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The hormonal pathway to cognitive impairment in older men

  • Hormonal Dysregulation and Cognition in the Elderly
  • Published:
The journal of nutrition, health & aging

Abstract

In older men there is a multiple hormonal dysregulation with a relative prevalence of catabolic hormones such as thyroid hormones and cortisol and a decline in anabolic hormones such as dehydroepiandrosterone sulphate, testosterone and insulin like growth factor 1 levels. Many studies suggest that this catabolic milieu is an important predictor of frailty and mortality in older persons. There is a close relationship between frailty and cognitive impairment with studies suggesting that development of frailty is consequence of cognitive impairment and others pointing out that physical frailty is a determinant of cognitive decline. Decline in cognitive function, typically memory, is a major symptom of dementia. The “preclinical phase” of cognitive impairment occurs many years before the onset of dementia. The identification of relevant modifiable factors, including the hormonal dysregulation, may lead to therapeutic strategies for preventing the cognitive dysfunction. There are several mechanisms by which anabolic hormones play a role in neuroprotection and neuromodulation. These hormones facilitate recovery after brain injury and attenuate the neuronal loss. In contrast, elevated thyroid hormones may increase oxidative stress and apoptosis, leading to neuronal damage or death. In this mini review we will address the relationship between low levels of anabolic hormones, changes in thyroid hormones and cognitive function in older men. Then, giving the contradictory data of the literature and the multi-factorial origin of dementia, we will introduce the hypothesis of multiple hormonal derangement as a better determinant of cognitive decline in older men.

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References

  1. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B. (2001) Current concepts in mild cognitive impairment. Arch Neurol 58:1985–1992

    Article  PubMed  CAS  Google Scholar 

  2. Elias MF, Beiser A, Wolf PA, Au R, White RF, D’Agostino RB. (2000) The preclinical phase of Alzheimer disease: a 22-year prospective study of the Framingham Cohort. Arch Neurol 57:808–813

    Article  PubMed  CAS  Google Scholar 

  3. La Rue A. (2001) Aging and neuropsychological assessment. 15th ed. New York: Plenum Press

    Google Scholar 

  4. Salthouse TA. (1996) The processing-speed theory of adult age differences in cognition. Psychol Rev 103:403–428

    Article  PubMed  CAS  Google Scholar 

  5. Bennett DA, Wilson RS, Schneider JA, Evans DA, Beckett LA, Aggarwal NT, Barnes LL, Fox JH, Bach J. (2002) Natural history of mild cognitive impairment in older persons. Neurology 59:198–205

    PubMed  CAS  Google Scholar 

  6. Salthouse TA. (2004) What and when of cognitive aging. Curr Dir Psychol Sci 13:140–144

    Article  Google Scholar 

  7. Ferrucci L, Guralnick JM, Studenski S, Fried L, Cutler GB, Waltson JD, for the Intervention on Frailty Working Group. (2004) Designing randomized, controlled trials aimed at preventing or delaying functional decline and disability in frail, older person: A consensus report. J Am Geriatr Soc 52:625–634

    Article  PubMed  Google Scholar 

  8. Samper-Ternent R, Al Snih S, Raji MA, Markides KS, and Ottenbacher KJ. (2008) Relationship between frailty and cognitive decline in older mexican americans. Am J Geriatr Soc Oct;56(10):1845–1852

    Article  Google Scholar 

  9. Maggio M, Cappola AR, Ceda GP, Basarla S, Chia CW, Valenti G, Ferrucci L. (2005) The hormonal pathway of frailty in older men. J Endocrinol Invest 28(11 Suppl Preceedings):15–19. Review.

    PubMed  CAS  Google Scholar 

  10. Wolf OT. (2009) Stress and memory in hmans:twelve years of progress? Brain Research 1293:142–154

    Article  PubMed  CAS  Google Scholar 

  11. Comijs HC, Gerritsen L, Penninx BW, Bremmer MA, Deeg DJ, Geerlings MI. (2010) The association between serum cortisol and cognitive decline in older persons. Am J Geriatr Psychiatry 18(1):42–50

    Article  PubMed  Google Scholar 

  12. Reynolds RM, Strachan MWJ, Labad J, Lee AJ, Frier BM, Fowkes FG, Mitchell R, Seckl JR, Deary IJ, Walker BR, Price JF. (2010) Morning cortisol levels and cogntive abilities in people with type 2 diabetes. Diabetes care 33:714–720

    Article  PubMed  CAS  Google Scholar 

  13. Labrie F, Belanger A, Cusan L, Gomez JL, Candas B. (1997) Marked decline in serum concentration of adrenal C 19 sex steroid precursor and conjugated androgen metabolites durin aging. J Clin Endocrinol Metab 82:2396–2402

    Article  PubMed  CAS  Google Scholar 

  14. Bjørnerem A, Straume B, Midtby M, Fønnebø V, Sundsfjord, Svartberg J, Acharya G, Oian P, Berntsen GK. (2004) Endogenous sex hormones in relation to age, sex, lifestyle factors, and chronic disease in a general population: the Tromsø Study. J Clin Endocrinol Metab 89:6039–6047

