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13 - The hypothalamic–pituitary–adrenal axis: cortisol, DHEA and mental and behavioural function

from Part 3 - Biological and behavioural processes

Published online by Cambridge University Press:  17 September 2009

By
Ian M. Goodyer
Edited by
Andrew Steptoe
Ian M. Goodyer
Affiliation:
Developmental Psychiatry Section, Department of Psychiatry, Cambridge University, Cambridge, UK
Andrew Steptoe
Affiliation:
University College London
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Summary

Introduction

Steroids are an extensive family of chemical agents distributed widely in the brain. They include the classical stress hormone cortisol, oestradiol, testosterone and progesterone (collectively known as the sex hormones), aldosterone and dehydroepiandrosterone (DHEA). Cortisol and DHEA are the most implicated in the response to demand. Both have a high density in the limbic system but are also found in the cortex. Circulating levels of steroids can be measured relatively easily in the periphery from blood, urine and saliva. These peripheral levels are correlated with levels in the cerebrospinal and ventricular fluid in the brain [1]. There is clear-cut evidence that certain steroids are manufactured in the brain and play a key role in brain development and plasticity [2]. These steroids include DHEA and its sulphate DHEAS. Within the brain, these neurosteroids modulate the effects of other transmitters, including gamma-aminobutyric acid (GABA) and glutamate. Neurosteroids can, therefore, alter neuronal excitability throughout the brain very rapidly by binding to receptors for inhibitory or excitatory neurotransmitters at the cell membrane. Alterations in levels of the adrenal steroids cortisol and DHEA have important implications for general cognitive and emotional function. These effects are brought about through altered sensitivity in receptors in steroid-sensitive areas of the brain, notably the limbic system, and their related frontal regions.

Cortisol, DHEA and the brain

Since the 1980s it has become increasingly apparent that steroids have key functions in the brain.

Keywords

behavioural patternsbenzodiazepine systemscortisoldehydroepiandrosteronehypothalamic-pituitary-adrenal axissevere conduct disordersglucocorticoid genetic variationgamma-aminobutyric acidsteroids
Type
Chapter
Information
Depression and Physical Illness , pp. 280 - 298
Publisher: Cambridge University Press
Print publication year: 2006

