Skip to main content
SpringerLink
Log in
Book cover

Animal Models of Human Cognitive Aging pp 1–31Cite as

Hormonal Influences on Brain Aging and Age-Related Cognitive Decline

  • Chapter
  • First Online:

  • 682 Accesses

Part of the book series: Aging Medicine ((AGME))

Abstract

Steroid hormones play a critical role in the developing brain and continue to modulate cognition with aging. The main steroid hormones include the adrenal gland hormones, mineralocorticoids , and glucocorticoids; and the gonadal hormones, androgen, estrogen, and progesterone. Steroid hormones transduce their effects via hormone-specific receptors which are localized throughout the brain. More importantly, the androgen, estrogen, progesterone, and the glucocorticoid receptors have been identified in brain regions associated with learning and memory such as the hippocampus. One consequence of aging is a shift in the relative proportion of hormone availability. For example, the sex hormones estrogen, testosterone, and progesterone decline with age, while hormones regulating the HPA axis, such as corticosteroids have been shown to increase with age. However, the change in hormone levels with age is oftentimes gender-specific. Steroid hormones act in concert with each other, thus separating out the contribution of one specific hormone can be difficult. For example, testosterone can be aromatized to estrogen, thus the loss of testosterone may also result in a reduction in estrogen. Further, the progesterone receptor contains an imperfect estrogen-binding site, thus loss of estrogen can potentially impact actions initiated through the progesterone receptor. The role of steroid hormones in cognition has been studied using both animal models and clinical trials. This chapter summarizes both the animal and clinical data on the effects of estrogen, progesterone, androgen, and the glucocorticoids on cognition with age and their role in neurodegenerative processes, specifically targeting Alzheimer’s disease.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Gower, D. (1979) Biosynthesis of corticosteroids, androgens and oestrogens. In Croom Helm, London, pp. 33–44.Steroid Hormones.

    Google Scholar 

  2. Toran-Allerand, C. (1976) Sex steroids and the development of the newborn mouse hypothalamus and preoptic area in vitro. : implications for sexual differentiation Brain Res 106, 407–412.

    PubMed  CAS  Google Scholar 

  3. Toran-Allerand, C., Gerlach, J., and McEwen, B. (1980) Autoradiographic localization of [3.]Hestradiol related to steroid responsiveness in cultures of the newborn mouse hypothalamus and preoptic area Brain Res 184, 517–522.

    PubMed  CAS  Google Scholar 

  4. Toran-Allerand, C. (1980) Sex steroids and the development of the newborn mouse hypothalamus and preoptic area in vitro. II. Morphological correlates and hormonal specificity. Brain Res 189, 413–427.

    PubMed  CAS  Google Scholar 

  5. Toran-Allerand, C. D., Hashimoto, K., Greenough, W., and Saltarelli, M. (1983) Sex steroids and the development of the newborn mouse hypothalamus and preoptic area in vitro. . III. Effects of estrogen on dendritic differentiation Dev Brain Res 7, 97–101.

    CAS  Google Scholar 

  6. Toran-Allerand, C. (1984) On the genesis of sexual differentiation of the central nervous system: morphogenetic consequences of steroidal exposure and possible role of a-Fetoprotein. Prog Brain Res 61, 63–98.

    PubMed  CAS  Google Scholar 

  7. Nishizuka, M., and Arai, Y. (1981) Sexual dimorphism in synaptic organization in the amygdala and its dependence on neonatal hormone environment. Brain Res 212, 31–38.

    PubMed  CAS  Google Scholar 

  8. Lustig, R., Sudol, M., Pfaff, D., and Federoff, H. (1991) Estrogenic regulation and sex dimorphism of growth-associated protein 43 (GAP-43) messenger RNA in the rat. Molec Brain Res 11, 125–132.

    PubMed  CAS  Google Scholar 

  9. Hammer, R., and JrJacobson, C. (1984) Sex differences in dendritic development of the sexually dimorphic nucleus of the preoptic area in the rat. Int J Dev Neurosci 2, 77–85.

    Google Scholar 

  10. Stanley, H., and Fink, G. (1986) Synthesis of specific brain proteins is influenced by testosterone at mRNA level in the neonatal rat. Brain Res 370, 223–231.

    PubMed  CAS  Google Scholar 

  11. Stanley, H., Borthwick, N., and Fink, G. (1986) Brain protein changes during development and sexual differentiation in the rat. Brain Res 370, 215–222.

    PubMed  CAS  Google Scholar 

  12. Gould, E., Woolley, C. S., Frankfurt, M., and McEwen, B. S. (1990) Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J Neurosci 10, 1286–1291.

    PubMed  CAS  Google Scholar 

  13. Woolley, C., and McEwen, B. (1992) Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci 12, 2549–2554.

    PubMed  CAS  Google Scholar 

  14. Woolley, C. S., Gould, E., Frankfurt, M., and McEwen, B. S. (1990) Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci 10, 4035–4039.

    PubMed  CAS  Google Scholar 

  15. Adams, M. M., Fink, S. E., Shah, R. A., et al. (2002) Estrogen and aging affect the subcellular distribution of estrogen receptor-alpha in the hippocampus of female rats. J Neurosci 22, 3608–3614.

    PubMed  CAS  Google Scholar 

  16. McEwen, B. S., and Alves, S. E. (1999) Estrogen Actions in the Central Nervous System. Endocr Rev 20, 279–307.

    PubMed  CAS  Google Scholar 

  17. Wood, G. E., and Shors, T. J. (1998) Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones. Proc Natl Acad Sci U S A 95, 4066–4071.

    PubMed  CAS  Google Scholar 

  18. Shors, T. J., Lewczyk, C., Pacynski, M., Mathew, P. R., and Pickett, J. (1998) Stages of estrous mediate the stress-induced impairment of associative learning in the female rat. Neuroreport 9, 419–423.

    PubMed  CAS  Google Scholar 

  19. Shors, T. J., Chua, C., and Falduto, J. (2001) Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus. J Neurosci 21, 6292–6297.

    PubMed  CAS  Google Scholar 

  20. Szymczak, S., Kalita, K., Jaworski, J., et al. (2006) Increased estrogen receptor beta expression correlates with decreased spine formation in the rat hippocampus. Hippocampus 16, 453–463.

    PubMed  CAS  Google Scholar 

  21. Fugger, H. N., Foster, T. C., Gustafsson, J., and Rissman, E. F. (2000) Novel effects of estradiol and estrogen receptor alpha and beta on cognitive function. Brain Res 883, 258–264.

    PubMed  CAS  Google Scholar 

  22. Simerly, R., Chang, C., Muramatsu, M., and Swanson, L. (1990) Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ. hybridization study J Comp Neurol 294, 76–95.

    PubMed  CAS  Google Scholar 

  23. Sar, M., and Parikh, I. (1986) Immunohistochemical localization of estrogen receptor in rat brain, pituitary and uterus with monoclonal antibodies. J Steroid Biochem 24, 497–503.

    PubMed  CAS  Google Scholar 

  24. Li, X., Schwartz, P. E., and Rissman, E. F. (1997) Distribution of estrogen receptor-beta-like immunoreactivity in rat forebrain. Neuroendocrinology 66, 63–67.

    PubMed  CAS  Google Scholar 

  25. Shughrue, P. J., and Merchenthaler, I. (2001) Distribution of estrogen receptor beta immunoreactivity in the rat central nervous system. J Comp Neurol 436, 64–81.

    PubMed  CAS  Google Scholar 

  26. Osterlund, M. K., Keller, E., and Hurd, Y. L. (2000) The human forebrain has discrete estrogen receptor alpha messenger RNA expression: high levels in the amygdaloid complex. Neuroscience 95, 333–342.

