Skip to main content Accessibility help
×
Home
  • Print publication year: 2009
  • Online publication date: July 2010

Chapter 4 - The critical window hypothesis: hormone exposures and cognitive outcomes after menopause

from Section 1 - Estrogens and cognition: perspectives and opportunities in the wake of the Women's Health Initiative Memory Study

Summary

Editors' introduction

Critical windows are a common phenomenon in biological systems. An exposure or experience at one point in time may elicit a different response, or even no response, at another time. In this chapter, Henderson considers several versions of the so-called critical window hypothesis as it relates to a woman's estrogenic exposures during middle age or during a later period of her life. These versions are based on timing of exposure, type of cognitive outcome, and timing of cognitive outcome assessment. At present, long-term cognitive effects of estrogenic exposures around the time of natural menopause are essentially unknown. As Henderson points out, some important but controversial clinical issues will be extraordinarily difficult to resolve. Partial answers may come from the ongoing Early versus Late Intervention Trial and the Kronos Early Estrogen Prevention Study. Truly convincing evidence regarding the critical window hypothesis can come only from randomized controlled trials in midlife women with follow-up extending into old age. Surrogate biomarkers may make some trial designs more feasible, and animal models and well designed observational studies can continue to provide valuable data. In the future, a variety of selective estrogen receptor modulators alone or in combination with an estrogen are certain to come to market, and similar issues may arise as more women are exposed to these compounds.

