Seminars in Oncology
Volume 35, Issue 6 , Pages 569-581 , December 2008

Cognitive Effects of Hormonal Therapy in Older Adults

  • Nicholas Mitsiades

      Affiliations

    • Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
  • ,
  • Denise Correa

      Affiliations

    • Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY
  • ,
  • Cary P. Gross

      Affiliations

    • Section of General Internal Medicine, Department of Medicine, Robert Wood Johnson Clinical Scholars Program, Yale University School of Medicine, New Haven, CT
  • ,
  • Arti Hurria

      Affiliations

    • Cancer and Aging Research Program, City of Hope, Duarte, CA
  • ,
  • Susan F. Slovin

      Affiliations

    • Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
    • Corresponding Author InformationAddress correspondence to Susan F. Slovin, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065

References 

  1. Janowsky JS. Thinking with your gonads: testosterone and cognition. Trends Cogn Sci. 2006;10:77–82
  2. Jenkins V, Atkins L, Fallowfield L. Does endocrine therapy for the treatment and prevention of breast cancer affect memory and cognition?. Eur J Cancer. 2007;43:1342–1347
  3. Sherwin BB. Estrogen and cognitive functioning in women. Endocr Rev. 2003;24:133–151
  4. McEwen BS, Alves SE. Estrogen actions in the central nervous system. Endocr Rev. 1999;20:279–307
  5. Roselli CE, Klosterman SA, Fasasi TA. Sex differences in androgen responsiveness in the rat brain: regional differences in the induction of aromatase activity. Neuroendocrinology. 1996;64:139–145
  6. Chowen JA, Torres-Aleman I, Garcia-Segura LM. Trophic effects of estradiol on fetal rat hypothalamic neurons. Neuroendocrinology. 1992;56:895–901
  7. Zaulyanov LL, Green PS, Simpkins JW. Glutamate receptor requirement for neuronal death from anoxia-reoxygenation: an in vitro model for assessment of the neuroprotective effects of estrogens. Cell Mol Neurobiol. 1999;19:705–718
  8. Behl C, Skutella T, Lezoualc'h F, Post A, Widmann M, Newton CJ, et al. Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol. 1997;51:535–541
  9. Simpkins JW, Rajakumar G, Zhang YQ, Simpkins CE, Greenwald D, Yu CJ, et al. Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J Neurosurg. 1997;87:724–730
  10. Fugger HN, Foster TC, Gustafsson J, Rissman EF. Novel effects of estradiol and estrogen receptor alpha and beta on cognitive function. Brain Res. 2000;883:258–264
  11. McCullough LD, Blizzard K, Simpson ER, Oz OK, Hurn PD. Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection. J Neurosci. 2003;23:8701–8705
  12. Azcoitia I, Sierra A, Veiga S, Honda S, Harada N, Garcia-Segura LM. Brain aromatase is neuroprotective. J Neurobiol. 2001;47:318–329
  13. Beyenburg S, Watzka M, Clusmann H, Blumcke I, Bidlingmaier F, Elger CE, et al. Androgen receptor mRNA expression in the human hippocampus. Neurosci Lett. 2000;294:25–28
  14. Celotti F, Negri-Cesi P, Poletti A. Steroid metabolism in the mammalian brain: 5alpha-reduction and aromatization. Brain Res Bull. 1997;44:365–375
  15. Hojo Y, Hattori TA, Enami T, Furukawa A, Suzuki K, Ishii HT, et al. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons. Proc Natl Acad Sci U S A. 2004;101:865–870
  16. Zwain IH, Yen SS. Dehydroepiandrosterone: biosynthesis and metabolism in the brain. Endocrinology. 1999;140:880–887
  17. Tirassa P, Thiblin I, Agren G, Vigneti E, Aloe L, Stenfors C. 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. 1997;47:198–207
  18. Pouliot WA, Handa RJ, Beck SG. Androgen modulates N-methyl-D-aspartate-mediated depolarization in CA1 hippocampal pyramidal cells. Synapse. 1996;23:10–19
  19. Ahlbom E, Prins GS, Ceccatelli S. Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism. Brain Res. 2001;892:255–262
  20. Leranth C, Prange-Kiel J, Frick KM, Horvath TL. Low CA1 spine synapse density is further reduced by castration in male non-human primates. Cereb Cortex. 2004;14:503–510
  21. Leranth C, Petnehazy O, MacLusky NJ. Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci. 2003;23:1588–1592
  22. Fuller SJ, Tan RS, Martins RN. Androgens in the etiology of Alzheimer's disease in aging men and possible therapeutic interventions. J Alzheimers Dis. 2007;12:129–142
  23. Gouras GK, Xu H, Gross RS, Greenfield JP, Hai B, Wang R, et al. Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci U S A. 2000;97:1202–1205
  24. Ramsden M, Nyborg AC, Murphy MP, Chang L, Stanczyk FZ, Golde TE. Androgens modulate beta-amyloid levels in male rat brain. J Neurochem. 2003;87:1052–1055
  25. Pike CJ. Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons. Brain Res. 2001;919:160–165