    PubMed  CAS  Google Scholar 

  27. Perez, S. E., Chen, E. Y., and Mufson, E. J. (2003) Distribution of estrogen receptor alpha and beta immunoreactive profiles in the postnatal rat brain. Developmental Brain Research 145, 117–139.

    PubMed  CAS  Google Scholar 

  28. Register, T. C., Shively, C. A., and Lewis, C. E. (1998) Expression of estrogen receptor a and b transcripts in female monkey hippocampus and hypothalamus. Brain Research 788, 320–322.

    PubMed  CAS  Google Scholar 

  29. Shughrue, P. J., Lane, M. V., and Merchenthaler, I. (1997) Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol 388, 507–525.

    PubMed  CAS  Google Scholar 

  30. Jezierski, M., and Sohrabji, F. (2000) Region- and peptide-specific regulation of the neurotrophins by estrogen. Mol Brain Res 85, 77–84.

    PubMed  CAS  Google Scholar 

  31. Mehra, R. D., Sharma, K., Nyakas, C., and Vij, U. (2005) Estrogen receptor alpha and beta immunoreactive neurons in normal adult and aged female rat hippocampus: a qualitative and quantitative study. Brain Res 1056, 22–35.

    PubMed  CAS  Google Scholar 

  32. Savaskan, E., Olivieri, G., Meier, F., Ravid, R., and Muller-Spahn, F. (2001) Hippocampal estrogen beta-receptor immunoreactivity is increased in Alzheimer’s disease. Brain Res 908, 113–119.

    PubMed  CAS  Google Scholar 

  33. Price, D. L., Cork, L. C., Struble, R. G., Whitehouse, P. J., Kitt, C. A., and Walker, L. C. (1985) The functional organization of the basal forebrain cholinergic system in primates and the role of this system in Alzheimer’s disease. Ann N Y Acad Sci 444, 287–295.

    PubMed  CAS  Google Scholar 

  34. Ishunina, T. A., and Swaab, D. F. (2001) Increased expression of estrogen receptor a and b in the nucleus basalis of Meynert in Alzheimer’s disease. Neurobiology of Aging 22, 417–426.

    PubMed  CAS  Google Scholar 

  35. Blaustein, J. D. (1993) Estrogen receptor immunoreactivity in rat brain: rapid effects of estradiol injection. Endocrinology 132, 1218–1224.

    PubMed  CAS  Google Scholar 

  36. Lu, Y. P., Zeng, M., Swaab, D. F., Ravid, R., and Zhou, J. N. (2004) Colocalization and alteration of estrogen receptor-a and -b in the hippocampus in Alzheimer’s disease. Human Pathol 35, 275–280.

    CAS  Google Scholar 

  37. Hu, X. Y., Qin, S., Lu, Y. P., Ravid, R., Swaab, D. F., and Zhou, J. N. (2003) Decreased estrogen receptor-alpha expression in hippocampal neurons in relation to hyperphosphorylated tau in Alzheimer patients. Acta Neuropathol (Berl) 106, 213–220.

    CAS  Google Scholar 

  38. Lu, Y. P., Zeng, M., Hu, X. Y., et al. (2003) Estrogen receptor a-immunoreactive astrocytes are increased in the hippocampus in Alzheimer’s disease. Exp Neurol 183, 482–488.

    PubMed  CAS  Google Scholar 

  39. Lambert, J.-C, Harris, J. M., Mann, D., et al. (2001) Are the estrogen receptors involved in Alzheimer’s disease? Neurosci Lett 306, 193–197.

    PubMed  CAS  Google Scholar 

  40. Monastero, R., Cefalu, A. B., Camarda, C., et al. (2006) Association of estrogen receptor alpha gene with Alzheimer’s disease: a case-control study. J Alzheimers Dis 9, 273–278.

    PubMed  CAS  Google Scholar 

  41. Porrello, E., Monti, M. C., Sinforiani, E., et al. (2006) Estrogen receptor alpha and APOEepsilon4 polymorphisms interact to increase risk for sporadic AD in Italian females. Eur J Neurol 13, 639–644.

    PubMed  CAS  Google Scholar 

  42. Wang, J. M., Irwin, R. W., and Brinton, R. D. (2006) Activation of estrogen receptor a increases and estrogen receptor b decreases apolipoprotein E expression in hippocampus in vitro and in vivo. PNAS 103, 16983–16988.

    PubMed  CAS  Google Scholar 

  43. Clancy, A. N., Bonsall, R. W., and Michael, R. P. (1992) Immunohistochemical labeling of androgen receptors in the brain of rat and monkey. Life Sci 50, 409–417.

    PubMed  CAS  Google Scholar 

  44. Bingaman, E. W., Baeckman, L. M., Yracheta, J. M., Handa, R. J., and Gray, T. S. (1994) Localization of androgen receptor within peptidergic neurons of the rat forebrain. Brain Res Bull 35, 379–382.

    PubMed  CAS  Google Scholar 

  45. Kumar, R. C., and Thakur, M. K. (2004) Androgen receptor mRNA is inversely regulated by testosterone and estradiol in adult mouse brain. Neurobiol Aging 25, 925–933.

    PubMed  CAS  Google Scholar 

  46. Warembourg, M., Logeat, F., and Milgrom, E. (1986) Immunocytochemical localization of progesterone receptor in the guinea pig central nervous system. Brain Res 384, 121–131.

    PubMed  CAS  Google Scholar 

  47. Blaustein, J. D., King, J. C., Toft, D. O., and Turcotte, J. (1988) Immunocytochemical localization of estrogen-induced progestin receptors in guinea pig brain. Brain Res 474, 1–15.

    PubMed  CAS  Google Scholar 

  48. MacLusky, N. J., and McEwen, B. S. (1980) Progestin receptors in the developing rat brain and pituitary. Brain Res 189, 262–268.

    PubMed  CAS  Google Scholar 

  49. Camacho-Arroyo, I., Perez-Palacios, G., Pasapera, A. M., and Cerbon, M. A. (1994) Intracellular progesterone receptors are differentially regulated by sex steroid hormones in the hypothalamus and the cerebral cortex of the rabbit. J Steroid Biochem Mol Biol 50, 299–303.

    PubMed  CAS  Google Scholar 

  50. Sarrieau, A., Dussaillant, M., Agid, F., Philibert, D., Agid, Y., and Rostene, W. (1986) Autoradiographic localization of glucocorticosteroid and progesterone binding sites in the human post-mortem brain. J Steroid Biochem 25, 717–721.

    PubMed  CAS  Google Scholar 

  51. Schrader, W. T., Birnbaumer, M. E., Hughes, M. R., Weigel, N. L., Grody, W. W., and O’Malley, B. W. (1981) Studies on the structure and function of the chicken progesterone receptor. Recent Prog Horm Res 37, 583–633.

    PubMed  CAS  Google Scholar 

  52. Guerra-Araiza, C., Reyna-Neyra, A., Salazar, A. M., Cerbon, M. A., Morimoto, S., and Camacho-Arroyo, I. (2001) Progesterone receptor isoforms expression in the prepuberal and adult male rat brain. Brain Res Bull 54, 13–17.

    PubMed  CAS  Google Scholar 

  53. Guerra-Araiza, C., Cerbon, M. A., Morimoto, S., and Camacho-Arroyo, I. (2000) Progesterone receptor isoforms expression pattern in the rat brain during the estrous cycle. Life Sci 66, 1743–1752.

    PubMed  CAS  Google Scholar 

  54. Camacho-Arroyo, I., Guerra-Araiza, C., and Cerbon, M. A. (1998) Progesterone receptor isoforms are differentially regulated by sex steroids in the rat forebrain. Neuroreport 9, 3993–3996.

    PubMed  CAS  Google Scholar 

  55. de Kloet, E. R., Reul, J. M., de Ronde, F. S., Bloemers, M., and Ratka, A. (1986) Function and plasticity of brain corticosteroid receptor systems: action of neuropeptides. J Steroid Biochem 25, 723–731.

