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Vol. 75, No. 4, 2002
Issue release date: April 2002
Neuroendocrinology 2002;75:241–249

Basal Hypothalamo-Pituitary-Adrenal Axis Activity and Corticotropin Feedback in Young and Older Men: Relationships to Magnetic Resonance Imaging-Derived Hippocampus and Cingulate Gyrus Volumes

Wolf O.T. · Convit A. · de Leon M.J. · Caraos C. · Qadri S.F.
aCenter for Brain Health, New York University School of Medicine, New York, N.Y., and bNathan Kline Institute for Psychiatric Research, Orangeburg, N.Y., USA

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Alterations in basal cortisol secretion and feedback sensitivity are reported in aging. However, it is not known whether these hypothalamus-pituitary-adrenal (HPA) axis alterations are related to structural brain changes. This study was designed to investigate these relationships in the human. Nine young (24.0 ± 1.2 years; mean ± SE; range: 19–30) and 11 older (69.0 ± 1.8 years; range: 59–76) men, in addition to having standardized magnetic resonance imaging of their brains, were given 0.5 mg/kg cortisol or placebo intravenously in a double-blind, crossover study. As expected, older men had significantly smaller volumes for all brain regions. Although the groups did not differ in baseline HPA axis activity, there were significant and specific relationships between the brain volumes and the baseline measures of HPA activity. Namely, for young and older subjects combined and after controlling for age and cerebral vault size, hippocampal volumes were inversely associated with 24-hour urinary cortisol and basal corticotropin (ACTH) levels, and the anterior cingulate gyrus volume was negatively correlated with baseline ACTH. Elderly subjects had a slower decrease in ACTH levels (percent of baseline level) during the first 30 min after cortisol administration. However, no associations were observed between the ACTH feedback indices and any brain measure. This report, although based on a small number of subjects, supports previous studies showing a blunted ACTH fast feedback during normal aging. Hippocampal atrophy appears to be related to increased basal measures of HPA axis activity, but not to fast ACTH feedback. It remains possible that age-associated changes in fast feedback may be related to changes to other brain sites, such as hypothalamus or pituitary.

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  1. Sapolsky RM: Do glucocorticoid concentrations rise with age in the rat? Neurobiol Aging 1992;13:171–174.
  2. Sapolsky RM, Krey LC, McEwen BS: The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocr Rev 1986;7:284–301.
  3. Seeman TE, Robbins RJ: Aging and hypothalamic-pituitary-adrenal response to challenge in humans. Endocr Rev 1994;15:233–260.
  4. Dodt C, Theine KJ, Uthgenannt D, Born J, Fehm HL: Basal secretory activity of the hypothalamo-pituitary-adrenocortical axis is enhanced in healthy elderly. An assessment during undisturbed night-time sleep. Eur J Endocrinol 1994;131:443–450.
  5. Van Cauter E, Leproult R, Kupfer DJ: Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996;81:2468–2473.
  6. Boscaro M, Paoletta A, Scarpa E, et al: Age-related changes in glucocorticoid fast feedback inhibition of adrenocorticotropin in man. J Clin Endocrinol Metab 1998;83:1380–1383.
  7. Wilkinson CW, Peskind ER, Raskind MA: Decreased hypothalamic-pituitary-adrenal axis sensitivity to cortisol feedback inhibition in human aging. Neuroendocrinology 1997;65:79–90.
  8. Wilkinson CW, Petrie EC, Murray SR, Colasurdo EA, Raskind MA, Peskind ER: Human glucocorticoid feedback inhibition is reduced in older individuals: Evening study. J Clin Endocrinol Metab 2001;86:545–550.