  26. Goodenough S, Engert S, Behl C. Testosterone stimulates rapid secretory amyloid precursor protein release from rat hypothalamic cells via the activation of the mitogen-activated protein kinase pathway. Neurosci Lett. 2000;296:49–52
  27. Papasozomenos SC. The heat shock-induced hyperphosphorylation of tau is estrogen-independent and prevented by androgens: implications for Alzheimer disease. Proc Natl Acad Sci U S A. 1997;94:6612–6617
  28. Petanceska SS, Nagy V, Frail D, Gandy S. Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain. Exp Gerontol. 2000;35:1317–13252000
  29. Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD. Serum total testosterone is lower in men with Alzheimer's disease. Neuro Endocrinol Lett. 2001;22:163–168
  30. Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, et al. Free testosterone and risk for Alzheimer disease in older men. Neurology. 2004;62:188–193
  31. Hogervorst E, Bandelow S, Combrinck M, Smith AD. Low free testosterone is an independent risk factor for Alzheimer's disease. Exp Gerontol. 2004;39:1633–1639
  32. Almeida OP, Waterreus A, Spry N, Flicker L, Martins RN. One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men. Psychoneuroendocrinology. 2004;29:1071–1081
  33. Lessov-Schlaggar CN, Reed T, Swan GE, Krasnow RE, DeCarli C, Marcus R, et al. Association of sex steroid hormones with brain morphology and cognition in healthy elderly men. Neurology. 2005;65:1591–1596
  34. Geerlings MI, Strozyk D, Masaki K, Remaley AT, Petrovitch H, Ross GW, et al. Endogenous sex hormones, cognitive decline, and future dementia in old men. Ann Neurol. 2006;60:346–355
  35. Rabbitt P, Lowe C. Patterns of cognitive ageing. Psychol Res. 2000;63:308–316
  36. Sherwin BB. The clinical relevance of the relationship between estrogen and cognition in women. J Steroid Biochem Mol Biol. 2007;106:151–156
  37. Maki PM. Estrogen effects on the hippocampus and frontal lobes. Int J Fertil Womens Med. 2005;50:67–71
  38. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA. 2001;285:1489–1499
  39. Haskell SG, Richardson ED, Horwitz RI. The effect of estrogen replacement therapy on cognitive function in women: a critical review of the literature. J Clin Epidemiol. 1997;50:1249–1264
  40. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology. 1988;13:345–357
  41. Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology. 1992;17:485–495
  42. Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E. Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Am J Med. 2002;113:543–548
  43. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. 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. 2003;289:2651–2662
  44. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321–333
  45. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701–1712
  46. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291:2947–2958
  47. Duka T, Tasker R, McGowan JF. The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females. Psychopharmacology (Berl). 2000;149:129–139
  48. Sherwin BB. The critical period hypothesis: can it explain discrepancies in the oestrogen-cognition literature?. J Neuroendocrinol. 2007;19:77–81
  49. Adams MM, Shah RA, Janssen WG, Morrison JH. Different modes of hippocampal plasticity in response to estrogen in young and aged female rats. Proc Natl Acad Sci U S A. 2001;98:8071–8076
  50. Gibbs RB. Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. Neurobiol Aging. 2000;21:107–116
  51. Jezierski MK, Sohrabji F. Neurotrophin expression in the reproductively senescent forebrain is refractory to estrogen stimulation. Neurobiol Aging. 2001;22:309–319
  52. Matthews K, Cauley J, Yaffe K, Zmuda JM. Estrogen replacement therapy and cognitive decline in older community women. J Am Geriatr Soc. 1999;47:518–523
  53. MacLennan AH, Henderson VW, Paine BJ, Mathias J, Ramsay EN, Ryan P, et al. Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study. Menopause. 2006;13:28–36
  54. Henderson VW, Guthrie JR, Dudley EC, Burger HG, Dennerstein L. Estrogen exposures and memory at midlife: a population-based study of women. Neurology. 2003;60:1369–1371
  55. Maki PM. Hormone therapy and cognitive function: is there a critical period for benefit?. Neuroscience. 2006;138:1027–1030
  56. Eberling JL, Wu C, Tong-Turnbeaugh R, Jagust WJ. Estrogen- and tamoxifen-associated effects on brain structure and function. Neuroimage. 2004;21:364–371
  57. Paganini-Hill A, Clark LJ. Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat. 2000;64:165–176
  58. Bender CM, Sereika SM, Berga SL, Vogel VG, Brufsky AM, Paraska KK, et al. Cognitive impairment associated with adjuvant therapy in breast cancer. Psychooncology. 2006;15:422–430