    Article  PubMed  CAS  Google Scholar 

  15. GISEG (Italian Study Group on Geriatric Endocrinology), Valenti G, Denti L, Saccò M, Ceresini G, Bossoni S, Giustina A, Maugeri D, Vigna GB, Fellin R, Paolisso G, Barbagallo M, Maggio M, Strollo F, Bollanti L, Romanelli F, Latini M. (2006) Consensus document substitution therapy with DHEA in the elderly. Aging Clin Exp Res 18:277–300

    PubMed  Google Scholar 

  16. Maninger N, Wolkowitz OM, Reus VI. (2009) Neurobiological and neuropsychiatrc affects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009 Jan;30(1):65–91

    Article  CAS  Google Scholar 

  17. Laurine E, Lafitte D, Grégoire C, Sérée E, Loret E, Douillard S, Michel B, Briand C, Verdier JM. (2003) Specific binding of dehydroepiandrosterone to the N terminus of the microtubule-associated protein MAP2. J Biol Chem. Aug 8;278(32): 29979–29986. Epub 2003 May 29.

    Google Scholar 

  18. Bologa L, Sharma J, Dahl D, Roberts E. (1987) Buffers and H2O2 reduce neuronal death and/or enhance differentiation of neurons and astrocytes in dissociated mouse brain cultures. Brain Res. May 19;411(2):282–290.

    CAS  Google Scholar 

  19. Compagnone NA, Mellon SH. (1998) Dehydroepiandrosterone: a potential signalling molecule for neocortical organization during development. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4678–4683.

    Article  PubMed  CAS  Google Scholar 

  20. Flood JF, Morley JE, Roberts E. (1992) Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1567–1571.

    Article  PubMed  CAS  Google Scholar 

  21. Majewska MD, Demirgören S, London ED. (1990) Binding of pregnenolone sulfate to rat brain membranes suggests multiple sites of steroid action at the GABAA receptor. Eur J Pharmacol. Oct 30;189(4–5):307–315.

    Article  Google Scholar 

  22. Steffensen SC, Jones MD, Hales K, Allison DW. (2006) Dehydroepiandrosterone sulphate and estrone sulphate reduce GABA-recurrent inhibition in hippocampus via muscarinic acetylcholine receptors. Hippocampus. 16(12):1080–1090.

    Article  PubMed  CAS  Google Scholar 

  23. Porter JR, Abadie JM, Wright BE, Browne ES, Svec F. (1995) The effect of discontinuing dehydroepiandrosterone supplementation on Zucker rat food intake and hypothalamic neurotransmitters.Int J Obes Relat Metab Disord. Jul;19(7):480–488.

    CAS  Google Scholar 

  24. Bastianetto S, Ramassamy C, Poirier J, Quirion R. (1999) Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage. Brain Res Mol Brain Res. Mar 20;66(1–2):35–41.

    Article  PubMed  CAS  Google Scholar 

  25. Kimonides VG, Khatibi NH, Svendsen CN, Sofroniew MV, Herbert J. (1998) Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci U S A. Feb 17; 95(4):1852–1857.

    Article  CAS  Google Scholar 

  26. Luppi C, Fioravanti M, Bertolini B, Inguscio M, Grugnetti A, Guerriero F, Rovelli C, Cantoni F, Guagnano P, Marazzi E, Rolfo E, Ghianda D, Levante D, Guerrini C, Bonacasa R, Solerte SB. (2009) Growth factors decrease in subjects with mild to moderate Alzheimer’s disease (AD): potential correction with dehydroepiandrosterone-sulphate (DHEAS). Arch Gerontol Geriatr. 49 Suppl 1:173–184.

    Article  CAS  Google Scholar 

  27. Kimonides VG, Spillantini MG, Sofroniew MV, Fawcett JW, Herbert J. (1999) Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures. Neuroscience. Mar;89(2):429–436.

    Article  PubMed  CAS  Google Scholar 

  28. Morley JE, Kaiser F, Raum WJ, Perry M, Flood JF, Jensen J, Silver AJ, Roberts J. (1997) Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decline in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sci USA Jul;94:7537–7542

    Article  PubMed  CAS  Google Scholar 

  29. Flood JF, Farr SA, Johnson DA, Li PK, Morley JE. (1999) Pheripheral steroids sulfatase inhibition potentiate improvement of memory retention for hippocampally administred dehydroepiandrosterone sulfate but not pregnenolone sulfate. Psychoneuroendocrinology 24:799–811

    Article  PubMed  CAS  Google Scholar 

  30. Kalmijn S, Launer LJ, Stolk RP, de Jong FH, Pols HA, Hofman A, Breteler MM, Lamberts SW. (1998) A prospective study on cortisol, dehydroepiandrosterone sulphate, and cognitive function in the elderly. J Clin Endocrinol Metab 83:3487–3492

    Article  PubMed  CAS  Google Scholar 

  31. Moffat SD, Zonderman AB, Harman SM, Blackman MR, Kawas C, Resnick SM. (2000) The relationship between longitudinal declines in dehydroepiandrosterone sulphate concentrations and cognitive performance in older men. Arch Inter Med 160:2193–2198

    Article  CAS  Google Scholar 

  32. Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. (2005) Age, hormones, and cognitive functioning among middle-aged and elderly men: crosssectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci Mar 60(3):385–390

    Article  PubMed  Google Scholar 

  33. Davis SR, Shah MS, McKenzie DP, Kulkarni J, Davidson SL, Bell RJ. (2008) Dehydroepiandrosterone sulfate levels are associated with more favourable cognitive function in women. J Clin Endocrinol Metab 93:801–808

    Article  PubMed  CAS  Google Scholar 

  34. Berr C, Lafont S, Debuire B, Dartigues JF, Baulieu EE. (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. Nov 12;93(23):13410–13415.

