (2002);288: pp. 2,123 2,129.
27. Hogervorst E,Williams J, Budge M, Riedel W, Jolles J, - The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis; , Neuroscience (2000);101: pp. 485 512.
28. Shumaker S A, Legault C, Kuller L, et al., - Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women:Women s Health Initiative Memory Study; , JAMA (2004);291: pp. 2,947 2,958.
29. Matthews K A, Kuller L H,Wing R R, et al.,- Prior to use of estrogen replacement therapy, are users healthier than non-users?; , Am J Epidemiol (1996);143: pp. 971 978.
30. Henderson V W, - Estrogen-containing hormone therapy and Alzheimer s disease risk: understanding discrepant inferences from observational and experimental research; , Neuroscience (2005 [e-published ahead of print]).
31. Henderson V W, Benke K S, Green R C, et al.,- Postmenopausal hormone therapy and Alzheimer s disease risk: interaction with age; , J Neurol Neurosurg Psychiatry (2005);76: pp. 103 105.
32. Torgerson D J, Bell-Syer S E, - Hormone replacement therapy and prevention of non-vertebral fractures: a meta-analysis of randomized trials; , JAMA (2001);285: pp. 2,891 2,289.
33. Mack W J, Slater C C, Xiang M, et al.,- Elevated subclinical atherosclerosis associated with oophorectomy is related to time since menopause rather than type of menopause; , Fertil Steril (2004);82: pp. 391 397.
34. Henderson V W, Paganini-Hill A, Miller B L, et al., - Estrogen for Alzheimer s disease in women: randomized, double-blind, placebo-controlled trial; , Neurology (2000);54: pp. 295 301.
35. Mulnard R A, Cotman C W, Kawas C, et al.,- Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial; , JAMA (2000);283: pp. 1,007 1,015.
36. Rigaud A S, Andre G,Vellas B,Touchon J, Pere J J, - No additional benefit of HRT on response to rivastigmine in menopausal women with AD; , Neurology (2003);60: pp. 148 149.
37. Asthana S, Baker L D, Craft S, et al., - High-dose estradiol improves cognition for women with AD: results of a randomized study; , Neurology (2001);57: pp. 605 612.
38. McDonnell D P, - The molecular pharmacology of SERMs; , Trends Endocrinol Metab (1999);10: pp. 301 311.
39. Zhou W, Koldzic-Zivanovic N, Clarke C H, et al., - Selective estrogen receptor modulator effects in the rat brain; , Neuroendocrinology (2002);75: pp. 24 33.
40. Yaffe K, Krueger K, Sarkar S, et al., - Cognitive function in postmenopausal women treated with raloxifene; , N Engl J Med (2001);344: pp. 1,207 1,213.
41. Yaffe K, Krueger K, Cummings S R, et al., - Effect of raloxifene on the prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial; , Am J Psychiatry (2005);162: pp. 680 693.
42. Paganini-Hill A, Clark L J,- Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen; , Breast Cancer Res Treat (2000);64: pp. 165 176.
43. Hersh A L, Stefanick M L, Stafford R S,- National use of postmenopausal hormone therapy: annual trends and response to recent evidence; , JAMA (2004);291: pp. 47 53.