    PubMed  CAS  Google Scholar 

  56. Rosenfeld, P., Sutanto, W., Levine, S., and De Kloet, E. R. (1988a) Ontogeny of type I and type II corticosteroid receptors in the rat hippocampus. Brain Res 470, 113–118.

    CAS  Google Scholar 

  57. Rosenfeld, P., Van Eekelen, J. A., Levine, S., and De Kloet, E. R. (1988b) Ontogeny of the type 2 glucocorticoid receptor in discrete rat brain regions: an immunocytochemical study. Brain Res 470, 119–127.

    CAS  Google Scholar 

  58. Pfaff, D. W., Gerlach, J. L., McEwen, B. S., Ferin, M., Carmel, P., and Zimmerman, E. A. (1976) Autoradiographic localization of hormone-concentrating cells in the brain of the female rhesus monkey. J Comp Neurol 170, 279–293.

    PubMed  CAS  Google Scholar 

  59. Sutanto, W., and De Kloet, E. R. (1987) Species-specificity of corticosteroid receptors in hamster and rat brains. Endocrinology 121, 1405–1411.

    PubMed  CAS  Google Scholar 

  60. Reul, J. M., and de Kloet, E. R. (1986) Anatomical resolution of two types of corticosterone receptor sites in rat brain with in vitro autoradiography and computerized image analysis. J Steroid Biochem 24, 269–272.

    PubMed  CAS  Google Scholar 

  61. Fuxe, K., Cintra, A., Agnati, L. F., et al. (1987) Studies on the cellular localization and distribution of glucocorticoid receptor and estrogen receptor immunoreactivity in the central nervous system of the rat and their relationship to the monoaminergic and peptidergic neurons of the brain. J Steroid Biochem 27, 159–170.

    PubMed  CAS  Google Scholar 

  62. McGimsey, W. C., Cidlowski, J. A., Stumpf, W. E., and Sar, M. (1991) Immunocytochemical localization of the glucocorticoid receptor in rat brain, pituitary, liver, and thymus with two new polyclonal antipeptide antibodies. Endocrinology 129, 3064–3072.

    PubMed  CAS  Google Scholar 

  63. Morimoto, M., Morita, N., Ozawa, H., Yokoyama, K., and Kawata, M. (1996) Distribution of glucocorticoid receptor immunoreactivity and mRNA in the rat brain: an immunohistochemical and in situ hybridization study. Neurosci Res 26, 235–269.

    PubMed  CAS  Google Scholar 

  64. Aronsson, M., Fuxe, K., Dong, Y., Agnati, L. F., Okret, S., and Gustafsson, J. A. (1988) Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization. PNAS 85, 9331–9335.

    PubMed  CAS  Google Scholar 

  65. Mitchell, S. J., Rawlins, J. N., Steward, O., and Olton, D. S. (1982) Medial septal area lesions disrupt theta rhythm and cholinergic staining in medial entorhinal cortex and produce impaired radial arm maze behavior in rats. J Neurosci 2, 292–302.

    PubMed  CAS  Google Scholar 

  66. Fontan-Lozano, A., Troncoso, J., Munera, A., Carrion, A. M., and Delgado-Garcia, J. M. (2005) Cholinergic septo-hippocampal innervation is required for trace eyeblink classical conditioning. Learn Mem 12, 557–563.

    PubMed  Google Scholar 

  67. Marston, H. M., Everitt, B. J., and Robbins, T. W. (1993) Comparative effects of excitotoxic lesions of the hippocampus and septum/diagonal band on conditional visual discrimination and spatial learning. Neuropsychologia 31, 1099–1118.

    PubMed  CAS  Google Scholar 

  68. Hagan, J. J., Salamone, J. D., Simpson, J., Iversen, S. D., and Morris, R. G. M. (1988) Place navigation in rats is impaired by lesions of medial septum and diagonal band but not nucleus basalis magnocellularis. Behav Brain Res 27, 9–20.

    PubMed  CAS  Google Scholar 

  69. Bartus, R. T., Flicker, C., Dean, R. L., Pontecorvo, M., Figueiredo, J. C., and Fisher, S. K. (1985) Selective memory loss following nucleus basalis lesions: long term behavioral recovery despite persistent cholinergic deficiencies. Pharmacol Biochem Behav 23, 125–135.

    PubMed  CAS  Google Scholar 

  70. Beninger, R. J., Wirsching, B. A., Jhamandas, K., Boegman, R. J., and el-Defrawy, S. R. (1986) Effects of altered cholinergic function on working and reference memory in the rat. Can J Physiol Pharmacol 64, 376–382.

    PubMed  CAS  Google Scholar 

  71. Dubois, B., Mayo, W., Agid, Y., Le Moal, M., and Simon, H. (1985) Profound disturbances of spontaneous and learned behaviors following lesions of the nucleus basalis magnocellularis in the rat. Brain Res 338, 249–258.

    PubMed  CAS  Google Scholar 

  72. Mayo, W., Kharouby, M., Le Moal, M., and Simon, H. (1988) Memory disturbances following ibotenic acid injections in the nucleus basalis magnocellularis of the rat. Brain Res 455, 213–222.

    PubMed  CAS  Google Scholar 

  73. Nakamura, S., and Ishihara, T. (1990) Task-dependent memory loss and recovery following unilateral nucleus basalis lesion: behavioral and neurochemical correlation. Behav Brain Res 39, 113–122.

    PubMed  CAS  Google Scholar 

  74. Ridley, R. M., Samson, N. A., Baker, H. F., and Johnson, J. A. (1988) Visuospatial learning impairment following lesion of the cholinergic projection to the hippocampus. Brain Res 456, 71–87.

    PubMed  CAS  Google Scholar 

  75. Stoehr, J. D., Mobley, S. L., Roice, D., et al. (1997) The effects of selective cholinergic basal forebrain lesions and aging upon expectancy in the rat. Neurobiol Learn Mem 67, 214–227.

    PubMed  CAS  Google Scholar 

  76. Chappell, J., McMahan, R., Chiba, A., and Gallagher, M. (1998) A re-examination of the role of basal forebrain cholinergic neurons in spatial working memory. Neuropharmacology 37, 481–487.

    PubMed  CAS  Google Scholar 

  77. Johnson, D. A., Zambon, N. J., and Gibbs, R. B. (2002) Selective lesion of cholinergic neurons in the medial septum by 192 IgG-saporin impairs learning in a delayed matching to position T-maze paradigm. Brain Res 943, 132–141.

    PubMed  CAS  Google Scholar 

  78. Fischer, W., Gage, F. H., and Bjorklund, A. (1989) Degenerative changes in forebrain cholinergic nuclei correlate with cognitive impairments in aged rats. Eur J Neurosci 1, 34–45.

    PubMed  Google Scholar 

  79. Miettinen, R. A., Kalesnykas, G., and Koivisto, E. H. (2002) Estimation of the total number of cholinergic neurons containing estrogen receptor-alpha in the rat basal forebrain. J Histochem Cytochem 50, 891–902.

    PubMed  CAS  Google Scholar 

  80. Horvath, K., Hårtig, W., Van der Veen, R., et al. (2002) 17b-estradiol enhances cortical cholinergic innervation and preserves synaptic density following excitotoxic lesions to the rat nucleus basalis magnocellularis. Neurosci 110, 489–504.

    CAS  Google Scholar 

  81. Miller, M. M., Hyder, S. M., Assayag, R., Panarella, S. R., Tousignant, P., and Franklin, K. B. (1999) Estrogen modulates spontaneous alternation and the cholinergic phenotype in the basal forebrain. Neuroscience 91, 1143–1153.

