Sex Hormone Therapy for Dementia

  • Victor W. Henderson
Part of the Endocrine Updates book series (ENDO, volume 8)

Abstract

The brain has receptors for steroid hormones, including estrogens, androgens, and progestogens. Many effects of sex hormones within the central nervous system are dependent on interactions with specific intracellular receptors. Pairs of hormone-receptor complexes, together with associated regulatory proteins, bind to portions of the genome known as hormone response elements in the promoter region of specific genes. Binding serves to enhance or inhibit downstream gene transcription and ultimately the synthesis of specific protein products within these target neurons (1).

Keywords

Estrogen Dementia Cortisol Testosterone Neurol 

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References

  1. 1.
    Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988; 249: 889–95.CrossRefGoogle Scholar
  2. 2.
    Breteler MMB, Claus JJ, van Duijn CM, Launer LJ, Hofman A. Epidemiology of Alzheimer’s disease. Epidemiol Rev 1992; 14: 59–82.PubMedGoogle Scholar
  3. 3.
    Ueda K, Kawano H, Hasuo Y, Fujishima M. Prevalence and etiology of dementia in a Japanese community. Stroke 1992; 23: 798–803.PubMedCrossRefGoogle Scholar
  4. 4.
    McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev 1995; 21: 195–218.PubMedCrossRefGoogle Scholar
  5. 5.
    Blacker D, Tanzi RE. The genetics of Alzheimer disease. Arch Neurol 1998; 55: 294–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Wong M, Thompson TL, Moss RL. Nongenomic actions of estrogen in the brain: physiological significance and cellular mechanisms. Crit Rev Neurobiol 1996; 10: 189–203.PubMedCrossRefGoogle Scholar
  7. 7.
    Shughrue P.T. Estrogen action in the estrogen receptor a-knockout mouse: is this due to ER-p? Mol Psychiatry 1998; 3: 299–302.PubMedCrossRefGoogle Scholar
  8. 8.
    Luine V. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp Neurol 1985; 89: 484–90.PubMedCrossRefGoogle Scholar
  9. 9.
    Gibbs RB, Pfaff DW. Effects of estrogen and fimbria/fornix transection on p75NGFR and ChAT expression in the medial septum and diagonal band of Broca. Exp Neurol 1992; 116: 23–39.PubMedCrossRefGoogle Scholar
  10. 10.
    Sar M, Stumpf WE. Central noradrenergic neurones concentrate 3H-oestradiol. Nature 1981; 289: 500–2.PubMedCrossRefGoogle Scholar
  11. 11.
    Fink G, Sumner BEH, McQueen JK, Wilson H, Rosie R. Sex steroid control of mood, mental state and memory. Clin Exp Pharmacol Physiol 1998; 25: 764–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Bartus RT, Dean RL, Beer B, Lippa AD. The cholinergic hypothesis of geriatric memory dysfunction. Science 1981; 217: 208–17.Google Scholar
  13. 13.
    Toran-Allerand CD, Miranda RC, Bentham WDL, et al. Estrogen receptors colocalize with lowaffmity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proc Natl Acad Sci USA 1992; 89: 4668–72.PubMedCrossRefGoogle Scholar
  14. 14.
    Fader AJ, Hendricson AW, Dohanich GP. Estrogen improves performance of reinforced T-maze alternation and prevents the amnestic effects of scopolamine administered systemically or intrahippocampally. Neurobiol Learn Memory 1998; 69: 225–40.CrossRefGoogle Scholar
  15. 15.
    Mooradian AD. Antioxidant properties of steroids. J Steroid Biochem Mol Biol 1993; 45: 509–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Singer CA, Rogers KL, Strickland TM, Dorsa DM. Estrogen protects primary cortical neurons from glutamate toxicity. Neurosci Lett 1996; 212: 13–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Simpkins JW, Rajakumar G, Zhang Y-Q, et al. Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J Neurosurg 1997; 87: 724–30.PubMedCrossRefGoogle Scholar
  18. 18.
    Behl C, Skutella T, Lezoualch F, et al. Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol 1997; 51: 535–41.PubMedGoogle Scholar