    Article  PubMed  CAS  Google Scholar 

  35. Valenti G, Ferrucci L, Lauretani F, Ceresini G, Bandinelli S, Luci M, Ceda GP, Maggio M, Schwartz RS. (2009) Dehydroepiandrosterone sulfate and cognitive function in the elderly: The InCHIANTI Study. J Endocrinol Invest 32:766–772

    PubMed  CAS  Google Scholar 

  36. Marx CE, Trost WT, Shampine LJ, Stevens RD, Hulette CM, Steffens DC, Ervin JF, Butterfield MI, Blazer DG, Massing MW, Lieberman JA. (2006) The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease. Biol Psychiatry 60:1287–1294

    Article  PubMed  CAS  Google Scholar 

  37. Marx CE, Steffens DC, Blazer DG, Ervin JF, Hulette CM, Massing MW, Butterfield MI, Lieberman JA, Shampine LJ. (2005) Deficits in the GABAergic neuroactive steroid allopregnanolone in Alzheimer’s disease and relevance to neuropathological disease stage: investigations in temporal cortex. Proc 44th Annual Meeting of the American College of Neuropsychopharmacology, Wailkoloa, Hawaii, p S79 (Abstract 7)

  38. Naylor JC, Hulette CM, Steffens DC, Shampine LJ, Ervin JF, Payne VM, Massing MW, Kilts JD, Strauss JL, Calhoun PS, Calnaido RP, Blazer DG, Lieberman JA, Madison RD, Marx CE. (2008) Cerebrospinal fluid dehydroepiandrosterone levels are correlated with brain dehydroepiandrosterone levels, elevated in Alzheimer’s disease, and related with neuropathological disease stage. J Clin Endocrinol Metab; 93:3178–3178

    Article  CAS  Google Scholar 

  39. Wolf OT, Neumann O, Hellhammer DH, Geiben AC, Strasburger CJ, Dressendörfer RA, Pirke KM, Kirschbaum C. (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

    Article  PubMed  CAS  Google Scholar 

  40. Wolf OT, Neumann O, Hellhammer DH, Kirschbaum C. (1998) Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory and well-being. J Gerontol A Biol Sci Med Sci 53:M385–M390

    Article  PubMed  CAS  Google Scholar 

  41. Wolf OT, Kudielka BM, Hellhammer DH, Hellhammer J, Kirschbaum C. (1998) Opposing effects of DHEA replacement in elderly subjects on declarative memory and attention after exposure to a laboratory stressor. Psychoneuroendocrinology 23:617–629

    Article  PubMed  CAS  Google Scholar 

  42. Van Niekerk JK, Huppert FA, Herbert J. (2001) Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effect of three months of DHEA supplementation. Psychoneuroendocrinology 26:591–612

    Article  PubMed  Google Scholar 

  43. Barnhart KT, Freeman E, Grisso JA, Rader DJ, Sammel M, Kapoor S, Nestler JE. (1999) The effect of deydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and healthrelated quality of life. J Clin Endocrinol Metab 84(11): 3896–3902

    Article  PubMed  CAS  Google Scholar 

  44. Wolkowitz OM, Kramer JH, Reus VI, Costa MM, Yaffe K, Walton P, Raskind M, Peskind E, Newhouse P, Sack D, De Souza E, Sadowsky C, Roberts E; DHEAAlzheimer’s Disease Collaborative Research. (2003) DHEA treatment of Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Neurology Apr 8;60(7):1071–1076.

    PubMed  CAS  Google Scholar 

  45. Huppert FA, Van Niekerk JK. (2007) WITHDRAWN: deydroepiandrosterone (DHEA) supplementation for cognitive function. Cochrane Database Syst Rev 18(2):CD000304

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Fedotova J, Sapronov N. (2004) Behavioural effects of dehydroepiandrosterone in adult male rats. Prog Neuropsychopharmacol Biol Psychiatry 28:1023–1027

    Article  PubMed  CAS  Google Scholar 

  48. Farr SA, Banks WA, Uezu K, Gaskin FS, Morley JE. (2004) DHEAS improves learning and memory in aged SAMP8 mice but not in diabetic mice. Life Sci 75:2775–2785

    Article  PubMed  CAS  Google Scholar 

  49. Sujkovic E, Mileusnic R, Fry JP, Rose SP. (2007) Temporal effects of dehydroepiandrosterone sulphate on memory formation in day-old chicks. Neuroscience 148:375–384

    Article  PubMed  CAS  Google Scholar 

  50. Lamberts SWJ, van den Beld AW, van der Lely AJ. (1997) The endocrinology of aging. Science 278:419–424.

    Article  PubMed  CAS  Google Scholar 

  51. Gouras GK, Xu H, Gross RS, Greenfield JP, Hai B, Wang R, Greengard P. (2000) Testosterone reduces neuronal secretion of Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci USA 97:1202–1205.