    PubMed  CAS  Google Scholar 

  82. Gibbs, R. B. (2000) Effects of gonadal hormone replacement on measures of basal forebrain cholinergic function. Neuroscience 101, 931–938.

    PubMed  CAS  Google Scholar 

  83. Frick, K. M., Burlingame, L. A., Arters, J. A., and Berger-Sweeney, J. (2000) Reference memory, anxiety and estrous cyclicity in C57BL/6NIA mice are affected by age and sex. Neuroscience 95, 293–307.

    PubMed  CAS  Google Scholar 

  84. Markowska, A. L. (1999) Sex dimorphisms in the rate of age-related decline in spatial memory: relevance to alterations in the estrous cycle. J Neurosci 19, 8122–8133.

    PubMed  CAS  Google Scholar 

  85. Tenover, J. L. (1997) Testosterone and the aging male. J Androl 18, 103–106.

    PubMed  CAS  Google Scholar 

  86. Abbasi, A. A., Drinka, P. J., Mattson, D. E., and Rudman, D. (1993) Low circulating levels of insulin-like growth factors and testosterone in chronically institutionalized elderly men. J Am Geriatr Soc 41, 975–982.

    PubMed  CAS  Google Scholar 

  87. Berr, C., Lafont, S., Debuire, B., Dartigues, J. F., and Baulieu, E. E. (1996) Relationships of dehydroepiandrosterone sulfate in the elderly with functional, psychological, and mental status, and short-term mortality: a French community-based study. Proc Natl Acad Sci U S A 93, 13410–13415.

    PubMed  CAS  Google Scholar 

  88. Twist, S. J., Taylor, G. A., Weddell, A., Weightman, D. R., Edwardson, J. A., and Morris, C. M. (2000) Brain oestradiol and testosterone levels in Alzheimer’s disease. Neurosci Lett 286, 1–4.

    PubMed  CAS  Google Scholar 

  89. Miller, D. B., and O’Callaghan, J. P. (2005) Aging, stress and the hippocampus. Ageing Res Rev 4, 123–140.

    PubMed  CAS  Google Scholar 

  90. Magri, F., Cravello, L., Barili, L., et al. (2006) Stress and dementia: the role of the hypothalamicpituitary-adrenal axis. Aging Clin Exp Res 18, 167–170.

    PubMed  CAS  Google Scholar 

  91. Vaucher, E., Reymond, I., Najaffe, R., et al. (2002) Estrogen effects on object memory and cholinergic receptors in young and old female mice. Neurobiol Aging 23, 87–95.

    PubMed  CAS  Google Scholar 

  92. Frick, K. M., Fernandez, S. M., and Bulinski, S. C. (2002) Estrogen replacement improves spatial reference memory and increases hippocampal synaptophysin in aged female mice. Neuroscience 115, 547–558.

    PubMed  CAS  Google Scholar 

  93. Flood, J. F., Farr, S. A., Kaiser, F. E., and Morley, J. E. (1995) Age-related impairment in learning but not memory in SAMP8 female mice. Pharmacol Biochem Behav 50, 661–664.

    PubMed  CAS  Google Scholar 

  94. Heikkinen, T., Puolivali, J., and Tanila, H. (2004) Effects of long-term ovariectomy and estrogen treatment on maze learning in aged mice. Exp Gerontol 39, 1277–1283.

    PubMed  CAS  Google Scholar 

  95. Heikkinen, T., Kalesnykas, G., Rissanen, A., et al. (2004) Estrogen treatment improves spatial learning in APP + PS1 mice but does not affect beta amyloid accumulation and plaque formation. Exp Neurol 187, 105–117.

    PubMed  CAS  Google Scholar 

  96. Luine, V., and Rodriguez, M. (1994) Effects of estradiol on radial arm maze performance of young and aged rats. Behav Neural Biol 62, 230–236.

    PubMed  CAS  Google Scholar 

  97. Granholm, A. C., Ford, K. A., Hyde, L. A., et al. (2002) Estrogen restores cognition and cholinergic phenotype in an animal model of Down syndrome. Physiol Behav 77, 371–385.

    PubMed  CAS  Google Scholar 

  98. Hunter, C. L., Bimonte-Nelson, H. A., Nelson, M., Eckman, C. B., and Granholm, A. C. (2004) Behavioral and neurobiological markers of Alzheimer’s disease in Ts65Dn mice: effects of estrogen. Neurobiol Aging 25, 873–884.

    PubMed  CAS  Google Scholar 

  99. Frye, C. A., Rhodes, M. E., and Dudek, B. (2005) Estradiol to aged female or male mice improves learning in inhibitory avoidance and water maze tasks. Brain Res 1036, 101–108.

    PubMed  CAS  Google Scholar 

  100. Daniel, J. M., Hulst, J. L., and Berbling, J. L. (2006) 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. Endocrinol 147, 607–614.

    CAS  Google Scholar 

  101. Markowska, A. L., and Savonenko, A. V. (2002) Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats. J Neurosci 22, 10985–10995.

    PubMed  CAS  Google Scholar 

  102. Sandstrom, N. J., and Williams, C. L. (2004) Spatial memory retention is enhanced by acute and continuous estradiol replacement. Horm Behav 45, 128–135.

    PubMed  CAS  Google Scholar 

  103. Rapp, P. R., Morrison, J. H., and Roberts, J. A. (2003) Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys. J Neurosci 23, 5708–5714.

    PubMed  CAS  Google Scholar 

  104. Gibbs, R. B. (2000) Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. Neurobiol Aging 21, 107–116.

    PubMed  CAS  Google Scholar 

  105. Tanabe, F., Miyasaka, N., Kubota, T., and Aso, T. (2004) Estrogen and progesterone improve scopolamine-induced impairment of spatial memory. J Med Dent Sci 51, 89–98.

    PubMed  Google Scholar 

  106. Sandstrom, N. J., and Williams, C. L. (2001) Memory retention is modulated by acute estradiol and progesterone replacement. Behav Neurosci 115, 384–393.

    PubMed  CAS  Google Scholar 

  107. Bimonte-Nelson, H. A., Singleton, R. S., Williams, B. J., and Granholm, A. C. (2004) Ovarian hormones and cognition in the aged female rat: II. progesterone supplementation reverses the cognitive enhancing effects of ovariectomy. Behav Neurosci 118, 707–714.

    PubMed  CAS  Google Scholar 

  108. Bimonte-Nelson, H. A., Francis, K. R., Umphlet, C. D., and Granholm, A. C. (2006) Progesterone reverses the spatial memory enhancements initiated by tonic and cyclic oestrogen therapy in middle-aged ovariectomized female rats. Eur J Neurosci 24, 229–242.

    PubMed  Google Scholar 

  109. Foster, T. C., Sharrow, K. M., Kumar, A., and Masse, J. (2003) Interaction of age and chronic estradiol replacement on memory and markers of brain aging. Neurobiol Aging 24, 839–852.

    PubMed  CAS  Google Scholar 

  110. Alonso, A., Fernandez, R., Moreno, M., et al. (2006) Positive effects of 17beta-estradiol on insulin sensitivity in aged ovariectomized female rats. J Gerontol A Biol Sci Med Sci 61, 419–426.

    PubMed  Google Scholar 

  111. Gresack, J. E., and Frick, K. M. (2006) Effects of continuous and intermittent estrogen treatments on memory in aging female mice. Brain Res 1115, 135–147.

    PubMed  CAS  Google Scholar 

  112. Markham, J. A., Pych, J. C., and Juraska, J. M. (2002) Ovarian hormone replacement to aged ovariectomized female rats benefits acquisition of the Morris water maze. Horm Behav 42, 284–293.

    PubMed  CAS  Google Scholar 

  113. Flood, J. F., Farr, S. A., Kaiser, F. E., La Regina, M., and Morley, J. E. (1995) Age-related decrease of plasma testosterone in SAMP8 mice: replacement improves age-related impairment of learning and memory. Physiol Behav 57, 669–673.