  19. 19.
    Toran-Allerand CD. Organotypic culture of the developing cerebral cortex and hypothalamus: relevance to sexual differentiation. Psychoneuroendocrinology 1991; 16: 7–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Brinton RD, Tran J, Proffitt P, Montoya M. 17 ß-estradiol enhances the outgrowth and survival of neocortical neurons in culture. Neurochem Res 1997; 22: 1339–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Foy MR, Henderson VW, Berger TW, Thompson RF. Estrogen and neural plasticity. Curr Dir Psychol Sci, in press.Google Scholar
  22. 22.
    Schneider MA, Brotherton PL, Hailes J. The effect of exogenous oestrogens on depression in menopausal women. Med J Australia 1977; 2: 162–3.PubMedGoogle Scholar
  23. 23.
    Fedor-Freybergh P. The influence of oestrogens on the wellbeing and mental performance in climacteric and postmenopausal women. Acta Obstet Gynecol Scand 1977;suppl. 64: 1–99.Google Scholar
  24. 24.
    Sherwin BB, Gelfand MM. Sex steroids and affect in the surgical menopause: a double-blind cross- over study. Psychoneuroendocrinology 1985; 10: 325–35.PubMedCrossRefGoogle Scholar
  25. 25.
    Ditkoff EC, Crary WG, Cristo M, Lobo RA. Estrogen improves psychological function in asymptomatic postmenopausal women. Obstet Gynecol 1991; 78: 991–5.PubMedGoogle Scholar
  26. 26.
    Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 1992; 17: 485–95.PubMedCrossRefGoogle Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    Polo-Kantola P, Portin R, Polo O, Helenius H, Irjala K, Erkkola R. The effect of short-term estrogen replacement therapy on cognition: a randomized, double-blind, cross-over trial in postmenopausal women. Obstet Gynecol 1998; 91: 459–66.PubMedCrossRefGoogle Scholar
  29. 29.
    Drake EB, Henderson VW, Stanczyk FZ, et al. Associations between circulating sex steroid hormones and cognition in normal elderly women. Neurology 2000; 54: 599–602.PubMedCrossRefGoogle Scholar
  30. 30.
    Yaffe K, Grady D, Pressman A, Cummings S. Serum estrogen levels, cognitive performance, and risk of cognitive decline in older community women. J Am Geriatr Soc 1998; 46: 816–21.PubMedGoogle Scholar
  31. 31.
    Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG. Estrogen replacement therapy in older women: comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch Neurol 1994; 51: 896–900.PubMedCrossRefGoogle Scholar
  32. 32.
    Mortel KF, Meyer JS. Lack of postmenopausal estrogen replacement therapy and the risk of dementia. J Neuropsychiatr Clin Neurosci 1995; 7: 334–7.Google Scholar
  33. 33.
    Henderson VW. The epidemiology of Alzheimer’s disease: the role of estrogen in reducing risk. In: Mayeux R, Christen Y, eds. Epidemiology of Alzheimer’s Disease: From Gene to Prevention. New York: Springer-Verlag, 1999: 49–63.CrossRefGoogle Scholar
  34. 34.
    Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol 1994; 140: 256–61.PubMedGoogle Scholar
  35. 35.
    Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer’s disease. Arch Intern Med 1996; 156: 2213–7.PubMedCrossRefGoogle Scholar
  36. 36.
    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: 2627.Google Scholar
  37. 37.
    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.PubMedCrossRefGoogle Scholar
  38. 38.
    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: 1517–21.PubMedCrossRefGoogle Scholar
  39. 39.
    Waring SC, Rocca WA, Petersen RC, O’Brien PC, Tangalos EG, Kokmen E. Postmenopausal estrogen replacement therapy and risk of AD: a population-based study. Neurology 1999; 52: 965–70.PubMedCrossRefGoogle Scholar
  40. 40.
    Henderson VW, Watt L, Buckwalter JG. Cognitive skills associated with estrogen replacement in women with Alzheimer’s disease. Psychoneuroendocrinology 1996; 21: 421–30.PubMedCrossRefGoogle Scholar