    Article  PubMed  CAS  Google Scholar 

  52. Kerr JE, Allore RJ, Beck SG, Handa RJ. (1995) Distribution and hormonal regulation of androgen receptor (AR) and AR messenger ribonucleic acid in the rat hippocampus. Endocrinology 136:3213–3221

    Article  PubMed  CAS  Google Scholar 

  53. Leranth C, Petnehazy O, MacLusky NJ. (2003) Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci 23:1588–1592.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  55. Brown TJ, Sharma M, Karsan N, Walters MJ, MacLusky NJ. (1995) In vitro autoradiographic measurement of gonadal steroid receptors in brain tissue sections. Steroids 60:726–737.

    Article  PubMed  CAS  Google Scholar 

  56. Pomerantz SM, Sholl SA. (1987) Analysis of sex and regional differences in androgen receptors in fetal rhesus monkey brain. Brain Res 433:151–154.

    PubMed  CAS  Google Scholar 

  57. Choate JV, Slayden OD, Resko JA. (1998) Immunocytochemical localization of androgen receptors in brains of developing and adult male rhesus monkeys. Endocrine 8:51–60.

    Article  PubMed  CAS  Google Scholar 

  58. Roselli CE, Klosterman S, Resko JA. (2001) Anatomic relationships between aromatase and androgen receptor mRNA expression in the hypothalamus and amygdala of adult male cynomolgus monkeys. J Comp Neurol 439:208–223

    Article  PubMed  CAS  Google Scholar 

  59. Clancy AN, Bonsall RW, Michael RP. (1992) Immunohistochemical labelling of androgen receptors in the brain of rat and monkey. Life Sci 50:409–417.

    Article  PubMed  CAS  Google Scholar 

  60. Bachevalier J, Hagger C (1991) Sex differences in the development of learning abilities in primates. Psychoneuroendocrinology 16:177–188.

    Article  PubMed  CAS  Google Scholar 

  61. Clark AS, Goldman-Rakic PS. (1989) Gonadal hormones influence the emergence of cortical function in nonhuman primates. Behav Neurosci 103:1287–1295

    Article  PubMed  CAS  Google Scholar 

  62. Rosario ER, Carroll J, Pike CJ. (2010) Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogens andandrogens pathways. Brain Research;1359:281–290

    Article  CAS  Google Scholar 

  63. Pouliot WA, Handa RJ, Beck SG. (1996) Androgen modulates N-methyl-daspartate-mediated depolarization in CA1 hippocampal pyramidal cells. Synapse 23:10–19

    Article  PubMed  CAS  Google Scholar 

  64. Morse JK, DeKosky ST, Scheff SW. (1992) Neurotrophic effects of steroids on lesion-induced growth in the hippocampus. II. Hormone replacement. Exp Neurol 118:47–52

    Article  PubMed  CAS  Google Scholar 

  65. Tirassa P, Thiblin I, Agren G, Vigneti E, Aloe L, Stenfors C. (1997) High-dose anabolic androgenic steroids modulate concentrations of nerve growth factor and expression of its low affinity receptor (p75-NGFr) in male rat brain. J Neurosci Res 47:198–207

    Article  PubMed  CAS  Google Scholar 

  66. Pike CJ, Carroll JC, Rosario ER, Barron AM. (2009) Protective actions of sex steroid hormones in Alzheimer disease. Frontiers in Neuroendocrinology 30 239–258. Review

    Article  PubMed  CAS  Google Scholar 

  67. Gandy S, Almeida OV, Fonte J, Lim D, Waterrus A, Spray N, Flicker N, Martins RN. (2001) Chemical andropause and -amyloid peptide. JAMA May 2;285(17):2195–2196

    Article  Google Scholar 

  68. Raber J, Bongers G, LeFevour A, Buttini M, Mucke L. (2002) Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci 22:5204–5209

    PubMed  CAS  Google Scholar 

  69. Raber J. (2004) Androgens, apoE, and Alzheimer’s disease. Science Aging Knowl Environ 2004:1–11

    Google Scholar 

  70. Hogervorst E, Lehmann DJ, Warden DR, McBroom J, Smith AD. (2002) Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer’s disease in men. Int J Geriatr Psychiatry 17:938–940

    Article  PubMed  CAS  Google Scholar 

  71. Panizzon MS, Hauger R, Dale AM, Eyler LJ, Fischl B, Fennema-Notestine C, Franz CE, Grant MD, Jak AJ, Jacobson KJ et al. (2010) Testosterone modifies the effect of APO E genotype on hippocampal volume in middle-aged men. Neurology 75:874–880

    Article  PubMed  CAS  Google Scholar 

  72. Lehmann DJ, Hogervorst E, Warden DR, Smith AD, Butler HD, Ragoussis J. (2004) The androgen receptor CAGrepeat and serum testosterone in the risk of Alzheimer’s disease in men. J Neurol Neurosurg Psychiatry 75;163–171

    Google Scholar 

  73. Kovacs D, Vassos E, Liu X, Sun X, Hu J, Breen G, Tompa P, Collier DA, Li T. (2009) The androgen receptor gene polyglycine repeat polymorphism is associated with memory performance in Chinese individuals. Psyconeuroendocrinology 34;947–952