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References

Guazzo, E. P., Kirkpatrick, P. J., Goodyer, I. M., Shiers, S., Herbert, J., Cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age. J. Clin. Endocrinol. Metab. 81 (1996), 3951–60.Google Scholar
Baulieu, E. E., Neurosteroids: a novel function of the brain. Psychoneuroendocrinology 23 (1998), 963–87.Google Scholar
Liu, D., Dillon, J. S., Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma membrane receptor coupled to Galpha(i2,3). J. Biol. Chem. 277 (2002), 21 379–88.Google Scholar
Karishma, K. K., Herbert, J., Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression. Eur. J. Neurosci. 16 (2002), 445–53.Google Scholar
Kimonides, V. G., Spillantini, M. G., Sofroniew, M. V., Fawcett, J. W., Herbert, J., Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures. Neuroscience 89 (1999), 429–36.Google Scholar
Kimonides, V. G., Khatibi, N. H., Svendsen, C. N., Sofroniew, M. V., Herbert, J., Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc. Natl. Acad. Sci. U. S. A. 95 (1998), 1852–7.Google Scholar
Chalmers, D. T., Kwak, S. P., Mansour, A., Akil, H., Watson, S. J., Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression. J. Neurosci. 13 (1993), 914–23.Google Scholar
Wissink, S., Meijers, O., Pearce, D., Berg, B., Saag, P., Regulation of the rat serotonin-1A receptor gene by corticosteroids. J. Biol. Chem. 275 (2000), 1321–6.Google Scholar
Rosmond, R., Chagnon, Y. C., Chagnon, M., et al., A polymorphism of the 5′-flanking region of the glucocorticoid receptor gene locus is associated with basal cortisol secretion in men. Metabolism 49 (2000), 1197–9.Google Scholar
Rosmond, R., Chagnon, M., Bouchard, C., Bjorntorp, P., A polymorphism in the regulatory region of the corticotropin-releasing hormone gene in relation to cortisol secretion, obesity, and gene–gene interaction. Metabolism 50 (2001), 1059–62.Google Scholar
Nemeroff, C. B., New directions in the development of antidepressants: the interface of neurobiology and psychiatry. Hum. Psychopharmacol. 17: Suppl 1 (2002), 13–16.Google Scholar
Smoller, J. W., Rosenbaum, J. F., Biederman, J., et al., Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition. Biol. Psychiatry 54 (2003), 1376–81.Google Scholar
Smoller, J. W., Rosenbaum, J. F., Biederman, J., et al., Genetic association analysis of behavioral inhibition using candidate loci from mouse models. Am. J. Med. Genet. 105 (2001), 226–35.Google Scholar
Challis, B. G., Luan, J., Keogh, J., et al., Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians. Int. J. Obes. Relat. Metab. Disord. 28 (2004), 442–6.Google Scholar
Gunnar, M. R., Donzella, B., Social regulation of the cortisol levels in early human development. Psychoneuroendocrinology 27 (2002), 199–220.Google Scholar
Bartels, M., Geus, E. J., Kirschbaum, C., Sluyter, F., Boomsma, D. I., Heritability of daytime cortisol levels in children. Behav. Genet. 33 (2003), 421–33.Google Scholar
Linkowski, P., Onderbergen, A., Kerkhofs, M., et al., Twin study of the 24-h cortisol profile: evidence for genetic control of the human circadian clock. Am. J. Physiol. 264 (1993), E173–81.Google Scholar
Meikle, A. W., Stringham, J. D., Woodward, M. G., Bishop, D. T., Heritability of variation of plasma cortisol levels. Metabolism 37 (1988), 514–17.Google Scholar
Goodyer, I. M., Herbert, J., Altham, P. M. E., et al., Adrenal secretion during major depression in 8 to 16 year olds: I. Altered diurnal rhythms in salivary cortisol and dehydroepiandrosterone (DHEA) at presentation. Psychol. Med. 19 (1996), 245–56.Google Scholar
Kirschbaum, C., Hellhammer, D., Salivary cortisol in psychoendocrine research: recent developments and applications. Psychoneuroendocrinology 19 (1994), 313–33.Google Scholar
Goodyer, I. M., Herbert, J., Tamplin, A., Altham, P. M., First-episode major depression in adolescents: affective, cognitive and endocrine characteristics of risk status and predictors of onset. Br. J. Psychiatry 176 (2000), 142–9.Google Scholar
Gunnar, M. R., Quality of early care and buffering of neuroendocrine stress reactions: potential effects on the developing human brain. Prev. Med. 27 (1998), 208–11.Google Scholar
Pruessner, J. C., Wolf, O. T., Hellhammer, D. H., et al., Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. Life Sci. 61 (1997), 2539–49.Google Scholar
Pruessner, J. C., Hellhammer, D. H., Kirschbaum, C., Burnout, perceived stress, and cortisol responses to awakening. Psychosom. Med. 61 (1999), 197–204.Google Scholar
Plotsky, P. M., Owens, M. J., Nemeroff, C. B., Psychoneuroendocrinology of depression: hypothalamic-pituitary-adrenal axis. Psychiatr. Clin. North Am. 21 (1998), 293–307.Google Scholar
Deuschle, M., Schweiger, U., Gotthardt, U., et al., The combined dexamethasone/corticotropin-releasing hormone stimulation test is more closely associated with features of diurnal activity of the hypothalamo-pituitary-adrenocortical system than the dexamethasone suppression test. Biol. Psychiatry 43 (1998), 762–6.Google Scholar