Related content

Powered by UNSILO

References

1. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58:1985–92.
2. Henderson VW. Hormone Therapy and the Brain: a Clinical Perspective on the Role of Estrogen. New York: Parthenon Publishing, 2000.
3. Burger HG. The endocrinology of the menopause. Maturitas. 1996;23:129–36.
4. Edwards DP. Regulation of signal transduction pathways by estrogen and progesterone. Annu Rev Physiol. 2005;67:335–76.
5. Behl C, Skutella T, Lezoualch F, et al. Neuroprotection against oxidative stress by estrogens: structure–activity relationship. Mol Pharmacol. 1997;51:535–41.
6. Shughrue PJ, Scrimo PJ, Merchenthaler I. Estrogen binding and estrogen receptor characterization (ERα and ERβ) in the cholinergic neurons of the rat basal forebrain. Neuroscience. 2000;96:41–9.
7. Luine V. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp Neurol. 1985;89:484–90.
8. Maki PM, Resnick SM. Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition. Neurobiol Aging. 2000;21:373–83.
9. Shaywitz SE, Shaywitz BA, Pugh KR, et al. Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA. 1999;281:1197–202.
10. Joffe H, Hall JE, Gruber S, et al. Estrogen therapy selectively enhances prefrontal cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women. Menopause. 2006;13:411–22.
11. Petanceska SS, Nagy G, Frail D, Gandy S. Ovariectomy and 17β-estradiol modulate the levels of Alzheimer's amyloid β peptides in brain. Neurology. 2000;54:2212–17.
12. Zheng H, Xu H, Uljon SN, et al. Modulation of Aβ peptides by estrogen in mouse models. J Neurochem. 2002;80:191–6.
13. Alvarez-De-La-Rosa M, Silva I, Nilsen J, et al. Estradiol prevents neural tau hyperphosphorylation characteristic of Alzheimer's disease. Ann N Y Acad Sci. 2005;1052:210–24.
14. Carroll JC, Rosario ER, Chang L, et al. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci. 2007;27:13357–65.
15. Stone DJ, Rozovsky I, Morgan TE, et al. Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro. Exp Neurol. 1997;143:313–18.
16. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. JAMA. 1997;278:1349–56.
17. Gibbs RB. Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. Neurobiol Aging. 2000;21:107–16.
18. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer's disease on older women: the Cache County study. JAMA. 2002;288:2123–9.
19. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer's disease. Arch Intern Med. 1996;156:2213–17.
20. 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;348:429–32.
21. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA. 2002;288:2170–2.
22. Brinton RD. Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Ann N Y Acad Sci. 2005;1052:57–74.
23. Jezierski MK, Sohrabji F. Neurotrophin expression in the reproductively senescent forebrain is refractory to estrogen stimulation. Neurobiol Aging. 2001;22:309–19.
24. Leranth C, Roth RH, Elswoth JD, et al. Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson's disease and memory. J Neurosci. 2000;20:8604–9.
25. Silva I, Mello LEAM, Freymüller E, Haidar MA, Baracat EC. Onset of estrogen replacement has a critical effect on synaptic density of CA1 hippocampus in ovariectomized adult rats. Menopause. 2003;10:406–11.
26. Suzuki S, Brown CM, Dela Cruz CD, et al. Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc Natl Acad Sci USA. 2007;104:6013–18.
27. Savonenko AV, Markowska AL. The cognitive effects of ovariectomy and estrogen replacement are modulated by aging. Neuroscience. 2003;119:821–30.
28. Daniel JM, Hulst JL, Berbling JL. Estradiol replacement enhances working memory in middle-aged rats when initiated immediately after ovariectomy but not after a long-term period of ovarian hormone deprivation. Endocrinology. 2006;147:607–14.
29. Stampfer MJ. Cardiovascular disease and Alzheimer's disease: common links. J Intern Med. 2006;260:211–23.
30. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69:2197–204.
31. Herrington DM, Espeland MA, Crouse JR, 3rd, et al. Estrogen replacement and brachial artery flow-mediated vasodilation in older women. Arterioscler Thromb Vasc Biol. 2001;21:1955–61.
32. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135:939–53.
33. Hodis HN, Mack WJ, Azen SP, et al. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. N Engl J Med. 2003;349:535–45.
34. Clarkson TB. Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression. Menopause. 2007;14:373–84.
35. Umetani M, Domoto H, Gormley AK, et al. 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat Med. 2007;13:1185–92.
36. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–77.
37. Sherwin BB, Tulandi T. “Add-back” estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. J Clin Endocrinol Metab. 1996;81:2545–9.
38. Resnick SM, Maki PM, Golski S, Kraut MA, Zonderman AB. Effects of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance. Horm Behav. 1998;34:171–82.
39. 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;101:485–512.
40. LeBlanc ES, Janowsky J, Chan BKS, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA. 2001;285:1489–99.
41. Brett KM, Chong Y. Hormone Replacement Therapy: Knowledge and Use in the United States. Hyattsville, MD: National Center for Health Statistics, 2001.
42. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology. 2000;54:295–301.
43. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA. 2000;283:1007–15.
44. Asthana S, Baker LD, Craft S, et al. High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology. 2001;57:605–12.
45. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study. JAMA. 2004;291:2947–58.
46. Rapp SR, Espeland MA, Shumaker SA, 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;289:2663–72.
47. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study. JAMA. 2004;291:2959–68.
48. Henderson VW, Espeland MA, Hogan PE, et al. Prior use of hormone therapy and incident Alzheimer's disease in the Women's Health Initiative Memory Study. Neurology. 2007;68(suppl. 1):A205.
49. Henderson VW. Hormone therapy and Alzheimer's disease: benefit or harm? Expert Opin Pharmacother. 2004;5:389–406.
50. Henderson VW. Estrogen-containing hormone therapy and Alzheimer's disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience. 2006;138:1031–9.
51. Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol. 1996;143:971–8.
52. Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA. Postmenopausal hormone therapy and Alzheimer's disease risk: interaction with age. J Neurol Neurosurg Psychiatry. 2005;76:103–5.
53. Brenner DE, Kukull WA, Stergachis A, et al. Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population-based case-control study. Am J Epidemiol. 1994;140:262–7.
54. Seshadri S, Zomberg GL, Derby LE, et al. Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease. Arch Neurol. 2001;58:435–40.
55. Kang JH, Weuve J, Grodstein F. Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women. Neurology. 2004;63:101–7.
56. Carlson MC, Zandi PP, Plassman BL, et al. Hormone replacement therapy and reduced cognitive decline in older women: the Cache County study. Neurology. 2001;57:2210–16.
57. Henderson VW, Sherwin BB. Surgical versus natural menopause: cognitive issues. Menopause. 2007;14:572–9.
58. Resnick SM, Maki PM, Rapp SR, et al. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab. 2006;91:1802–10.
59. 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;113:543–8.
60. Viscoli CM, Brass LM, Kernan WN, et al. Estrogen therapy and risk of cognitive decline: results from the Women's Estrogen for Stroke Trial (WEST). Am J Obstet Gynecol. 2005;192:387–93.
61. Almeida OP, Lautenschlager NT, Vasikaran S, et al. 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life. Neurobiol Aging. 2006;27:141–9.
62. Yaffe K, Vittinghoff E, Ensrud KE, et al. Effects of ultra-low-dose transdermal estradiol on cognition and health-related quality of life. Arch Neurol. 2006;63:945–50.
63. Xu J, Bartoces M, Neale AV, et al. Natural history of menopause symptoms in primary care patients: a MetroNet study. J Am Board Fam Pract. 2005;18:374–82.
64. Henderson VW, Dudley EC, Guthrie JR, Burger HG, Dennerstein L. Estrogen exposures and memory at midlife: a population-based study of women. Neurology. 2003;60:1369–71.
65. Herlitz A, Thilers P, Habib R. Endogenous estrogen is not associated with cognitive performance before, during, or after menopause. Menopause. 2007;14:425–31.
66. Luetters C, Huang MH, Seeman T, et al. Menopause transition stage and endogenous estradiol and follicle-stimulating hormone levels are not related to cognitive performance: cross-sectional results from the study of women's health across the nation (SWAN). J Women's Health. 2007;16:331–44.
67. 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. 2006;53:447–53.
68. Kok HS, Kuh D, Cooper R, et al. Cognitive function across the life course and the menopausal transition in a British birth cohort. Menopause. 2006;13:19–27.
69. Maki PM, Gast MJ, Vieweg A, Burriss SW, Yaffe K. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology. 2007;69:1322–30.
70. Woods NF, Mitchell ES, Adams C. Memory functioning among midlife women: observations from the Seattle Midlife Women's Health Study. Menopause. 2000;7:257–65.
71. Shaywitz SE, Naftolin F, Zelterman D, et al. Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen. Menopause. 2003;10:420–6.
72. Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology. 1992;17:485–95.
73. Rocca WA, Bower JH, Ahlskog JE, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–83.
74. MacLennan AH, Henderson VW, Paine BJ, et al. Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study. Menopause. 2006;13:28–36.
75. Bagger YZ, Tankó LB, Alexandersen P, Qin G, Christiansen C. Early postmenopausal hormone replacement therapy may prevent cognitive impairment later in life. Menopause. 2005;12:12–17.
76. Toran-Allerand CD. Estrogen as treatment for Alzheimer disease [letter]. JAMA. 2000;284:307–8.
77. Karim R, Hodis HN, Stanczyk FZ, Lobo RA, Mack WJ. Relationship between serum levels of sex hormones and progression of subclinical atherosclerosis in postmenopausal women. J Clin Endocrinol Metab. 2008;93:131–8.
78. Kritz-Silverstein D, Barrett-Connor E. Hysterectomy, oophorectomy, and cognitive function in older women. J Am Geriatr Soc. 2002;50:55–61.