    PubMed  CAS  Google Scholar 

  114. Perrot-Sinal, T. S., Kavaliers, M., and Ossenkopp, K. P. (1998) Spatial learning and hippocampal volume in male deer mice: relations to age, testosterone and adrenal gland weight. Neuroscience 86, 1089–1099.

    PubMed  CAS  Google Scholar 

  115. Flood, J. F., and Roberts, E. (1988) Dehydroepiandrosterone sulfate improves memory in aging mice. Brain Res 448, 178–181.

    PubMed  CAS  Google Scholar 

  116. Farr, S. A., Banks, W. A., Uezu, K., Gaskin, F. S., and Morley, J. E. (2004) DHEAS improves learning and memory in aged SAMP8 mice but not in diabetic mice. Life Sci 75, 2775–2785.

    PubMed  CAS  Google Scholar 

  117. Markowski, M., Ungeheuer, M., Bitran, D., and Locurto, C. (2001) Memory-enhancing effects of DHEAS in aged mice on a win-shift water escape task. Physiol Behav 72, 521–525.

    PubMed  CAS  Google Scholar 

  118. Sherwin, B. (1988) Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendo 13, 345–357.

    CAS  Google Scholar 

  119. Sherwin, B. B., and Tulandi, T. (1996) “Add-back” estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. J Clin Endocrinol Metab 81, 2545–2549.

    PubMed  CAS  Google Scholar 

  120. Robinson, D., Friedman, L., Marcus, R., Tinklenberg, J., and Yesavage, J. (1994) Estrogen replacement therapy and memory in older women. J Am Geriatr Soc 42, 919–922.

    PubMed  CAS  Google Scholar 

  121. Resnick, S. M., Maki, P. M., Golski, S., Kraut, M. A., and Zonderman, A. B. (1998) Effects of Estrogen Replacement Therapy on PET Cerebral Blood Flow and Neuropsychological Performance. Horm Behav 34, 171–182.

    PubMed  CAS  Google Scholar 

  122. Yaffe, K., Lui, L. Y., Grady, D., Cauley, J., Kramer, J., and Cummings, S. R. (2000) Cognitive decline in women in relation to non-protein-bound oestradiol concentrations. Lancet 356, 708–712.

    PubMed  CAS  Google Scholar 

  123. Lebrun, C. E., van der Schouw, Y. T., de Jong, F. H., Pols, H. A., Grobbee, D. E., and Lamberts, S. W. (2005) Endogenous oestrogens are related to cognition in healthy elderly women. Clin Endocrinol (Oxf) 63, 50–55.

    CAS  Google Scholar 

  124. Dunkin, J., Rasgon, N., Wagner-Steh, K., David, S., Altshuler, L., and Rapkin, A. (2005) Reproductive events modify the effects of estrogen replacement therapy on cognition in healthy postmenopausal women. Psychoneuroendocrinology 30, 284–296.

    PubMed  CAS  Google Scholar 

  125. Duka, T., Tasker, R., and McGowan, J. F. (2000) The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females. Psychopharmacology (Berl) 149, 129–139.

    CAS  Google Scholar 

  126. Rice, M. M., Graves, A. B., McCurry, S. M., et al. (2000) Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women: the Kame Project. Arch Intern Med 160, 1641–1649.

    PubMed  CAS  Google Scholar 

  127. Luoto, R., Manolio, T., Meilahn, E., et al. (2000) Estrogen replacement therapy and MRI-demonstrated cerebral infarcts, white matter changes, and brain atrophy in older women: the Cardiovascular Health Study. J Am Geriatr Soc 48, 467–472.

    PubMed  CAS  Google Scholar 

  128. Grady, D., Yaffe, K., Kristof, M., Lin, F., Richards, C., and Barrett-Connor, E. (2002) Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Am J Med 113, 543–548.

    PubMed  CAS  Google Scholar 

  129. File, S. E., Heard, J. E., and Rymer, J. (2002) Trough oestradiol levels associated with cognitive impairment in post-menopausal women after 10 years of oestradiol implants. Psychopharmacology (Berl) 161, 107–112.

    CAS  Google Scholar 

  130. Binder, E. F., Schechtman, K. B., Birge, S. J., Williams, D. B., and Kohrt, W. M. (2001) Effects of hormone replacement therapy on cognitive performance in elderly women. Maturitas 38, 137–146.

    PubMed  CAS  Google Scholar 

  131. Yaffe, K., Vittinghoff, E., Ensrud, K. E., et al. (2006) Effects of ultra-low-dose transdermal estradiol on cognition and health-related quality of life. Arch Neurol 63, 945–950.

    PubMed  Google Scholar 

  132. Mitchell, J. L., Cruickshanks, K. J., Klein, B. E., Palta, M., and Nondahl, D. M. (2003) Postmenopausal hormone therapy and its association with cognitive impairment. Arch Intern Med 163, 2485–2490.

    PubMed  CAS  Google Scholar 

  133. Low, L. F., Anstey, K. J., Jorm, A. F., Christensen, H., and Rodgers, B. (2006) Hormone replacement therapy and cognition in an Australian representative sample aged 60–64 years. Maturitas 54, 86–94.

    PubMed  CAS  Google Scholar 

  134. Wolf, O. T., Heinrich, A. B., Hanstein, B., and Kirschbaum, C. (2005) Estradiol or estradiol/progesterone treatment in older women: no strong effects on cognition. Neurobiol Aging 26, 1029–1033.

    PubMed  CAS  Google Scholar 

  135. Low, L. F., Anstey, K. J., Maller, J., et al. (2006) Hormone replacement therapy, brain volumes and white matter in postmenopausal women aged 60–64 years. Neuroreport 17, 101–104.

    PubMed  Google Scholar 

  136. Yaffe, K., Barnes, D., Lindquist, K., et al. (2007) Endogenous sex hormone levels and risk of cognitive decline in an older biracial cohort. Neurobiol Aging 28, 171–178.

    PubMed  CAS  Google Scholar 

  137. Wolf, O. T., and Kirschbaum, C. (2002) Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men. Horm Behav 41, 259–266.

    PubMed  CAS  Google Scholar 

  138. Drake, E. B., Henderson, V. W., Stanczyk, F. Z., et al. (2000) Associations between circulating sex steroid hormones and cognition in normal elderly women. Neurology 54, 599–603.

    PubMed  CAS  Google Scholar 

  139. Almeida, O. P., Waterreus, A., Spry, N., et al. (2001) Effect of testosterone deprivation on the cognitive performance of a patient with Alzheimer’s disease. Int J Geriatr Psychiatr 16, 823–825.

    CAS  Google Scholar 

  140. Almeida, O. P., Waterreus, A., Spry, N., Flicker, L., and Martins, R. N. (2004) One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men. Psychoneuroendocrinology 29, 1071–1081.

    PubMed  CAS  Google Scholar 

  141. Salminen, E. K., Portin, R. I., Koskinen, A., Helenius, H., and Nurmi, M. (2004) Associations between serum testosterone fall and cognitive function in prostate cancer patients. Clin Cancer Res 10, 7575–7582.

    PubMed  CAS  Google Scholar 

  142. Skalba, P., Korfanty, A., Mroczka, W., and Wojtowicz, M. (2001) [Changes of SHBG concentrations in postmenopausal women]. Ginekol Pol 72, 1388–1392.

    PubMed  CAS  Google Scholar 

  143. Stomati, M., Hartmann, B., Spinetti, A., et al. (1996) Effects of hormonal replacement therapy on plasma sex hormone-binding globulin, androgen and insulin-like growth factor-1 levels in postmenopausal women. J Endocrinol Invest 19, 535–541.

