AGE

, Volume 32, Issue 1, pp 61–67 | Cite as

Dehydroepiandrosterone and age-related cognitive decline

Article

Abstract

In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.

Keywords

Dehydroepiandrosterone Cognitive decline Intracrinology Neurosteroidogenesis 

References

  1. Abbott DH, Bird IM (2008) Nonhuman primates as models for human adrenal androgen production: function and dysfunction Rev Endocr Metab Disord doi:10.1007/s11154-008-9099-8
  2. Arlt W, Callies F, van Vlijmen JC et al (1999) Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 341:1013–1020CrossRefPubMedGoogle Scholar
  3. Arlt W, Callies F, Koehler I et al (2001) Dehydroepiandrosterone supplementation in healthy men with and age-related decline of dehydroepiandrosterone secretion. J Clin Endocrinol Metab 86:4684–4692CrossRefGoogle Scholar
  4. Bastianetto S, Ramassamy C, Poirer J et al (1999) Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage. Mol Brain Res 66:35–41CrossRefPubMedGoogle Scholar
  5. Bélanger N, Grégoire L, Bédard PJ et al (2006) DHEA improves symptomatic treatment of moderately and severely impaired MPTP monkeys. Neurobiol Aging 27:1684–1693CrossRefPubMedGoogle Scholar
  6. Bloch M, Schmidt PJ, Danaceau MA et al (1999) Dehydroepiandrosterone treatment of midlife dysthymia. Biol Psychiatry 45:1533–1541CrossRefPubMedGoogle Scholar
  7. Bohacek J, Bearl AM, Daniel JM (2008) Long-term ovarian hormone deprivation alters the ability of sebsewuent oestradiol replacement to regulate choline acetyltransferase protein levels in the hippocampus and prefrontal cortex of middle-aged rats. J Neuroendocrinol 20:1023–1027CrossRefPubMedGoogle Scholar
  8. Chen F, Knecht K, Birzin E et al (2005) Direct agonist/antagonist functions of DHEA. Endocrinology 146:4568–4576CrossRefPubMedGoogle Scholar
  9. Chen L, Miyamoto Y, Furuya K et al (2006) Chronic DHEAS administration facilitates hippocampal long-term potentiation via an amplification of Src-dependent MDA receptor signaling. Neuropharmacology 51:659–670CrossRefPubMedGoogle Scholar
  10. Conley AJ, Pattison JC, Bird IM (2004) Variations in adrenal androgen production among (nonhuman) primates. Sem Reprod Med 22:311–326CrossRefGoogle Scholar
  11. Corpechot C, Robel P, Axelson M et al (1981) Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci USA 78:4704–4707CrossRefPubMedGoogle Scholar
  12. Craig MC, Maki PM, Murphy DGM (2005) The Women’s Health Initiative Memory Study: findings and implications for treatment. Lancet Neurol 4:190–194PubMedGoogle Scholar
  13. Daniel JM, Julst JL, Berbling JL (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. Endocrinology 147:607–614CrossRefPubMedGoogle Scholar
  14. Davis SR, Shah SM, McKEnzie DP et al (2008) Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 93:801–808CrossRefPubMedGoogle Scholar
  15. DeNicola AF, Pietranera L, Beauquis J et al (2008) Steroid protection in aging and age-associated diseases. Exp Gerontol 44:34–40CrossRefGoogle Scholar
  16. Downs JL, Urbanski HF (2006) Neuroendocrine changes in the aging reproductive axis of female rhesus macaques (Macacaca mulatta). Biol Reprod 75:539–546CrossRefPubMedGoogle Scholar
  17. Downs JL, Mattison JA, Ingram DK et al (2008) Effect of age and caloric restriction on circadian adrenal steroid rhythms in rhesus macaques. Neurobiol Aging 29:1412–1422CrossRefPubMedGoogle Scholar
  18. Flood JF, Roberts E (1988) Dehydroepiandrosterone improves memory in aging mice. Brain Res 448:178–181CrossRefPubMedGoogle Scholar