    External Resources

  9. Heuser IJ, Gotthardt U, Schweiger U, et al: Age-associated changes of pituitary-adrenocortical hormone regulation in humans: Importance of gender. Neurobiol Aging 1994;15:227–231.
  10. O’Brien JT, Schweitzer I, Ames D, Tuckwell V, Mastwyk M: Cortisol suppression by dexamethasone in the healthy elderly: Effects of age, dexamethasone levels, and cognitive function. Biol Psychiatry 1994;36:389–394.
  11. Ansseau M, Depauw Y, Charles G, et al: Age and gender effects on the diagnostic power of the DST. J Affect Disord 1987;12:185–191.
  12. Huizenga NA, Koper JW, de Lange P, et al: Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. J Clin Endocrinol Metab 1998;83:47–54.
  13. Waltman C, Blackman MR, Chrousos GP, Riemann C, Harman SM: Spontaneous and glucocorticoid-inhibited adrenocorticotropin hormone and cortisol secretion are similar in healthy young and old men. J Clin Endocrinol Metab 1991;73:495–502.

    External Resources

  14. Jacobson L, Sapolsky R: The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev 1991;12:118–134.
  15. Diorio D, Viau V, Meaney MJ: The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci 1993;13:3839–3847.
  16. Meaney MJ, Aitken DH: [3H]Dexamethasone binding in rat frontal cortex. Brain Res 1985;328:176–180.
  17. Sullivan RM, Gratton A: Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats. J Neurosci 1999;19:2834–2840.
  18. Hibberd C, Yau JL, Seckl JR: Glucocorticoids and the ageing hippocampus. J Anat 2000;197:553–562.
  19. Meaney MJ, Diorio J, Francis D, et al: Early environmental regulation of forebrain glucocorticoid receptor gene expression: Implications for adrenocortical responses to stress. Dev Neurosci 1996;18:49–72.
  20. Meaney MJ, O’Donnell D, Rowe W, et al: Individual differences in hypothalamic-pituitary-adrenal activity in later life and hippocampal aging. Exp Gerontol 1995;30:229–251.

    External Resources

  21. Bradbury MJ, Strack AM, Dallman MF: Lesions of the hippocampal efferent pathway (fimbria-fornix) do not alter sensitivity of adrenocorticotropin to feedback inhibition by corticosterone in rats. Neuroendocrinology 1993;58:396–407.

    External Resources

  22. Keller-Wood ME, Dallman MF: Corticosteroid inhibition of ACTH secretion. Endocr Rev 1984;5:1–24.
  23. van Haarst AD, Oitzl MS, de Kloet ER: Facilitation of feedback inhibition through blockade of glucocorticoid receptors in the hippocampus. Neurochem Res 1997;22:1323–1328.

    External Resources

  24. Lupien SJ, de Leon M, de Santi S, et al: Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1998;1:69–73.
  25. Starkman MN, Giordani B, Gebarski SS, et al: Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease. Biol Psychiatry 1999;46:1595–1602.
  26. Starkman MN, Gebarski SS, Berent S, Schteingart DE: Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 1992;32:756–765.
  27. de Leon MJ, McRae T, Tsai JR, et al: Abnormal cortisol response in Alzheimer’s disease linked to hippocampal atrophy. Lancet 1988;ii:391–392.
  28. O’Brien JT, Ames D, Schweitzer I, Colman P, Desmond P, Tress B: Clinical and magnetic resonance imaging correlates of hypothalamic-pituitary-adrenal axis function in depression and Alzheimer’s disease. Brit J Psychiatry 1996;168:679–687.
  29. de Leon MJ, McRae T, Rusinek H, et al: Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimer’s disease. J Clin Endocrinol Metab 1997;82:3251–3259.
  30. Marcus S, Robins LN, Buchholz K: Quick Diagnostic Interview Schedule III-R, version 1.0. Department of Psychiatry, Washington University School of Medicine, St. Louis, Mo., USA, 1998.
  31. Folstein MF, Robins LN, Helzer JE: The Mini-Mental State Examination. Arch Gen Psychiatry 1983;40:812.
  32. Wolf OT, Convit A, McHugh PF, et al: Cortisol differentially affects memory in young and elderly men. Behav Neurosci 2001;105:1002–1011.