    PubMed  CAS  Google Scholar 

  144. Moffat, S. D., Zonderman, A. B., Metter, E. J., Blackman, M. R., Harman, S. M., and Resnick, S. M. (2002) Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab 87, 5001–5007.

    PubMed  CAS  Google Scholar 

  145. Barrett-Connor, E., and Goodman-Gruen, D. (1999a) Cognitive function and endogenous sex hormones in older women. J Am Geriatr Soc 47, 1289–1293.

    CAS  Google Scholar 

  146. Yaffe, K., Lui, L. Y., Zmuda, J., and Cauley, J. (2002) Sex hormones and cognitive function in older men. J Am Geriatr Soc 50, 707–712.

    PubMed  Google Scholar 

  147. Muller, M., Aleman, A., Grobbee, D. E., de Haan, E. H., and van der Schouw, Y. T. (2005) Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level? Neurology 64, 866–871.

    PubMed  CAS  Google Scholar 

  148. Thilers, P. P., Macdonald, S. W., and Herlitz, A. (2006) The association between endogenous free testosterone and cognitive performance: a population-based study in 35 to 90 year-old men and women. Psychoneuroendocrinology 31, 565–576.

    PubMed  CAS  Google Scholar 

  149. Perry, P. J., Lund, B. C., Arndt, S., et al. (2001) Bioavailable testosterone as a correlate of cognition, psychological status, quality of life, and sexual function in aging males: implications for testosterone replacement therapy. Ann Clin Psychiatry 13, 75–80.

    PubMed  CAS  Google Scholar 

  150. Aleman, A., de Vries, W. R., Koppeschaar, H. P., et al. (2001) Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men. Exp Aging Res 27, 283–291.

    PubMed  CAS  Google Scholar 

  151. Yonker, J. E., Eriksson, E., Nilsson, L. G., and Herlitz, A. (2006) Negative association of testosterone on spatial visualization in 35 to 80 year old men. Cortex 42, 376–386.

    PubMed  Google Scholar 

  152. Cherrier, M. M., Asthana, S., Plymate, S., et al. (2001) Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 57, 80–88.

    PubMed  CAS  Google Scholar 

  153. Janowsky, J. S., Oviatt, S. K., and Orwoll, E. S. (1994) Testosterone influences spatial cognition in older men. Behav Neurosci 108, 325–332.

    PubMed  CAS  Google Scholar 

  154. Sih, R., Morley, J. E., Kaiser, F. E., Perry, H. M., 3rd, Patrick, P., and Ross, C. (1997) Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 82, 1661–1667.

    PubMed  CAS  Google Scholar 

  155. Kenny, A. M., Bellantonio, S., Gruman, C. A., Acosta, R. D., and Prestwood, K. M. (2002) Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 57, M321–325.

    PubMed  Google Scholar 

  156. Wolf, O. T., Preut, R., Hellhammer, D. H., Kudielka, B. M., Schurmeyer, T. H., and Kirschbaum, C. (2000) Testosterone and cognition in elderly men: a single testosterone injection blocks the practice effect in verbal fluency, but has no effect on spatial or verbal memory. Biol Psychiatry 47, 650–654.

    PubMed  CAS  Google Scholar 

  157. Berkman, L. F., Seeman, T. E., Albert, M., et al. (1993) High, usual and impaired functioning in community-dwelling older men and women: findings from the MacArthur Foundation Research Network on Successful Aging. J Clin Epidemiol 46, 1129–1140.

    PubMed  CAS  Google Scholar 

  158. Glei, D. A., Goldman, N., Weinstein, M., and Liu, I. W. (2004) Dehydroepiandrosterone sulfate (DHEAS) and health: does the relationship differ by sex? Exp Gerontol 39, 321–331.

    PubMed  CAS  Google Scholar 

  159. Moffat, S. D., Zonderman, A. B., Harman, S. M., Blackman, M. R., Kawas, C., and Resnick, S. M. (2000) The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. Arch Intern Med 160, 2193–2198.

    PubMed  CAS  Google Scholar 

  160. van Niekerk, J. K., Huppert, F. A., and Herbert, J. (2001) Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation. Psychoneuroendocrinology 26, 591–612.

    PubMed  CAS  Google Scholar 

  161. Wolf, O. T., Neumann, O., Hellhammer, D. H., et al. (1997) Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 82, 2363–2367.

    PubMed  CAS  Google Scholar 

  162. Barnhart, K. T., Freeman, E., Grisso, J. A., et al. (1999) The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life. J Clin Endocrinol Metab 84, 3896–3902.

    PubMed  CAS  Google Scholar 

  163. Yaffe, K., Ettinger, B., Pressman, A., et al. (1998) Neuropsychiatric function and dehydroepiandrosterone sulfate in elderly women: a prospective study. Biol Psychiatr 43, 694–700.

    CAS  Google Scholar 

  164. Kahonen, M. H., Tilvis, R. S., Jolkkonen, J., Pitkala, K., and Harkonen, M. (2000) Predictors and clinical significance of declining plasma dehydroepiandrosterone sulfate in old age. Aging (Milano) 12, 308–314.

    CAS  Google Scholar 

  165. Breuer, B., Martucci, C., Wallenstein, S., et al. (2002) Relationship of endogenous levels of sex hormones to cognition and depression in frail, elderly women. Am J Geriatr Psychiatry 10, 311–320.

    PubMed  Google Scholar 

  166. Shilling, V., Jenkins, V., Fallowfield, L., and Howell, T. (2003) The effects of hormone therapy on cognition in breast cancer. J Steroid Biochem Mol Biol 86, 405–412.

    PubMed  CAS  Google Scholar 

  167. Paganini-Hill, A., and Clark, L. J. (2000) Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 64, 165–176.

    PubMed  CAS  Google Scholar 

  168. Yaffe, K., Krueger, K., Cummings, S. R., et al. (2005) Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the multiple outcomes of raloxifene evaluation (MORE) randomized trial. Am J Psychiatry 162, 683–690.

    PubMed  Google Scholar 

  169. Yaffe, K., Krueger, K., Sarkar, S., et al. (2001) Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med 344, 1207–1213.

    PubMed  CAS  Google Scholar 

  170. Goekoop, R., Duschek, E. J., Knol, D. L., et al. (2005) Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior. Neuroimage 25, 63–75.

    PubMed  CAS  Google Scholar 

  171. Goekoop, R., Barkhof, F., Duschek, E. J., et al. (2006) Raloxifene treatment enhances brain activation during recognition of familiar items: a pharmacological fMRI study in healthy elderly males. Neuropsychopharmacology 31, 1508–1518.

    PubMed  CAS  Google Scholar 

  172. Jacobson, L., and Sapolsky, R. (1991) The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev 12, 118–134.

    PubMed  CAS  Google Scholar 

  173. Yehuda, R., Fairman, K. R., and Meyer, J. S. (1989) Enhanced brain cell proliferation following early adrenalectomy in rats. J Neurochem 53, 241–248.

    PubMed  CAS  Google Scholar 

  174. Vicedomini, J. P., Nonneman, A. J., DeKosky, S. T., and Scheff, S. W. (1986) Perinatal glucocorticoids disrupt learning: a sexually dimorphic response. Physiol Behav 36, 145–149.

    PubMed  CAS  Google Scholar 

  175. Gould, E., Woolley, C. S., and McEwen, B. S. (1991) Adrenal steroids regulate postnatal development of the rat dentate gyrus: I. Effects of glucocorticoids on cell death. J Comp Neurol 313, 479–485.

    PubMed  CAS  Google Scholar 

  176. Brown, E. S., Woolston, D. J., Frol, A., et al. (2004) Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol Psychiatr 55, 538–545.

    CAS  Google Scholar 

  177. Davis, K. L., Davis, B. M., Greenwald, B. S., et al. (1986) Cortisol and Alzheimer’s disease, I: basal studies. Am J Psychiatry 143, 300–305.