  41. 41.
    Doraiswamy PM, Bieber F, Kaiser L, Krishnan KR, Reuning-Scherer J, Gulanski B. The Alzheimer’s disease assessment scale: patterns and predictors of baseline cognitive performance in multicenter Alzheimer’s disease trials. Neurology 1997; 48: 1511–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Honjo H, Ogino Y, Tanaka K, et al. An effect of conjugated estrogen to cognitive impairment in women with senile dementia–Alzheimer’s type: a placebo-controlled double blind study. J Jpn Menopause Soc 1993; 1: 167–71.Google Scholar
  43. 43.
    Asthana S, Craft S, Baker LD, et al. Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer’s disease: results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology 1999; 24: 657–77.PubMedCrossRefGoogle Scholar
  44. 44.
    Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled study. Neurology 2000; 54: 295–301.PubMedCrossRefGoogle Scholar
  45. 45.
    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; 23; 283(8): 1007–15.Google Scholar
  46. 46.
    Schneider LS, Farlow MR, Henderson VW, Pogoda JM. Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer’s disease. Neurology 1996; 46: 1580–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Espeland MA, Applegate W, Furberg CD, Lefkowitz D, Rice L, Hunninghake D. Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. Am J Epidemiol 1995; 142: 1011–9.PubMedGoogle Scholar
  48. 48.
    O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SKJ. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340: 14–22.PubMedCrossRefGoogle Scholar
  49. 49.
    Ohkura T, Teshima Y, Isse K, et al. Estrogen increases cerebral and cerebellar blood flows in postmenopausal women. Menopause 1995; 2: 13–8.CrossRefGoogle Scholar
  50. 50.
    Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335: 453–61.PubMedCrossRefGoogle Scholar
  51. 51.
    Petitti DB, Sidney S, Quesenberry CPJ, Bernstein A. Ischemic stroke and use of estrogen and estrogen/progestogen as hormone replacement therapy. Stroke 1998; 29: 23–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Paganini-Hill A. Estrogen replacement therapy and stroke. Prog Cardiovasc Dis 1995; 38: 223–42.PubMedCrossRefGoogle Scholar
  53. 53.
    Simerly RB, Chang C, Muramatsu M, Swanson LW. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol 1990; 294: 7695.CrossRefGoogle Scholar
  54. 54.
    Wood RI, Newman SW. Androgen and estrogen receptors coexist within individual neurons in the brain of the Syrian hamster. Neuroendocrinology 1995; 62: 487–97.PubMedCrossRefGoogle Scholar
  55. 55.
    Brown TJ, Scherz B, Hochberg RB, MacLusky NJ. Regulation of estrogen receptor con-centrations in the rat brain: effects of sustained androgen and estrogen exposure. Neuroendocrinology 1996; 63: 53–60.PubMedCrossRefGoogle Scholar
  56. 56.
    Poletti A, Martini L. Androgen-activating enzymes in the central nervous system. J Steroid Biochem Mol Biol 1999; 69: 117–22.PubMedCrossRefGoogle Scholar
  57. 57.
    Naftolin F, Horvath TL, Jakab RL, Leranth C, Harada N, Balhazart J. Aromatase immunoreactivity in axon terminals of the vertebrate brain. Neuroendocrinology 1996; 63: 149–55.PubMedCrossRefGoogle Scholar
  58. 58.
    Roof RL, Havens MD. Testosterone improves maze performance and induces development of male hippocampus in females. Brain Res 1992; 572: 310–3.PubMedCrossRefGoogle Scholar
  59. 59.
    Goudsmit E, Van De Poll NE, Swaab DF. Testosterone fails to reverse spatial memory decline in aged rats and impairs retention in young and middle-aged animals. Behav Neural Biol 1990; 53: 6–20.PubMedCrossRefGoogle Scholar
  60. 60.
    Dobie DJ, Miller MA, Raskind MA, Dorsa DM. Testosterone reverses a senescent decline in extrahypothalamic vasopressin mRNA. Brain Res 1992; 583: 247–52.PubMedCrossRefGoogle Scholar
  61. 61.