  19. Flood JF, Smith GE, Roberts E (1988) Dehydroepiandrosterone and its sulfate enhance memory retention in mice. Brain Res 447:269–278CrossRefPubMedGoogle Scholar
  20. Gottfried-Blackmore A, Sierra A, Jellinck PH et al (2008) Brain microglia express steroid-converting enzymes in the mouse. J Steroid Biochem Mol Biol 109:96–107CrossRefPubMedGoogle Scholar
  21. Grimley Evans J, Malouf R, Huppert F et al. (2006) Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people. Cochrane Database of Syst Rev CD006221Google Scholar
  22. Hao J, Rapp PR, Janssen WGM et al (2007) Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex. Proc Natl Acad Sci USA 104:11465–11470CrossRefPubMedGoogle Scholar
  23. Herndon JG, Lacreuse A, Ladinsky E et al (1999) Age-related decline in DHEAS is not related to cognitive impairement in aged monkeys. NeuroReport 10:3507–3511CrossRefPubMedGoogle Scholar
  24. Hojo Y, Hattori T, Enami T et al (2003) Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P450c17α and P450 aromatase localized in neurons. Proc Natl Acad Sci USA 101:865–870CrossRefPubMedGoogle Scholar
  25. Hu L, Yue Y, Zuo PP et al (2006) Evaluation of neuroprotective effects of long-term low dose hormone replacement therapy on postmenopausal women brain hippocampus using magnetic resonance scanner. Chin Med Sci J 21:214–218PubMedGoogle Scholar
  26. Hunt PJ, Gurnell EM, Huppert FA et al (2000) Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison's disease in a randomized, double blind trial. J Clin Endocrinol Metab 85:4650–4656CrossRefPubMedGoogle Scholar
  27. Kaasik A, Kalda A, Jaako K et al (2001) Dehydroepiandrosterone sulphate prevents oxygen-glucose deprivation-induced injury in cerebellar granule cell culture. Neuroscience 102:427–432CrossRefPubMedGoogle Scholar
  28. Kang JH, Weuve J, Grodstein F (2004) Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women. Neurology 63:101–107PubMedGoogle Scholar
  29. Karishma KK, Herbert J (2002) DHEA stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons, and prevents corticosterone-induced suppression. Eur J NeuroSci 16:445–453CrossRefPubMedGoogle Scholar
  30. Kimonides VG, Khatibi NH, Svendsen CN et al (1998) Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci USA 95:1852–1857CrossRefPubMedGoogle Scholar
  31. Kohchi C, Ukena K, Tsutsui K (1998) Age- and region-specific expressions of the mRNAs encoding for steroidogenic enzymes P450scc, P450c17, and 3bhsd in the postnatal rat brain. Brain Res 801:233–238CrossRefPubMedGoogle Scholar
  32. Kretz O, Fester L, Wehrenberg U et al (2004) Hippocampal synapses depend on hippocampal estrogen synthesis. J Neurosci 24:5913–5921CrossRefPubMedGoogle Scholar
  33. Kritz-Silverstein D, von Muhlen D, Laughlin GA et al (2008) Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and wellness (DAWN) trial. J Am Geriatr Soc 56:1292–1298CrossRefPubMedGoogle Scholar
  34. Kumar P, Taha A, Sharma D et al (2008) Effect of DHEA on MAO activity, lipid peroxidation, and lipofuscin accumulation in aging rat brain regions. Biogerontology 9:235–246CrossRefPubMedGoogle Scholar
  35. Labrie F (1991) Intracrinology. Mol Cell Endocrinol 78:C113–C118CrossRefPubMedGoogle Scholar
  36. Labrie F, Bélanger A, Cusan L et al (1997) Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 82:2396–2402CrossRefPubMedGoogle Scholar
  37. Labrie F, Bélanger A, Luu-The V et al (1998) DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids 63:322–328CrossRefPubMedGoogle Scholar
  38. Larrabee GJ, Crook TH (1994) Estimated prevalence of age-associated memory impairment derived from standardized tests of memory function. Int Psychogeriatr 6:95–104CrossRefPubMedGoogle Scholar