    PubMed  CAS  Google Scholar 

  178. Gurevitch, D., Siegel, B., Dumlao, M. S., et al. (1989) The relationship between cognitive impairment plasma cortisol levels and HPA responsibility to dexamethasone in dementia. Prog Clin Biol Res 317, 175–187.

    PubMed  CAS  Google Scholar 

  179. Kalmijn, S., Launer, L. J., Stolk, R. P., et al. (1998) A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab 83, 3487–3492.

    PubMed  CAS  Google Scholar 

  180. O’Brien, J. T., Schweitzer, I., Ames, D., Tuckwell, V., and Mastwyk, M. (1994) Cortisol suppression by dexamethasone in the healthy elderly: effects of age, dexamethasone levels, and cognitive function. Biol Psychiatry 36, 389–394.

    PubMed  Google Scholar 

  181. Lupien, S., Lecours, A. R., Lussier, I., Schwartz, G., Nair, N. P., and Meaney, M. J. (1994) Basal cortisol levels and cognitive deficits in human aging. J Neurosci 14, 2893–2903.

    PubMed  CAS  Google Scholar 

  182. Porter, R. J., Barnett, N. A., Idey, A., McGuckin, E. A., and O’Brien, J. T. (2002) Effects of hydrocortisone administration on cognitive function in the elderly. J Psychopharmacol 16, 65–71.

    PubMed  CAS  Google Scholar 

  183. Domes, G., Heinrichs, M., Reichwald, U., and Hautzinger, M. (2002) Hypothalamic-pituitary-adrenal axis reactivity to psychological stress and memory in middle-aged women: high responders exhibit enhanced declarative memory performance. Psychoneuroendocrinology 27, 843–853.

    PubMed  CAS  Google Scholar 

  184. Ferrari, E., Mirani, M., Barili, L., et al. (2004) Cognitive and affective disorders in the elderly: a neuroendocrine study. Arch Gerontol Geriatr Suppl 9, 171–182.

    PubMed  CAS  Google Scholar 

  185. de Bruin, V. M., Vieira, M. C., Rocha, M. N., and Viana, G. S. (2002) Cortisol and dehydroepiandosterone sulfate plasma levels and their relationship to aging, cognitive function, and dementia. Brain Cogn 50, 316–323.

    PubMed  CAS  Google Scholar 

  186. Carlson, L. E., and Sherwin, B. B. (1999) Relationships among cortisol (CRT), dehydroepiandrosterone-sulfate (DHEAS), and memory in a longitudinal study of healthy elderly men and women. Neurobiol Aging 20, 315–324.

    PubMed  CAS  Google Scholar 

  187. Li, G., Cherrier, M. M., Tsuang, D. W., et al. (2006) Salivary cortisol and memory function in human aging. Neurobiol Aging 27, 1705–1714.

    PubMed  CAS  Google Scholar 

  188. Karlamangla, A. S., Singer, B. H., Chodosh, J., McEwen, B. S., and Seeman, T. E. (2005) Urinary cortisol excretion as a predictor of incident cognitive impairment. Neurobiol Aging 26, (Suppl 1)80–84.

    PubMed  Google Scholar 

  189. Seeman, T. E., McEwen, B. S., Singer, B. H., Albert, M. S., and Rowe, J. W. (1997) Increase in urinary cortisol excretion and memory declines: MacArthur studies of successful aging. J Clin Endocrinol Metab 82, 2458–2465.

    PubMed  CAS  Google Scholar 

  190. Tsolaki, M., Grammaticos, P., Karanasou, C., et al. (2005) Serum estradiol, progesterone, testosterone, FSH and LH levels in postmenopausal women with Alzheimer’s dementia. Hell J Nucl Med 8, 39–42.

    PubMed  Google Scholar 

  191. Cunningham, C. J., Sinnott, M., Denihan, A., et al. (2001) Endogenous sex hormone levels in postmenopausal women with Alzheimer’s disease. J Clin Endocrinol Metab 86, 1099–1103.

    PubMed  CAS  Google Scholar 

  192. Hoskin, E. K., Tang, M. X., Manly, J. J., and Mayeux, R. (2004) Elevated sex-hormone binding globulin in elderly women with Alzheimer’s disease. Neurobiol Aging 25, 141–147.

    PubMed  CAS  Google Scholar 

  193. Moffat, S. D., Zonderman, A. B., Metter, E. J., et al. (2004) Free testosterone and risk for Alzheimer disease in older men. Neurology 62, 188–193.

    PubMed  CAS  Google Scholar 

  194. Pardridge, W. M., Mietus, L. J., Frumar, A. M., Davidson, B. J., and Judd, H. L. (1980) Effects of human serum on transport of testosterone and estradiol into rat brain. Am J Physiol 239, E103–108.

    PubMed  CAS  Google Scholar 

  195. Paganini-Hill, A., and Henderson, V. (1996) Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med 156, 2213–2217.

    PubMed  CAS  Google Scholar 

  196. Tang, M. X., Jacobs, D., Stern, Y., et al. (1996) Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348, 429–432.

    PubMed  CAS  Google Scholar 

  197. Zandi, P., Carlson, M., Plassman, B., et al. (2002) Hormone replacement therapy and incidence of Alzheimer disease in older women. JAMA 288, 2123–2129.

    PubMed  CAS  Google Scholar 

  198. Ohkura, T., Isse, K., Akazawa, K., Hamamoto, M., Yaoi, Y., and Hagino, N. (1995) Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer type: 7 case reports. Dementia 6, 99–107.

    PubMed  CAS  Google Scholar 

  199. Ohkura, T., Isse, K., Akazawa, K., Hamamoto, M., Yaoi, Y., and Hagino, N. (1994) Evaluation of estrogen treatment in female patients with dementia of the Alzheimer type. Endocr J 41, 361–371.

    PubMed  CAS  Google Scholar 

  200. Yoon, B. K., Kim, D. K., Kang, Y., Kim, J. W., Shin, M. H., and Na, D. L. (2003) Hormone replacement therapy in postmenopausal women with Alzheimer’s disease: a randomized, prospective study. Fertil Steril 79, 274–280.

    PubMed  Google Scholar 

  201. Mulnard, R., Cotman, C., Kawas, C., et al. (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. JAMA 283, 1007–1015.

    PubMed  CAS  Google Scholar 

  202. Shumaker, S., Legault, C., Rapp, S., 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. JAMA 289, 2651–2662.

    PubMed  CAS  Google Scholar 

  203. Espeland, M., Rapp, S., Shumaker, S., et al. (2004) Conjugated equine estrogens and global cognitive function in postmenopausal women. JAMA 291, 2959–2968.

    PubMed  CAS  Google Scholar 

  204. Honjo, H., Iwasa, K., Kawata, M., et al. (2005) Progestins and estrogens and Alzheimer’s disease. J Steroid Biochem Mol Biol 93, 305–308.

    PubMed  CAS  Google Scholar 

  205. Hogervorst, E., Bandelow, S., Combrinck, M., and Smith, A. D. (2004) Low free testosterone is an independent risk factor for Alzheimer’s disease. Exp Gerontol 39, 1633–1639.

    PubMed  CAS  Google Scholar 

  206. Hogervorst, E., Williams, J., Budge, M., Barnetson, L., Combrinck, M., and Smith, A. D. (2001) Serum total testosterone is lower in men with Alzheimer’s disease. Neuroendocrinol Lett 22, 163–168.

    PubMed  CAS  Google Scholar 

  207. Burkhardt, M. S., Foster, J. K., Clarnette, R. M., et al. (2006) Interaction between testosterone and Apolipoprotein E {epsilon}4 status on cognition in healthy older men. J Clin Endocrinol Metab 91, 1168–1172.