    Google Scholar 

  74. Lee DM, Ulubaev A, Tajar A, Pye SR, Pendleton N, Purandare N, O’Neill TW, O’Connor DB, Labrie F, Platt D, Payne D, Bartfai G, Boonen F, Casanueva SS, Finn JD, Forti G, Giwercman A, Han TS, Huhtaniemi IT, Kula K, Lean ME, Punab B, Silman AJ, Vandershueren D, Wu FC; EMAS Study Group. (2010) Endogenous hormones, androgen receptor CAG repeat length and fluid cognition in middle-aged and older men: results from the European Male Ageing Study. Eur J Endocrinol Jun;162(6):1155–1164. Epub 2010 Mar 15

    Article  PubMed  CAS  Google Scholar 

  75. Moffat SD, Hampson E. (1996) A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference. Psychoneuroendocrinology 21:323–337

    Article  PubMed  CAS  Google Scholar 

  76. Muller M, Aleman A, Grobbee DE, De Haan EH, van der Schouw YT. (2005) Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level? Neurology 64:866–871

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  78. Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM. (2002) Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab 87:5001–5007

    Article  PubMed  CAS  Google Scholar 

  79. Martin DM, Wittert G, Burns NR, Haren MT, Sugarman R. (2007) Testosterone and cognitive function in ageing men: data from the Florey Adelaide Male Aging Study (FAMAS). Maturitas 57:182–194

    Article  PubMed  CAS  Google Scholar 

  80. Chu LW, Tam S, Wong RL, Yik PY, Song Y, Cheung BM, Morley JE, Lam KS. (2010) Bioavailable testosterone predicts a lower risk of Alzheimer’s Disease in older men. J Alzheimers Dis Aug 6. Epub ahead of print.

  81. Chu LW, Tam S, Lee PWH, Wong RLC, Yik PY, Tsui W, Song Y, Cheung BMY, Morley JE, Lam KSL. (2008) Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men. Clin Endocrinol 68:589–598.

    Article  CAS  Google Scholar 

  82. Yeap BB, Almeida OP, Hyde Z, Chubb SAP, Hankey GJ, Jamrozik K, Flicker R. (2008) Higher serum free testosterone is associated with better cognitive function in older men, while total testosterone is not. The Health In Men Study. Clin Endocrinol 68; 404–412

    CAS  Google Scholar 

  83. Maggio M, Ceda GP, Lauretani F, Bandinelli S, Metter EJ, Guralnik JK, Basaria S, Cattabiani C, Luci M, Dall’Aglio E, Vignali A, Volpi R, Valenti G, Ferrucci L. (2010) Gonadal Status and physical performance in older men. 92th Endo Society Annual Meeting Abstract Book 2010.

  84. Beer TM, Bland LB, Bussiere JR, Neiss MB, Wersinger EM, Garzotto M, Ryan CW, Janowsky JS. (2006) Testosterone loss and estradiol administration modify memory in men. J Urol Jan 175;130–135

    Article  CAS  Google Scholar 

  85. Nelson CJ, Lee JS, Gamboa MC, Roth AJ. (2008) Cognitive effects of hormone therapy in men with prostate cancer. Cancer;113:1097–11

    Article  PubMed  CAS  Google Scholar 

  86. Alibhai SMH, Mahmoud S, Hussain F, Naglie G, Tannock I, Tomlinson G, Fleshner N, Krahn M, Warde P, Klots L, Breunis H, Leach M, Canning SD. (2010) Leveles of sex hormones have limited effect on cognition in older men with or without prostate cancer. Critical Reviews in Oncology and Hematology 73:167–175

    Article  CAS  Google Scholar 

  87. Wolf OT, Kirschbaum C. (2002) Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men. Horm and Behavior 41:259–266

    Article  CAS  Google Scholar 

  88. Lessov-Schlaggar CN, Reed T, Swan GE, krasnow RE, DeCarli C, Marcus R, Holloway L, Wolf PA, Carmelli D. (2005) Association of sex steroid hormones with brain morphology and cognition in healthy elderly men. Neurology 65:1591–1596

    Article  PubMed  CAS  Google Scholar 

  89. Yonker JE; Eriksson E, Nilsson LG, Herlitz A. (2006) Negative association of testosterone on spatial visualization in 35 to 50 years old men. Cortex Apr;42(3):376–386

    Article  PubMed  Google Scholar 

  90. Janowsky JS, Oviatt SK, Orwoll ES. (1994) Testosterone influences spatial cognition in older men. Behav. Neurosci 108:325–332.

    Article  PubMed  CAS  Google Scholar 

  91. Postma A, Meyer G, Tuiten A, van Honk J, Kessels RP, Thijssen J. (2000) Effects of testosterone administration on selective aspects of object-location memory in healthy young women. Psychoneuroendocrinology 25:563–575.

    Article  PubMed  CAS  Google Scholar 

  92. Wolf OT, Preut R, Hellhammer DH, Kudielka BM, Schurmeyer TH, 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.

    Article  PubMed  CAS  Google Scholar 

  93. Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, LaTendresse S, Craft S. (2001) Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 57:80–88.

    PubMed  CAS  Google Scholar 

  94. Cherrier MM, Anawalt BD, Herbst KL, Amory JK, Craft S, Matsumoto AM, Bremner WJ. (2002) Cognitive effects of short-term manipulation of serum sex steroids in healthy young men. J. Clin. Endocrinol. Metab 87:3090–3096.