  39. Lethaby A, Hovervorst E, Richards M et al. (2008) Hormone replacement therapy for cognitive function in postmenopausal women. Chochrane Database of Syst Rev CD003122Google Scholar
  40. Lhullier FLR, Nicolaidis R, Riera NG et al (2004) Dehydroepiandrosterone increases synaptosomal glutamate release and improves the performance in inhibitory avoidance task. Pharmacol Biochem Behav 77:601–606CrossRefPubMedGoogle Scholar
  41. Liu CH, Laughlin GA, Fischer UG et al (1990) Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17, 20-desmolase activity. J Clin Endocrinol Metab 71:900–906CrossRefPubMedGoogle Scholar
  42. Løkkegaard E, Pederson AT, Laursen P et al (2002) The influence of hormone replacement therapy on the aging-related change in cognitive performance. Analysis based on a Danish cohort study. Maturitas 42:209–218CrossRefPubMedGoogle Scholar
  43. Majewska MD (1992) Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 38:379–395CrossRefPubMedGoogle Scholar
  44. Mao X, Barger SW (1998) Neuroprotection by dehydroepiandrosterone-sulfate: role of an NFκB-like factor. NeuroReport 9:759–763CrossRefPubMedGoogle Scholar
  45. Mellon SH, Griffin LD (2002) Neurosteroids: biochemistry and clinical significance. Trends Endocrinol Metab 13:35–42CrossRefPubMedGoogle Scholar
  46. Micheal A, Jenaway A, Paykel ES et al (2000) Altered salivary dehydroepiandrosterone levels in major depression in adults. Biol Psychiatry 48:989–995CrossRefGoogle Scholar
  47. Morrison MF, Katz IR, Parmelee P et al (1998) Dehydroepiandrosterone sulfate (DHEA-S) and psychiatric and laboratory measures of frailty in a residential care population. Am J Geriatr Psychiatry 6:277–284PubMedGoogle Scholar
  48. Morrison MG, Redei E, TenHave T et al (2000) Dehydroepiandrosterone sulfate and psychiatric measures in a frail, elderly residential care population. Biol Psychiatry 47:144–150CrossRefPubMedGoogle Scholar
  49. Mukai H, Tsuruqizawa T, Ogiue-Ikeda M et al (2006) Local neurosteroid production in the hippocampus: influence on synaptic plasticity of memory. Neuroendocrinology 84:255–263CrossRefPubMedGoogle Scholar
  50. Nguyen AD, Conley AJ (2008) Adrenal androgens in humans and nonhuman primates: production, zonation and regulation. In: Flück CE, Miller WL (eds) Disorders of the human adrenal cortex. Endocr Dev Karger Basel 13:33–54Google Scholar
  51. Orentreich N, Brind JL, Vogelman JH et al (1992) Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab 75:1002–1004CrossRefPubMedGoogle Scholar
  52. Parsons TD, Kratz KM, Thompson E et al (2006) DHEA supplementation and cognition in postmenopausal women. Int J Neurosci 116:141–155CrossRefPubMedGoogle Scholar
  53. Racchi M, Balduzzi C, Corsini E (2003) Dehydroeiandrosterone (DHEA) and the aging brain: flipping a coin in the “fountain of youth”. CNS Drug Rev 9:21–40PubMedGoogle Scholar
  54. Robel P, Bourreau E, Corpechot C et al (1987) Neuro-steroids: 3β-hydroxy-Δ5-derivatives in rat and monkey brain. J Steroid Biochem 27:649–655CrossRefPubMedGoogle Scholar
  55. Rohan TE, Negassa A, Chlebowski RT et al (2008) Conjugated equine estrogen and risk of benign proliferative breast disease: a randomized controlled trial. J Natl Cancer Inst 100:563–571CrossRefPubMedGoogle Scholar
  56. Rune GM, Frotscher M (2005) Neurosteroid synthesis in the hippocampus: role in synaptic plasticity. Neurosci 136:833–842CrossRefGoogle Scholar
  57. Saravia F, Beauquis J, Pietranera et al (2007) Neuroprotective effects of estradiol in hippocampal neurons and glia of middle age mice. Psychoneuroendocrinology 32:480–492CrossRefPubMedGoogle Scholar