Watson, S., Gallagher, P., Del-Estal, D., et al., Hypothalamic-pituitary-adrenal axis function in patients with chronic depression. Psychol. Med. 32 (2002), 1021–8.Google Scholar
Park, S. B., Williamson, D. J., Cowen, P. J., 5-HT neuroendocrine function in major depression: prolactin and cortisol responses to d-fenfluramine. Psychol. Med. 26 (1996), 1191–6.Google Scholar
Goodyer, I. M., Herbert, J., Tamplin, A., Altham, P. M., Recent life events, cortisol, dehydroepiandrosterone and the onset of major depression in high-risk adolescents. Br. J. Psychiatry 177 (2000), 499–504.Google Scholar
Harris, T. O., Borsanyi, S., Messari, S., et al., Morning cortisol as a risk factor for subsequent major depressive disorder in adult women. Br. J. Psychiatry 177 (2000), 505–10.Google Scholar
Strickland, P. L., Deakin, J. F., Percival, C., et al., Bio-social origins of depression in the community: interactions between a. dversity. social, cortisol and serotonin neurotransmission. Br. J. Psychiatry 180 (2002), 168–73.Google Scholar
Goodyer, I. M., Herbert, J., Tamplin, A., Psychoendocrine antecedents of persistent first-episode major depression in adolescents: a community-based longitudinal enquiry. Psychol. Med. 33 (2003), 601–10.Google Scholar
Newcomer, J. W., Selke, G., Melson, A. K., et al., Decreased memory performance in healthy humans induced by stress-level cortisol treatment. Arch. Gen. Psychiatry 56 (1999), 527–33.Google Scholar
Lupien, S. J., Wilkinson, C. W., Briere, S., et al., The modulatory effects of corticosteroids on cognition: studies in young human populations. Psychoneuroendocrinology 27 (2002), 401–16.Google Scholar
Lupien, S. J., Lepage, M., Stress, memory, and the hippocampus: can't live with it, can't live without it. Behav. Brain Res. 127 (2001), 137–58.Google Scholar
Lupien, S. J., King, S., Meaney, M. J., McEwen, B. S., Can poverty get under your skin? Basal cortisol levels and cognitive function in children from low and high socioeconomic status. Devel. Psychopathol. 13 (2001), 653–76.Google Scholar
Lupien, S. J., Wilkinson, C. W., Briere, S., et al., Acute modulation of aged human memory by pharmacological manipulation of glucocorticoids. J. Clin. Endocrinol. Metab. 87 (2002), 3798–807.Google Scholar
Lupien, S. J., King, S., Meaney, M. J., McEwen, B. S., Child's stress hormone levels correlate with mother's socioeconomic status and depressive state. Biol. Psychiatry 48 (2000), 976–80.Google Scholar
Drevets, W. C., Neuroimaging abnormalities in the amygdala in mood disorders. Ann. N. Y. Acad. Sci. 985 (2003), 420–44.Google Scholar
Seminowicz, D. A., Mayberg, H. S., McIntosh, A. R., et al., Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 22 (2004), 409–18.Google Scholar
Liotti, M., Mayberg, H. S., Brannan, S. K., et al., Differential limbic–cortical correlates of sadness and anxiety in healthy subjects: implication for affective disorders. Biol. Psychiatry 48 (2000), 30–42.Google Scholar
Meyer, J. H., Kapur, S., Eisfeld, B., et al., The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. Am. J. Psychiatry 158 (2001), 78–85.Google Scholar
Wust, S., Rossum, E. F., Federenko, I. S., et al., Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J. Clin. Endocrinol. Metab. 89 (2004), 565–73.Google Scholar
Stevens, A., Ray, D. W., Zeggini, E., et al., Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype. J. Clin. Endocrinol. Metab. 89 (2004), 892–7.Google Scholar
Rossum, E. F., Voorhoeve, P. G., Velde, S. J. te, et al., The ER22/23EK polymorphism in the glucocorticoid receptor gene is associated with a beneficial body composition and muscle strength in young adults. J. Clin. Endocrinol. Metab. 89 (2004), 4004–4009.Google Scholar
Rossum, E. F., Koper, J. W., Beld, A. W., et al., Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin. Endocrinol. (Oxf.) 59 (2003), 585–92.Google Scholar
Kroboth, P. D., Salek, F. S., Pittenger, A. L., Fabian, T. J., Frye, R. F., DHEA and DHEA-S: a review. J. Clin. Pharmacol. 39 (1999), 327–48.Google Scholar
Parker, C. R., Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging. Steroids 64 (1999), 640–47.Google Scholar
Labrie, F., Belanger, A., Cusan, L., Gomez, J. L., Candas, B., Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J. Clin. Endocrinol. Metab. 82 (1997), 2396–402.Google Scholar
Kroboth, P. D., Amico, J. A., Stone, R. A., et al., Influence of DHEA administration on 24-hour cortisol concentrations. J. Clin. Psychopharmacol. 23 (2003), 96–9.Google Scholar
Goodyer, I. M., Park, R. J., Herbert, J., Psychosocial and endocrine features of chronic first-episode major depression in 8–16 year olds. Biol. Psychiatry 50 (2001), 351–7.Google Scholar
