The role of androgens in cognition and brain aging in men

Losses of working and long-term memory are hallmarks of human aging and may signal impending neurodegenerative disease. The maintenance of neural elements in brain systems that support memory, such as synapse formation in prefrontal cortex and hippocampus, are critical for cognitive health in aging. This paper reviews the biological basis for androgens as neuroprotectants or neuromodulators in aging and the importance of androgens on the brain systems important for memory. We relate biological effects to cognitive outcomes in elderly men under a variety of androgen conditions. In brief, androgen deprivation causes significant loss of synapses in the hippocampus in rodent and nonhuman primates, increases amyloid deposition in human and rodent models and causes changes in neurotransmission in prefrontal cortex in rodent models. Recent work suggests that these changes modify age-related cognitive loss, particularly to memory in men. In addition, the conversion of testosterone to its androgen metabolites or to estradiol may play a special role in the preservation of memory in aging. This paper reviews discrepancies between studies using animal models and studies of human cognition, and suggests new directions that are likely to be fruitful in the future for understanding the role of androgens in brain aging. This review suggests that studies of low androgen levels in older men may not index the same biological mechanisms and behavioral effects as the studies of gonadectomy in animal models.

[1]  J. Morrison,et al.  The aging brain: morphomolecular senescence of cortical circuits , 2004, Trends in Neurosciences.

[2]  M. Greicius,et al.  Regional analysis of hippocampal activation during memory encoding and retrieval: fMRI study , 2003, Hippocampus.

[3]  M. Kritzer,et al.  Immunoreactivity for intracellular androgen receptors in identified subpopulations of neurons, astrocytes and oligodendrocytes in primate prefrontal cortex. , 1999, Journal of neurobiology.

[4]  J. Kaye,et al.  Neurologic function in the optimally healthy oldest old , 1993, Neurology.

[5]  A. Dale,et al.  Building memories: remembering and forgetting of verbal experiences as predicted by brain activity. , 1998, Science.

[6]  L. Flicker,et al.  Testosterone and dementia: too much ado about too little data. , 2003 .

[7]  A. Vermeulen.  Clinical review 24: Androgens in the aging male. , 1991, The Journal of clinical endocrinology and metabolism.

[8]  B. Mcewen,et al.  Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat [published erratum appears in J Neurosci 1992 Oct;12(10):following table of contents] , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[9]  L R Squire,et al.  Amnesia, memory and brain systems. , 1997, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[10]  A. Benton,et al.  Frontal Lobe Function and Dysfunction , 1991 .

[11]  J. Simpkins,et al.  The Use of Estrogens and Related Compounds in the Treatment of Damage from Cerebral Ischemia , 2003, Annals of the New York Academy of Sciences.

[12]  J. Janowsky,et al.  Hormone replacement therapy and cognition: systematic review and meta-analysis. , 2001, JAMA.

[13]  E. Barrett-Connor,et al.  Endogenous sex hormones and cognitive function in older men. , 1999, The Journal of clinical endocrinology and metabolism.

[14]  G. Cunningham,et al.  Andropause: is androgen replacement therapy indicated for the aging male? , 2005, Annual review of medicine.

[15]  Holly Soares,et al.  Cerebrospinal fluid β-amyloid1–42 and tau in control subjects at risk for Alzheimer’s disease: The effect of APOE ε4 allele , 2004, Biological Psychiatry.

[16]  B. Sherwin.  Estrogen effects on cognition in menopausal women , 1997, Neurology.

[17]  S. Resnick,et al.  Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. , 2002, The Journal of clinical endocrinology and metabolism.

[18]  C. Frye,et al.  Testosterone's analgesic, anxiolytic, and cognitive-enhancing effects may be due in part to actions of its 5alpha-reduced metabolites in the hippocampus. , 2004, Behavioral neuroscience.

[19]  L. Parvinen,et al.  Androgen deprivation and cognition in prostate cancer , 2003, British Journal of Cancer.

[20]  R. Melcangi,et al.  Testosterone 5 alpha-reductase activity in the rat brain is highly concentrated in white matter structures and in purified myelin sheaths of axons. , 1988, Journal of steroid biochemistry.