    Article  PubMed  CAS  Google Scholar 

  95. Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, Raskind MA, Craft S. (2005) Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 64;2063–2068

    Article  PubMed  CAS  Google Scholar 

  96. Fukai S, Akishita M, Yamada S, Toba K, Ouchi Y. (2010) Effects of testosterone in older men with mild-to-moderate cognitive impairment. J Am Geriatr Soc 58:1419–1421.

    Article  PubMed  Google Scholar 

  97. Haren MT, Wittert GA, Chapman IM, Coates P, Morley JE. (2005) Effects of oral testosterone undecanoate on visuospatial cognition, mood and quality of life in elderly men with low-normal gonadal status. Maturitas 50:124–133

    Article  PubMed  CAS  Google Scholar 

  98. Vaughan C, Goldstein FC, Tenover JL. (2007) Exogenous testosterone alone or with finasteride does not improve measurements of cognition in healthy older men with low serum testosterone. J Androl 28:875–882.

    Article  PubMed  CAS  Google Scholar 

  99. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT. (2008) Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA Jan 2;299(1):39–52.

    Article  Google Scholar 

  100. Maki PM, Ernst M, London ED, Merdecai KL, Perschler P, Durso SC, Brandt J, Dobs A, Resnick SM. (2007) Intramuscular testosterone treatment in elderly men: evidence of memory decline and altered brain function. J Clin Endocrinol Metab Nov;92(11):4107–4114. Epub 2007 Aug 28.

    Article  PubMed  CAS  Google Scholar 

  101. Lu Ph, Masterman DA, Mulnard R, Cotman C, Miller, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL. (2006) Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol Feb;63(2):177–185. Epub 2005 Dec 12.

    Article  PubMed  Google Scholar 

  102. Asthana S, Craft S, Baker LD, Raskind MA, Birnbaum RS, Lofgreen CP, Veith RC, Plymate SR. (1999) Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer’s disease: results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology 24:657–677.

    Article  PubMed  CAS  Google Scholar 

  103. Hogervorst E, Boshuisen M, Riedel W, Willeken C, Jolles J. (1999) Richter Award. The effect of hormone replacement therapy on cognitive function in elderly women. Psychoneuroendocrinology 24:43–68.

    Article  PubMed  CAS  Google Scholar 

  104. Miles C, Green R, Sanders G, Hines M. (1998) Estrogen and memory in a transsexual population. Horm Behav 34:199–208

    Article  PubMed  CAS  Google Scholar 

  105. Barrett-Connor E, Goodman-Gruen D, Patay B. (1999) Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 84: 3681–3685.

    Article  PubMed  CAS  Google Scholar 

  106. Yaffe K, Lui LY, Grady D, Cauley J, Kramer J, Cummings SR. (2000) Cognitive decline in women in relation to non-protein-bound oestradiol concentration. Lancet 356:708–712.

    Article  PubMed  CAS  Google Scholar 

  107. Geerlings MI, Lauren LJ, de Jong FH, Ruitenberg A, Stijnen T, van Swieten JC, Hofman A, Witteman JC, Pols HA, Breteler MM; Rotterdam Study. (2003) Endogenous estradiol and risk of dementia in women and men: The Rotterdam Study. Ann Neurol 53:607–615.

    Article  PubMed  CAS  Google Scholar 

  108. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J; WHIMS Investigators. (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

    Article  PubMed  CAS  Google Scholar 

  109. Muller M, van den Beld AW, Grobbee DE, de Jong FH, Lamberts SW. (2009) Sex hormones and cognitive decline in elderly men. Psychoneuroendocrinology 34:27–31

    Article  PubMed  CAS  Google Scholar 

  110. Laughlin GA, Kritz-Silverstein D, Barrett-Connor E. (2010) Endogenous oestrogens predict 4-year decline in verbal fluency in postmenopausal women: the Rancho Bernardo Study. Clin Endocrinol 72:99–106

    Article  CAS  Google Scholar 

  111. Le Blanc ES, Wang PY, Janowsky JS, Neiss MB, Fink HA, Yaffe K, Marshall LM, Lapidus JA, Stefanick ML, Orwoll ES; Osteoporotic Fractures in Men (MrOS) Research Group. (2010) Association between sex steroids and cognition in elderly men. Clin Endocrinol 72(3); 393–403

    Article  CAS  Google Scholar 

  112. Rosario ER, Chang L, Stanczyk FZ, Pike CJ. (2004) Age-related testosterone depletion and the development of Alzheimer disease. JAMA 292(12): 1431–1432

    Article  PubMed  CAS  Google Scholar 

  113. Corpas E, Harman SM, Blackman MR. (1993) Human growth hormone and human aging. Endocr Rev 14:20–39

    PubMed  CAS  Google Scholar 

  114. Hoffman AR, Pyka G, Lieberman SA, et al. (1993) The somatopause. In: Muller EE, Cocchi D, Locatelli V, eds. Growth hormone and somatomedins during lifespan. Berlin: Springer Verlag

    Google Scholar 

  115. Jörgensen JOL, Pedersen SA, Thuesen L, Jørgensen J, Ingemann-Hansen T, Skakkebaek NE, Christiansen JS. (1989) Beneficial effects of GH treatment in GHD adults. Lancet 1:1221–1225.