  59. Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359:2131–2139
  60. Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S. Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? (A pilot study). Psychooncology. 2004;13:61–66
  61. Shilling V, Jenkins V, Fallowfield L, Howell T. The effects of hormone therapy on cognition in breast cancer. J Steroid Biochem Mol Biol. 2003;86:405–412
  62. Bender CM, Sereika SM, Brufsky AM, Ryan CM, Vogel VG, Rastogi P, et al. Memory impairments with adjuvant anastrozole versus tamoxifen in women with early-stage breast cancer. Menopause. 2007;14:995–998
  63. Juul A, Skakkebaek NE. Androgens and the ageing male. Hum Reprod Update. 2002;8:423–433
  64. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005;26:833–876
  65. Lamberts SW, van den Beld AW, van der Lely AJ. The endocrinology of aging. Science. 1997;278:419–424
  66. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men (Baltimore Longitudinal Study of Aging). J Clin Endocrinol Metab. 2001;86:724–731
  67. Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM. Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab. 2002;87:5001–5007
  68. Yaffe K, Lui LY, Zmuda J, Cauley J. Sex hormones and cognitive function in older men. J Am Geriatr Soc. 2002;50:707–712
  69. Fonda SJ, Bertrand R, O'Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci. 2005;60:385–390
  70. Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, et al. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology. 2001;57:80–88
  71. Cherrier MM, Matsumoto AM, Amory JK, Ahmed S, Bremner W, Peskind ER, et al. The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology. 2005;64:290–296
  72. Janowsky JS, Chavez B, Orwoll E. Sex steroids modify working memory. J Cogn Neurosci. 2000;12:407–414
  73. Janowsky JS, Oviatt SK, Orwoll ES. Testosterone influences spatial cognition in older men. Behav Neurosci. 1994;108:325–332
  74. Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab. 1999;84:3681–3685
  75. Moffat SD, Hampson E. A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference. Psychoneuroendocrinology. 1996;21:323–337
  76. Muller M, Aleman A, Grobbee DE, de Haan EH, van der Schouw YT. Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level?. Neurology. 2005;64:866–871
  77. Sih R, Morley JE, Kaiser FE, Perry HM, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997;82:1661–1667
  78. Kenny AM, Bellantonio S, Gruman CA, Acosta RD, Prestwood KM. 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. 2002;57:M321–M325
  79. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA. 2008;299:39–52
  80. Vaughan C, Goldstein FC, Tenover JL. Exogenous testosterone alone or with finasteride does not improve measurements of cognition in healthy older men with low serum testosterone. J Androl. 2007;28:875–882
  81. Alibhai SM, Gogov S, Allibhai Z. Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review. Crit Rev Oncol Hematol. 2006;60:201–215
  82. Jenkins VA, Bloomfield DJ, Shilling VM, Edginton TL. Does neoadjuvant hormone therapy for early prostate cancer affect cognition? (Results from a pilot study). BJU Int. 2005;96:48–53
  83. Salminen EK, Portin RI, Koskinen A, Helenius H, Nurmi M. Associations between serum testosterone fall and cognitive function in prostate cancer patients. Clin Cancer Res. 2004;10:7575–7582
  84. Salminen E, Portin R, Korpela J, Backman H, Parvinen LM, Helenius H, et al. Androgen deprivation and cognition in prostate cancer. Br J Cancer. 2003;89:971–976
  85. Cherrier MM, Rose AL, Higano C. The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer. J Urol. 2003;170:1808–1811
  86. Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, et al. Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU Int. 2002;90:427–432
  87. Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, et al. Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial. BJU Int. 2004;93:975–979
  88. Joly F, Alibhai SM, Galica J, Park A, Yi QL, Wagner L, et al. Impact of androgen deprivation therapy on physical and cognitive function, as well as quality of life of patients with nonmetastatic prostate cancer. J Urol. 2006;176:2443–2447
  89. Taxel P, Stevens MC, Trahiotis M, Zimmerman J, Kaplan RF. The effect of short-term estradiol therapy on cognitive function in older men receiving hormonal suppression therapy for prostate cancer. J Am Geriatr Soc. 2004;52:269–273
  90. Vardy J, Wefel JS, Ahles T, Tannock IF, Schagen SB. Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop. Ann Oncol. 2008;19:623–629

PII: S0093-7754(08)00185-1

doi: 10.1053/j.seminoncol.2008.08.002

Seminars in Oncology
Volume 35, Issue 6 , Pages 569-581 , December 2008