  58. Schmidt PJ, Daly RC, Bloch M et al (2005) Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry 62:154–162CrossRefPubMedGoogle Scholar
  59. Sherwin BB (2007a) The clinical relevance of the relationship between estrogen and cognition in women. J Steroid Biochem Mol Biol 106:151–156CrossRefPubMedGoogle Scholar
  60. Sherwin BB (2007b) The critical period hypothesis: can it explain discrepancies in the oestrogen-cognition literature? J Neuroendocrinol 19:77–81CrossRefPubMedGoogle Scholar
  61. Stoffel-Wagner B (2003) Neurosteroid biosynthesis in the human brain and its clinical implications. Ann N Y Acad Sci 1007:64–78CrossRefPubMedGoogle Scholar
  62. Suzuki M, Wright LS, Marwah P et al (2004) Mitotic and neurogenic effects of DHEA on human neural stem cell cultures derived from the fetal cortex. Proc Natl Acad Sci USA 101:3202–3207CrossRefPubMedGoogle Scholar
  63. Urbanski HF, Downs JL, Garyfallou VT et al (2004) Effect of caloric restriction on the 24-hour plasma DHEAS and cortisol profiles of young and old male rhesus macaques. Ann N Y Acad Sci 1019:443–447CrossRefPubMedGoogle Scholar
  64. van Niekerk JK, Huppert JA, 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 26:591–612CrossRefPubMedGoogle Scholar
  65. Varadhan R, Walston J, Cappola AR et al (2008) Higher levels and blunted diurnal variation of cortisol in frail older women. J Gerontol A Biol Sci Med Sci 63:190–195PubMedGoogle Scholar
  66. Verhaeghen P, Salthouse TA (1997) Meta-analyses of age-cognition relations in adulthood: estimates of linear and nonlinear age effects and structural models. Psychol Bull 122:231–249CrossRefPubMedGoogle Scholar
  67. Weill-Engerer S, David JP, Sazdovitch V et al (2002) Neurosteroid quantification in human brain regions: comparison between Alzheimer’s and non-demented patients. J Clin Endocrinol Metab 87:5238–5142CrossRefGoogle Scholar
  68. Wolf OT, Kirschbaum C (1999) Actions of dehydroepiandrosterone and its sulfate in the central nervous system: effects on cognition and emotion in animals and humans. Brain Res Rev 30:264–288CrossRefPubMedGoogle Scholar
  69. Wolf OT, Neumann O, Hellhammer DH 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 82:2363–2367CrossRefPubMedGoogle Scholar
  70. Wolf OT, Kudielka BM, Hellhammer DH et al (1998) Opposing effects of DHEA replacement in elderly subjects on declarative memory and attention after exposure to a laboratory stressor. Psychoneuroendocrinology 23:617–629CrossRefPubMedGoogle Scholar
  71. Wolkowitz OM, Kramer JH, Reus VI et al (1999) Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 156:646–649PubMedGoogle Scholar
  72. Wolkowitz OM, Kramer JH, Reus VI et al (2003) DHEA treatment of Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Neurology 60:1071–1076PubMedGoogle Scholar
  73. Yue Y, Hu L, Tian QJ et al (2007) Effects of long-term, low-dose sex hormone replacement therapy on hippocampus and cognition of postmenopausal women of different apoE genotypes. Acta Pharmacol Sin 28:1129–1135CrossRefPubMedGoogle Scholar
  74. Zwain IH, Yen SSC (1999) DHEA: biosynthesis and metabolism in the brain. Endocrinology 140:880–887CrossRefPubMedGoogle Scholar

Copyright information

© American Aging Association, Media, PA, USA 2009

Authors and Affiliations

  1. 1.Division of NeuroscienceOregon National Primate Research CenterBeavertonUSA
  2. 2.Department of Behavioral NeuroscienceOregon Health and Science UniversityPortlandUSA

Personalised recommendations