[21]  C. Higano,et al.  The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer. , 2003, The Journal of urology.

[22]  R. Rosellini,et al.  The testosterone metabolite and neurosteroid 3α-androstanediol may mediate the effects of testosterone on conditioned place preference , 2001, Psychoneuroendocrinology.

[23]  B. Milner,et al.  Deficits on subject-ordered tasks after frontal- and temporal-lobe lesions in man , 1982, Neuropsychologia.

[24]  P. Taxel,et al.  The Effect of Short‐Term Estradiol Therapy on Cognitive Function in Older Men Receiving Hormonal Suppression Therapy for Prostate Cancer , 2004, Journal of the American Geriatrics Society.

[25]  P. Abel,et al.  Transdermal estradiol therapy for advanced prostate cancer--forward to the past? , 2003, The Journal of urology.

[26]  V. Magnotta,et al.  A Controlled Quantitative MRI Volumetric Investigation of Hippocampal Contributions to Immediate and Delayed Memory Performance , 2003, Journal of clinical and experimental neuropsychology.

[27]  D. Salat,et al.  Selective preservation and degeneration within the prefrontal cortex in aging and Alzheimer disease. , 2001, Archives of neurology.

[28]  R. Casaburi,et al.  Dose-dependent effects of testosterone on sexual function, mood, and visuospatial cognition in older men. , 2005, The Journal of clinical endocrinology and metabolism.

[29]  S. Bhasin,et al.  Mechanisms of gonadotropin-releasing hormone agonist action in the human male. , 1986, Endocrine reviews.

[30]  N. J. Sandstrom,et al.  Memory retention is modulated by acute estradiol and progesterone replacement. , 2001, Behavioral neuroscience.

[31]  L. Squire,et al.  Cognitive impairment following frontal lobe damage and its relevance to human amnesia. , 1989 .

[32]  R. Clark,et al.  The medial temporal lobe. , 2004, Annual review of neuroscience.

[33]  R. Gardiner,et al.  Quality of life compared during pharmacological treatments and clinical monitoring for non‐localized prostate cancer: a randomized controlled trial , 2004, BJU international.

[34]  L. Garcia-Segura,et al.  Role of astroglia in estrogen regulation of synaptic plasticity and brain repair. , 1999, Journal of neurobiology.

[35]  A. Guyton,et al.  Textbook of Medical Physiology , 1961 .

[36]  H. Pols,et al.  The importance of oestrogens in males , 2003, Clinical endocrinology.

[37]  P. Greengard,et al.  Estrogen alters hippocampal dendritic spine shape and enhances synaptic protein immunoreactivity and spatial memory in female mice , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Piérart,et al.  Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. , 1997, The New England journal of medicine.

[39]  J. Janowsky,et al.  Sex Steroids Modify Working Memory , 2000, Journal of Cognitive Neuroscience.

[40]  C. Léránth,et al.  Gonadal Hormones Affect Spine Synaptic Density in the CA1 Hippocampal Subfield of Male Rats , 2003, The Journal of Neuroscience.

[41]  A. Dale,et al.  Age-related alterations in white matter microstructure measured by diffusion tensor imaging , 2005, Neurobiology of Aging.

[42]  S. Resnick,et al.  Free testosterone and risk for Alzheimer disease in older men , 2004, Neurology.

[43]  M J de Leon,et al.  Hippocampal formation size predicts declining memory performance in normal aging , 1996, Neurology.

[44]  S. Asthana,et al.  Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment , 2005, Neurology.

[45]  J. Manola,et al.  Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. , 1999, The New England journal of medicine.

[46]  B. McEwen.  The Molecular and Neuroanatomical Basis for Estrogen Effects in the Central Nervous System , 1999 .

[47]  E. Leblanc,et al.  Hormone Replacement Therapy and Cognition , 2002 .

[48]  R. Gardiner,et al.  Altered cognitive function in men treated for prostate cancer with luteinizing hormone‐releasing hormone analogues and cyproterone acetate: a randomized controlled trial , 2002, BJU international.