    External Resources

  33. Convit A, McHugh P, Wolf OT, et al: MRI volume of the amygdala: A reliable method allowing separation from the hippocampal formation. Psychiatry Res 1999;90:113–123.
  34. Fox NC, Freeborough PA: Brain atrophy progression measured from registered serial MRI: Validation and application to Alzheimer’s disease. J Magn Reson Imaging 1997;7:1069–1075.
  35. Fox NC, Freeborough PA, Rossor MN: Visualisation and quantification of rates of atrophy in Alzheimer’s disease. Lancet 1996;348:94–97.
  36. Jack CR Jr, Petersen RC, Xu Y, et al: Rate of medial temporal lobe atrophy in typical aging and Alzheimer’s disease. Neurology 1998;51:993–999.
  37. Convit A, de Leon MJ, Tarshish C, et al: Specific hippocampal volume reductions in individuals at risk for Alzheimer’s disease. Neurobiol Aging 1997;18:131–138.

    External Resources

  38. Convit A, Wolf OT, de Leon MJ, et al: Volumetric analysis of the pre-frontal regions: Findings in aging and schizophrenia. Psychiatry Res 2001;107:61–73.
  39. Convit A, de Leon MJ, Hoptman MJ, et al: Age-related changes in brain: I. Magnetic resonance imaging measures of temporal lobe volumes in normal subjects. Psychiatr Q 1995;66:343–355.
  40. Jack CR Jr, Petersen RC, Xu YC, et al: Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology 1997;49:786–794.
  41. Murphy DG, DeCarli C, McIntosh AR, et al: Sex differences in human brain morphometry and metabolism: An in vivo quantitative magnetic resonance imaging and positron emission tomography study on the effect of aging. Arch Gen Psychiatry 1996;53:585–594.
  42. Pruessner JC, Collins DL, Pruessner M, Evans AC: Age and gender predict volume decline in the anterior and posterior hippocampus in early adulthood. J Neurosci 2001;21:194–200.
  43. Raz N, Gunning FM, Head D, et al: Selective aging of the human cerebral cortex observed in vivo: Differential vulnerability of the prefrontal gray matter. Cereb Cortex 1997;7:268–282.

    External Resources

  44. Goudsmit E, Hofman MA, Fliers E, Swaab DF: The supraoptic and paraventricular nuclei of the human hypothalamus in relation to sex, age and Alzheimer’s disease. Neurobiol Aging 1990;11:529–536.
  45. Hofman MA: Lifespan changes in the human hypothalamus. Exp Gerontol 1997;32:559–575.

    External Resources

  46. Raadsheer FC, Oorschot DE, Verwer RW, Tilders FJ, Swaab DF: Age-related increase in the total number of corticotropin-releasing hormone neurons in the human paraventricular nucleus in controls and Alzheimer’s disease: Comparison of the disector with an unfolding method. J Comp Neurol 1994;339:447–457.
  47. Lurie SN, Doraiswamy PM, Husain MM, et al: In vivo assessment of pituitary gland volume with magnetic resonance imaging: The effect of age. J Clin Endocrinol Metab 1990;71:505–508.
  48. Terano T, Seya A, Tamura Y, Yoshida S, Hirayama T: Characteristics of the pituitary gland in elderly subjects from magnetic resonance images: Relationship to pituitary hormone secretion. Clin Endocrinol (Oxf) 1996;45:273–279.
  49. Beresford T, Arciniegas D, Rojas D, et al: Hippocampal to pituitary volume ratio: A specific measure of reciprocal neuroendocrine alterations in alcohol dependence. J Stud Alcohol 1999;60:586–588.

    External Resources

  50. Axelson DA, Doraiswamy PM, Boyko OB, et al: In vivo assessment of pituitary volume with magnetic resonance imaging and systematic stereology: Relationship to dexamethasone suppression test results in patients. Psychiatry Res 1992;44:63–70.
  51. Krishnan KR, Doraiswamy PM, Lurie SN, et al: Pituitary size in depression. J Clin Endocrinol Metab 1991;72:256–259.

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