Beishuizen, A., Thijs, L. G., Vermes, I., Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve?Crit. Care 6 (2002), 434–8.Google Scholar
Marx, C., Petros, S., Bornstein, S. R., et al., Adrenocortical hormones in survivors and nonsurvivors of severe sepsis: diverse time course of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol. Crit. Care Med. 31 (2003), 1382–8.Google Scholar
Huppert, F. A., Niekerk, J. K., Dehydroepiandrosterone (DHEA) supplementation for cognitive function. Cochrane Database Syst. Rev. 2 (2001), CD000304.Google Scholar
Hunt, P. J., Gurnell, E. M., Huppert, F. A., et al., Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison's disease in a randomized, double blind trial. J. Clin. Endocrinol. Metab. 85 (2000), 4650–56.Google Scholar
Niekerk, J. K., Huppert, F. A., Herbert, J., 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 (2001), 591–612.Google Scholar
Wolkowitz, O. M., Reus, V. I., Keebler, A., et al., Double-blind treatment of major depression with dehydroepiandrosterone. Am. J. Psychiatry 156 (1999), 646–9.Google Scholar
Strous, R. D., Maayan, R., Lapidus, R., et al., Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch. Gen. Psychiatry 60 (2003), 133–41.Google Scholar
Weaver, I. C., Cervoni, N., Champagne, F. A., et al., Epigenetic programming by maternal behavior. Nat. Neurosci. 7 (2004), 847–54.Google Scholar
Halligan, S. L., Herbert, J., Goodyer, I. M., Murray, L., Exposure to postnatal depression predicts elevated cortisol in adolescent offspring. Biol. Psychiatry 55 (2004), 376–81.Google Scholar
Champoux, M., Bennett, A., Shannon, C., et al., Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Mol. Psychiatry 7 (2002), 1058–63.Google Scholar
Caspi, A., Sugden, K., Moffitt, T. E., et al., Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301 (2003), 386–9.Google Scholar
Gunnar, M. R., Morison, S. J., Chisholm, K., Schuder, M., Salivary cortisol levels in children adopted from Romanian orphanages. Dev. Psychopathol. 13 (2001), 611–28.Google Scholar
Yehuda, R., Halligan, S. L., Golier, J. A., Grossman, R., Bierer, L. M., Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder. Psychoneuroendocrinology 29 (2004), 389–404.Google Scholar
Loeber, R., Green, S. M., Lahey, B. B., Frick, P. J., McBurnett, K., Findings on disruptive behavior disorders from the first decade of the Developmental Trends Study. Clin. Child. Fam. Psychol. Rev. 3 (2000), 37–60.Google Scholar
Pajer, K., Gardner, W., Rubin, R. T., Perel, J., Neal, S., Decreased cortisol levels in adolescent girls with conduct disorder. Arch. Gen. Psychiatry 58 (2001), 297–302.Google Scholar
Stone, A. A., Schwartz, J. E., Smyth, J., et al., Individual differences in the diurnal cycle of salivary free cortisol: a replication of flattened cycles for some individuals. Psychoneuroendocrinology 26 (2001), 295–306.Google Scholar
Goozen, S. H., Matthys, W., Cohen-Kettenis, P. T., et al., Salivary cortisol and cardiovascular activity during stress in oppositional-defiant disorder boys and normal controls. Biol. Psychiatry 43 (1998), 531–9.Google Scholar
Goozen, S. H., Matthys, W., Cohen-Kettenis, P. T., Buitelaar, J. K., Engeland, H., Hypothalamic-pituitary-adrenal axis and autonomic nervous system activity in disruptive children and matched controls. J. Am. Acad. Child. Adolesc. Psychiatry 39 (2000), 1438–45.Google Scholar
Raine, A., Venables, P. H., Mednick, S. A., Low resting heart rate at age 3 years predisposes to aggression at age 11 years: evidence from the Mauritius Child Health Project. J. Am. Acad. Child. Adolesc. Psychiatry 36 (1997), 1457–64.Google Scholar
Raine, A., Reynolds, C., Venables, P. H., Mednick, S. A., Farrington, D. P., Fearlessness, stimulation-seeking, and large body size at age 3 years as early predispositions to childhood aggression at age 11 years. Arch. Gen. Psychiatry 55 (1998), 745–51.Google Scholar
Blair, R. J., Colledge, E., Murray, L., Mitchell, D. G., A selective impairment in the processing of sad and fearful expressions in children with psychopathic tendencies. J. Abnorm. Child Psychol. 29 (2001), 491–8.Google Scholar
Raine, A., Lencz, T., Bihrle, S., LaCasse, L., Colletti, P., Reduced prefrontal gray matter volume and reduced autonomic activity in antisocial personality disorder. Arch. Gen. Psychiatry 57 (2000), 119–27.Google Scholar
Dolan, M., Deakin, W. J., Roberts, N., Anderson, I., Serotonergic and cognitive impairment in impulsive aggressive personality disordered offenders: are there implications for treatment?Psychol. Med. 32 (2002), 105–17.Google Scholar
DeRijk, R., Schaaf, M., Kloet, E., Glucocorticoid receptor variants: clinical implications. J. Steroid. Biochem. Mol. Biol. 81 (2002), 103–22.Google Scholar
Raison, C. L., Miller, A. H., When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am. J. Psychiatry 160 (2003), 1554–65.Google Scholar

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