    Christiansen K, Knussmann R. Sex hormones and cognitive functioning in men. Neuropsychobiology 1987; 18: 27–36.PubMedCrossRefGoogle Scholar
  62. 62.
    Gouchie C, Kimura D. The relationship between testosterone levels and cognitive ability patterns. Psychoneuroendocrinology 1991; 16: 323–34.PubMedCrossRefGoogle Scholar
  63. 63.
    Simon D, Preziosi P, Barrett-Connor E, et al. The influence of aging on plasma sex hormones in men: the Telecom study. Am J Epidemiol 1992; 1992: 783–91.Google Scholar
  64. 64.
    Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 1999; 84: 3681–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Janowsky JS, Oviatt SK, Orwoll ES. Testosterone influences spatial cognition in older men. Behav Neurosci 1994; 108: 325–32.PubMedCrossRefGoogle Scholar
  66. 66.
    Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988; 13: 345–57.PubMedCrossRefGoogle Scholar
  67. 67.
    Barrett-Connor E, Goodman-Gruen D. Cognitive function and endogenous sex hormones in older women. J Am Geriatr Soc 1999; 47: 1289–93.PubMedGoogle Scholar
  68. 68.
    Gouras GK, Xu H, Gross RS, et al. Testosterone reduces neuronal secretion of Alzheimer’s (3amyloid peptides. Proc Natl Acad Sci USA 2000; 97: 1202–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Baulieu EE. Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Rec Progr Hormone Res 1997; 52: 1–32.Google Scholar
  70. 70.
    Guazzo EP, Kirkpatrick PJ, Goodyer IM, Shiers HM, Herbert J. Cortisol, dehydorepiandrosterone (DHEA), and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age. J Clin Endocrinol Metab 1996; 81: 3951–60.PubMedCrossRefGoogle Scholar
  71. 71.
    Berr C, Lafont S, Debuire B, Dartigues J-F, Baulieu E-E. Relationships of dehydroepi-androsterone sulfate in the elderly with functional, psychological, and mental status, and short-term mortality: a French community-based study. Proc Natl Acad Sci USA 1996; 93: 13410–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Kalmijn S, Launer LJ, Stolk RP, et al. A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab 1998; 83: 3487–92.PubMedCrossRefGoogle Scholar
  73. 73.
    Barrett-Connor E, Edelstein SL. A prospective study of dehydroepiandrosterone sulfate and cognitive function in an older population: the Rancho Bernardo study. J Am Geriatr Soc 1994; 42: 420–3.PubMedGoogle Scholar
  74. 74.
    NAsman B, Olsson T, Bäckstróm T, et al. Serum dehydroepiandrosterone sulfate in Alzheimer’s disease and in multi-infarct dementia. Biol Psychiatry 1991; 30: 684–90.PubMedCrossRefGoogle Scholar
  75. 75.
    Yanase T, Fukahori M, Taniguchi S, et al. Serum dehydroepiandrosterone (DHEA) and DHEA- sulfate (DHEA-S) in Alzheimer’s disease and in cerebrovascular dementia. Endocr J 1996; 43: 1 1923.Google Scholar
  76. 76.
    Schneider LS, Hinsey M, Lyness S. Plasma dehydroepiandrosterone sulfate in Alzheimer’s disease. Biol Psychiatry 1992; 31: 205–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Kato J, Hirata S, Nozawa A, Yamada-Mouri N. Gene expression of progesterone receptor isoforms in the rat brain. Honor Behav 1994; 28: 454–63.CrossRefGoogle Scholar
  78. 78.
    Woolley CS, McEwen BS. Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol 1993; 336: 293–306.PubMedCrossRefGoogle Scholar
  79. 79.
    Ohkura T, Isse K, Akazawa K, Hamamoto M, Yaoi Y, Hagino N. Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer type: 7 case reports. Dementia 1995; 6: 99107.Google Scholar
  80. 80.
    Roof RL, Duvdevani R, Stein DG. Progesterone treatment attenuates brain edema following contusion injury in male and female rats. Restor Neurol Neurosci 1992; 4: 425–7.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Victor W. Henderson
    • 1
  1. 1.University of Southern CaliforniaLos AngelesUSA

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