    Article  PubMed  Google Scholar 

  116. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE. (1990) Effects of human growth hormone in men over 60 years old. N Engl J Med 323:1–6.

    Article  PubMed  CAS  Google Scholar 

  117. Papadakis MA, Grady D, Black D, Tierney MJ, Gooding GA, Schamberlan M, Grunfeld C. (1996) Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Int Med 124:708–716.

    PubMed  CAS  Google Scholar 

  118. Sartorio A, Conti A, Molinari E, Riva G, Morabito F, Faglia G. (1996) Growth, growth hormone and cognitive functions. Horm Res 45:23–29.

    Article  PubMed  CAS  Google Scholar 

  119. Kelijman M. (1991) Age related alterations of the growth hormone/insulin-like growth factor I axis. J Am Geriatr Soc 39:295–307.

    PubMed  CAS  Google Scholar 

  120. Bondy CA, Cheng CM. (2004) Signalling by insulin-like growth factor 1 in brain. Eur J Pharmacol 490:25–31

    Article  PubMed  CAS  Google Scholar 

  121. Carro E, Torrs-Aleman I. (2006) Serum Isulin-like growth factor I in brain function. Keio J Med 55 (2): 59–63

    Article  PubMed  CAS  Google Scholar 

  122. Trejo J, Piriz J, Llorens-Martin MV, Fernandez AM, Bolós M, LeRoith D, Nuñez A, Torres-Aleman I. (2007) Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects. Mol. Psychiatry 12, 1118–1128

    Article  PubMed  CAS  Google Scholar 

  123. Sonntag WE, Bennett SA, Khan AS, Thornton PL, Xu X, Ingram RL, Brunso-Bechtold JK. (2000) Age and insulin-like growth factor-1 modulate N-methyl-Daspartate receptor subtype expression in rats. Brain Res. Bull. 51, 331–338.

    Article  PubMed  CAS  Google Scholar 

  124. Aleman A, Torres-Aleman I. (2009) Circulating insulin-like growth factor I and cognitive function: neuromodulation throughout the lifespan. Progress in Neurobiology 89 256–265

    Google Scholar 

  125. Paolisso G, Ammendola S, Del Buono A, Gambardella A, Riondino M, Tagliamonte MR, Rizzo MR, Carella C, Varricchio M. (1997) Serum levels of insulinlike growth factor-I (IGF-I) and IGF-I binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action and cognitive function. J Clin Endocrinol Metab 82:2204–2209

    Article  PubMed  CAS  Google Scholar 

  126. Aleman A, Verhaar HJJ, de Haan EHF, De Vries WR, Samson MM, Drent ML, Van der Veen EA, Koppeschaar HP. (1999) Insulin-like growth factor-I and cognitive function in healthy older men. J Clin Endocrinol Metab 84:471–475.

    Article  PubMed  CAS  Google Scholar 

  127. Rollero A, Murialdo G, Fonzi S, Garrone S, Gianelli S, Gazzerro E, Barreca A, Polleri A. (1998) Relationship between cognitive function, growth hormone and insulin-like growth factor I plasma levels in aged subjects. Neuropsychobiology 38:73–79.

    Article  PubMed  CAS  Google Scholar 

  128. Abbott D, Rotnem D, Genel M, Cohen DJ. (1982) Cognitive and emotional functioning in hypopituitary short-statured children. Schizophr Bull 8:310–319.

    PubMed  CAS  Google Scholar 

  129. Siegel PT. (1990) Intellectual and academic functioning in children with growth delay. In: Holmes CS, ed. Psychoneuroendocrinology; brain, behavior and hormonal interactions. New York: Springer-Verlag

    Google Scholar 

  130. Deijen JB, de Boer H, Blok GJ, van der Veen EA. (1996) Cognitive impairments and mood disturbances in growth hormone deficient men. Psychoneuroendocrinology 21:313–322

    Article  PubMed  CAS  Google Scholar 

  131. Kalmijn S, Janssen JA, Pols HA, Lamberts SW, Breteler MM. (2000) A prospective study on circulating insulin-like growth factor I (IGF-I), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab Dec;85(12):4551–4555.

    Article  PubMed  CAS  Google Scholar 

  132. Zelissen PMJ, Heijnen VA, Koppeschaar, HPF, De Haan EHF, Hijman R. (1995) Neuropsychological profile in growth hormone deficient adults: preliminary results. In: Von Werder R, Stalla GK, Clemmons DR, Gunnarsson R, eds. Proc 20th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism, Berlin, Sept., 138

  133. Papadakis MA, Grady D, Tierney MJ, Black D, Wells L, Grunfeld C. (1995) Insulinlike growth factor 1 and functional status in healthy older men. J Am Geriatr Soc. 43, 1350–1355

    PubMed  CAS  Google Scholar 

  134. Dik MG, Pluijmm SM, Jonker C, Deeg DJ, Lomecky MZ, Lips P. (2003) Insulinlike growth factor I (IGF-I) and cognitive decline in older persons. Neurobiol. Aging 24, 573–581.