    PubMed  CAS  Google Scholar 

  208. Pennanen, C., Laakso, M. P., Kivipelto, M., Ramberg, J., and Soininen, H. (2004) Serum testosterone levels in males with Alzheimer’s disease. J Neuroendocrinol 16, 95–98.

    PubMed  CAS  Google Scholar 

  209. Geerlings, M. I., Strozyk, D., Masaki, K., et al. (2006) Endogenous sex hormones, cognitive decline, and future dementia in old men. Ann Neurol 60, 346–355.

    PubMed  CAS  Google Scholar 

  210. Nasman, B., Olsson, T., Seckl, J. R., et al. (1995) Abnormalities in adrenal androgens, but not of glucocorticoids, in early Alzheimer’s disease. Psychoneuroendocrinology 20, 83–94.

    PubMed  CAS  Google Scholar 

  211. Genedani, S., Rasio, G., Cortelli, P., et al. (2004) Studies on homocysteine and dehydroepiandrosterone sulphate plasma levels in Alzheimer’s disease patients and in Parkinson’s disease patients. Neurotox Res 6, 327–332.

    PubMed  CAS  Google Scholar 

  212. Rasmuson, S., Nasman, B., Carlstrom, K., and Olsson, T. (2002) Increased levels of adrenocortical and gonadal hormones in mild to moderate Alzheimer’s disease. Dement Geriatr Cogn Disord 13, 74–79.

    PubMed  CAS  Google Scholar 

  213. Lu, P. H., Masterman, D. A., Mulnard, R., et al. (2006) Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol 63, 177–185.

    PubMed  Google Scholar 

  214. Cherrier, M. M., Matsumoto, A. M., Amory, J. K., et al. (2005) Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 64, 2063–2068.

    PubMed  CAS  Google Scholar 

  215. Tan, R. S., and Pu, S. J. (2003) A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male 6, 13–17.

    PubMed  CAS  Google Scholar 

  216. Murialdo, G., Barreca, A., Nobili, F., et al. (2001) Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia. J Endocrinol Invest 24, 139–146.

    PubMed  CAS  Google Scholar 

  217. Carlson, L. E., Sherwin, B. B., and Chertkow, H. M. (1999) Relationships between dehydroepiandrosterone sulfate (DHEAS) and cortisol (CRT) plasma levels and everyday memory in Alzheimer’s disease patients compared to healthy controls. Horm Behav 35, 254–263.

    PubMed  CAS  Google Scholar 

  218. Weiner, M. F., Vobach, S., Svetlik, D., and Risser, R. C. (1993) Cortisol secretion and Alzheimer’s disease progression: a preliminary report. Biol Psychiatry 34, 158–161.

    PubMed  CAS  Google Scholar 

  219. Rasmuson, S., Nasman, B., Eriksson, S., Carlstrom, K., and Olsson, T. (1998) Adrenal responsivity in normal aging and mild to moderate Alzheimer’s disease. Biol Psychiatr 43, 401–407.

    CAS  Google Scholar 

  220. O’Brien, J. T., Lloyd, A., McKeith, I., Gholkar, A., and Ferrier, N. (2004) A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. Am J Psychiatr 161, 2081–2090.

    PubMed  Google Scholar 

  221. Bernick, C., Katz, R., Smith, N. L., et al. (2005) Statins and cognitive function in the elderly: the Cardiovascular Health Study. Neurology 65, 1388–1394.

    PubMed  CAS  Google Scholar 

  222. Shepherd, J., Blauw, G. J., Murphy, M. B., et al. (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360, 1623–1630.

    PubMed  CAS  Google Scholar 

  223. Li, G., Higdon, R., Kukull, W. A., et al. (2004) Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology 63, 1624–1628.

    PubMed  CAS  Google Scholar 

  224. Kennedy, G. J., Golde, T. E., Tariot, P. N., and Cummings, J. L. (2007) Amyloid-Based interventions in Alzheimer’s disease. CNS Spectr 12, 1–14.

    Google Scholar 

  225. Sampaolo, S., Campos-Barros, A., Mazziotti, G., et al. (2005) Increased Cerebrospinal Fluid Levels of 3, 3’, 5’-Triiodothyronine in Patients with Alzheimer’s Disease. J Clin Endocrinol Metab 90, 198–202.

    PubMed  CAS  Google Scholar 

  226. Stern, R. A., Davis, J. D., Rogers, B. L., et al. (2004) Preliminary study of the relationship between thyroid status and cognitive and neuropsychiatric functioning in euthyroid patients with Alzheimer dementia. Cogn Behav Neurol 17, 219–223.

    PubMed  Google Scholar 

  227. Wahlin, A., Bunce, D., and Wahlin, T. B. R. (2005) Longitudinal evidence of the impact of normal thyroid stimulating hormone variations on cognitive functioning in very old age. Psychoneuroendocrinology 30, 625–637.

    PubMed  CAS  Google Scholar 

  228. de Jong, F. J., den Heijer, T., Visser, T. J., et al. (2006) Thyroid hormones, dementia, and atrophy of the medial temporal lobe. J Clin Endocrinol Metab 91, 2569–2573.

    PubMed  Google Scholar 

  229. Casadesus, G., Garrett, M. R., Webber, K. M., et al. (2006a) The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer’s disease. Drugs R D 7, 187–193.

    CAS  Google Scholar 

  230. Schupf, N., Kapell, D., Nightingale, B., Rodriguez, A., Tycko, B., and Mayeux, R. (1998) Earlier onset of Alzheimer’s disease in men with Down syndrome. Neurology 50, 991–995.

    PubMed  CAS  Google Scholar 

  231. Hasen, J., Boyar, R. M., and Shapiro, L. R. (1980) Gonadal function in trisomy 21. Horm Res 12, 345–350.

    PubMed  CAS  Google Scholar 

  232. Hsiang, Y. H., Berkovitz, G. D., Bland, G. L., Migeon, C. J., and Warren, A. C. (1987) Gonadal function in patients with Down syndrome. Am J Med Genet 27, 449–458.

    PubMed  CAS  Google Scholar 

  233. Short, R. A., Bowen, R. L., O’Brien, P. C., and Graff-Radford, N. R. (2001) Elevated gonadotropin levels in patients with Alzheimer disease. Mayo Clin Proc 76, 906–909.

    PubMed  CAS  Google Scholar 

  234. Palomba, S., Orio, F., Russo, T., Falbo, A., Amati, A., and Zullo, F. (2004) Gonadotropin-releasing hormone agonist with or without raloxifene: effects on cognition, mood, and quality of life. Fertil Steril 82, 480–482.

    PubMed  CAS  Google Scholar 

  235. Casadesus, G., Webber, K. M., Atwood, C. S., et al. (2006b) Luteinizing hormone modulates cognition and amyloid-b deposition in Alzheimer APP transgenic mice. Biochim Biophys Acta (BBA) – Mol Basis Dis 1762, 447–452.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, College Station, 77843-1114, TX

    Danielle K. Lewis

  2. Department of Neuroscience and Experimental Therapeutics, TAMU Health Science Center, College Station, TX, USA

    Farida Sohrabji

Authors
  1. Danielle K. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Farida Sohrabji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Farida Sohrabji .

Editor information

Editors and Affiliations

  1. Dept. Psychology, Behavioral & Cellular, Texas A & M University, College Station, 77843-4235, U.S.A.

    Jennifer L. Bizon

  2. Padure Biomedical Consulting, Seeley Street 250, Brooklyn, 11218, U.S.A.

    Alisa Woods

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Humana Press, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Lewis, D.K., Sohrabji, F. (2009). Hormonal Influences on Brain Aging and Age-Related Cognitive Decline. In: Bizon, J., Woods, A. (eds) Animal Models of Human Cognitive Aging. Aging Medicine. Humana Press. https://doi.org/10.1007/978-1-59745-422-3_7

Download citation

Publish with us

Policies and ethics

Search

Navigation