[49]  J. Janowsky,et al.  Androgen deprivation impairs memory in older men. , 2005, Behavioral neuroscience.

[50]  O. Schober,et al.  Changes in cerebral glucose metabolism and visuospatial capability in hypogonadal males under testosterone substitution therapy. , 2001, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[51]  L. Light.  Memory and aging: four hypotheses in search of data. , 1991, Annual review of psychology.

[52]  Christian E Elger,et al.  Androgen receptor mRNA expression in the human hippocampus , 2000, Neuroscience Letters.

[53]  L. Chang,et al.  Androgens modulate β‐amyloid levels in male rat brain , 2003 .

[54]  D. Blazer,et al.  Testosterone and Aging , 2004 .

[55]  Joseph R. Manns,et al.  Recognition Memory and the Human Hippocampus , 2003, Neuron.

[56]  R. Tan,et al.  A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer's disease , 2003, The aging male : the official journal of the International Society for the Study of the Aging Male.

[57]  S. Malkowicz.  The role of diethylstilbestrol in the treatment of prostate cancer. , 2001, Urology.

[58]  Tao Lu,et al.  The aging brain. , 2008, Annual review of pathology.

[59]  W. Rosner,et al.  Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. , 1995, The Journal of clinical endocrinology and metabolism.

[60]  R. Martins,et al.  One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men , 2004, Psychoneuroendocrinology.

[61]  B. Dudek,et al.  Estradiol to aged female or male mice improves learning in inhibitory avoidance and water maze tasks , 2005, Brain Research.

[62]  Eleanor A Maguire,et al.  The brain network associated with acquiring semantic knowledge , 2004, NeuroImage.

[63]  C. Reynolds,et al.  Wechsler memory scale-revised , 1988 .

[64]  P. Wise,et al.  Are estrogens protective or risk factors in brain injury and neurodegeneration? Reevaluation after the Women's health initiative. , 2005, Endocrine reviews.

[65]  J. Janowsky,et al.  Testosterone influences spatial cognition in older men. , 1994, Behavioral neuroscience.

[66]  C. Roselli,et al.  Anatomic relationships between aromatase and androgen receptor mRNA expression in the hypothalamus and amygdala of adult male cynomolgus monkeys , 2001, The Journal of comparative neurology.

[67]  A. Smith,et al.  Testosterone and gonadotropin levels in men with dementia. , 2003, Neuro endocrinology letters.

[68]  M. Barry,et al.  Androgen deprivation therapy for asymptomatic advanced prostate cancer in the prostate specific antigen era: a national survey of urologist beliefs and practices. , 1998, The Journal of urology.

[69]  E. Peskind,et al.  The role of aromatization in testosterone supplementation , 2005, Neurology.

[70]  S. Yen,et al.  Endocrine function of the postmenopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood. , 1974, The Journal of clinical endocrinology and metabolism.

[71]  Walter J. Greenleaf,et al.  Hormonal changes and sexual function in aging men. , 1983, The Journal of clinical endocrinology and metabolism.

[72]  Elizabeth A. Kensinger,et al.  What Neural Correlates Underlie Successful Encoding and Retrieval? A Functional Magnetic Resonance Imaging Study Using a Divided Attention Paradigm , 2003, The Journal of Neuroscience.

[73]  S. Craft,et al.  Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report. , 2003, Journal of andrology.

[74]  E. D. de Haan,et al.  Endogenous sex hormone levels and cognitive function in aging men , 2005, Neurology.

[75]  W. E. Barnes,et al.  Testosterone treatment enhances regional brain perfusion in hypogonadal men. , 2003, The Journal of clinical endocrinology and metabolism.

[76]  Leah L. Light,et al.  Memory and Aging , 1996 .

[77]  C. Léránth,et al.  Low CA1 spine synapse density is further reduced by castration in male non-human primates. , 2004, Cerebral cortex.

[78]  M. Kritzer,et al.  Gonadectomy Impairs T-Maze Acquisition in Adult Male Rats , 2001, Hormones and Behavior.