    Article  PubMed  CAS  Google Scholar 

  135. Roberts LM, Pattison H, Roalfe A, Franklyn J, Wilson S, Hobbs FD, Parle JV. (2006) Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann Intern Med 145:573–581

    PubMed  Google Scholar 

  136. Wilson S, Parle JV, Roberts LM, Roalfe AK, Hobbs FD, Clark P, Sheppard MC, Gammage MD, Pattison HM, Franklyn JA; Birmingham Elderly Thyroid Study Team. (2006) Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: A community-based cross-sectional survey. J Clin Endocrinol Metab 9:4809–4816

    Article  CAS  Google Scholar 

  137. Aghini-Lombardi F, Antonangeli L, Marino E, Vitti P, Maccherini D, Leoli F, Rago T, Grasso L, Valeriano R, Balestrieri A, Pinchera A.(1999) The spectrum of thyroid disorders in an iodine-deficient community: The Pescopagano survay. J Clin Endocrinol Metab 84:561–566.

    Article  PubMed  CAS  Google Scholar 

  138. Cooper DS. (2004) Subclinical thyroid disease: consensus or conundrum? Clin Endocrinol 60:410–412.

    Article  Google Scholar 

  139. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ. (2004) Subclinical thyroid disease. Scientific Review and Guidelines for Diagnosis and Management. JAMA 291:228–238.

    Article  PubMed  CAS  Google Scholar 

  140. Trentin GA. (2006) Thyroid hormones and astrocyte morphogenesis. Journal of Endocrinology; 189:189–197.

    Article  PubMed  CAS  Google Scholar 

  141. Nedel Mendes-de-Aguiar CB, Alchini R, Decker H, Alvarez-Silva M, Tasca CI, Trentin AG. (2008) Thyroid hormone Increases Astrocytic Glutamate Uptake and Protects Astrocytes and neurons against Glutamate Toxicity. J Neurosci Res 86;3117-3125.

  142. Ceresini G, Lauretani F, Maggio M, Ceda GP, Moranti S, Usberti E, Chezzi C, Valcavi R, Bandinelli S, Guralnick JM, Cappola AR, Valenti G, Ferrucci L. (2009) Thyroid function abnormalities and cognitive impairment in the elderly. Results of the InCHIANTI study. J Am Geriatr Soc; 57(1):89–93

    Article  PubMed  Google Scholar 

  143. Gussekloo J, vanExel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG. (2004) Thyroid status, disability and cognitive function, and survival in old age. JAMA 292:2591–2599.

    Article  PubMed  CAS  Google Scholar 

  144. Jorde R, Waterloo K, Storhaugh H, Nyrnes A, Sundsfjord J, Jenssen TG. (2006) Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab 91:145–153.

    Article  PubMed  CAS  Google Scholar 

  145. Kalmijn S, Mehta KM, Pols HA, Hofman A, Drexhage HA, Breteler MM. (2000) Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study. Clin Endocrinol 53:733–737.

    Article  CAS  Google Scholar 

  146. Etgen T, Bickel H, Förstl H. (2010) Metabolic and endocrine factors in mild cognitive impairment. Ageing Res Review 9:280–288

    Article  CAS  Google Scholar 

  147. Roberts LM, Pattison H, Roalfe A, Franklyn J, Wilson S, Hobbs FD, Parle JV. (2006) Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann. Intern. Med. 145, 573–581

    PubMed  Google Scholar 

  148. Ceresini G, Lauretani F, Maggio M, Ceda GP, Morganti S, Usberti E, Chezzi C, Valcavi R, Bandinelli S, Guralnik JM, Cappola AR, Valenti G, Ferrucci L. (2009) Thyroid function abnormalities and cognitive impairment in the Elderly. Results of the InCHIANTI Study. J Am Geriatr Soc 57:89–93.

    Article  PubMed  Google Scholar 

  149. Quinlan P, Nordlund A, Lind K, Gustafson D, Edman A, Wallin A. (2010) Thyroid Hormones are associated with poorer cognition in mild cognitive impairment. Dement Geriatr Cogn Disord. 26;30(3):205–211. [Epub ahead of print]

    Article  PubMed  CAS  Google Scholar 

  150. Biondi B, Cooper DS. (2008) The clinical significance of subclinical thyroid dysfunction. Endocr Rev 29:76–131

    Article  PubMed  CAS  Google Scholar 

  151. Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, Heath C, Sheppard M, Franklyn J, Hobbs FD. (2010) A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: The Birmingham Elderly Thyroid Study. J Clin Endocrinol Metab 95:3623–3632

    Article  PubMed  CAS  Google Scholar 

  152. Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, Harper S, Griffith L, Carbotte R. (1996) Does treatment with L-thyroxine influence health status in middle age and older adults with subclinical hypothyroidism? J Gen Intern Med 11:744–749.

    Article  PubMed  CAS  Google Scholar 

  153. Maggio M, Lauretani F, Ceda GP, Bandinelli S, Ling SM, Metter EJ, Artoni A, Carassale L, Cazzato A, Ceresini G, Guralnik JM, Basaria S, Valenti G, Ferrucci L. (2007) Relationship between low levels of anabolic hormones and 6-years mortality in older men: the aging in the Chianti Area (InCHIANTI) Study. Arch Intern Med 167:2249–2254.

    Article  PubMed  CAS  Google Scholar 

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Maggio, M., Dall’Aglio, E., Lauretani, F. et al. The hormonal pathway to cognitive impairment in older men. J Nutr Health Aging 16, 40–54 (2012). https://doi.org/10.1007/s12603-012-0002-7

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