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Pituitary Adrenal Function and Depression: An Outline for Research

Pituitary Adrenal Function and Depression: An Outline for Research Abstract OVER the past two decades, since Selye1 introduced the concept of the "general adaptation syndrome," an impressive body of psychoendocrine studies has described increased 17-hydroxycorticosteroid (17-OHCS) excretion and elevated plasma 17-OHCS levels in association with psychological responses to both naturally occurring and experimentally contrived stress situations. Relatively greater and more sustained increases in indices of pituitary adrenal function have been well documented in some severely depressed patients. The potential now exists to pursue a new level of investigation of the role of pituitary adrenal function in depression, and perhaps in a broader sense, in human behavior. This paper reviews current data relating depression and pituitary adrenal function and proposes an outline for future research in this field. A consideration of the relationship of steroid metabolism to depression suggests three overall questions. (1) Is there evidence that a consistent significant alteration References 1. The test is based on the fact that dexamethasone, a potent glucocorticoid, acts like cortisol to inhibit the anterior pituitary. It is not measured, however, as 17-OHCS in urine. When normal individuals are given 2 mg of dexamethasone daily, adrenal function is suppressed to the extent that urinary 17-OHCS levels are decreased to less than half of the baseline levels within two days. Patients with adrenal hyperplasia fail to suppress to this extent. 2. Methopyrapone acts by inhibiting the formation of cortisol from 11-deoxycortisol by temporary enzyme inhibition, as shown in Fig 1. As stated previously, cortisol is the major compound involved in the feedback mechanism which inhibits the output of ACTH from the anterior pituitary. Methopyrapone blocks this feedback inhibition and provokes increased ACTH secretion. As shown in Fig 1, ACTH stimulates the adrenal cortex, which results in an increase in the precursor of cortisol, 11-deoxycortisol. Increases in 11-deoxycortisol are reflected in measurements of urinary 17-OHCS. Therefore, an increase in the activity of the anterior pituitary and in ACTH will be reflected as an increase in urinary 17-OHCS. 3. Selye, H.: Stress and General Adaptation Syndrome (Heberden Oration) , Brit Med J 1:1383-1392, 1950.Crossref 4. Sabshin, M., et al: Significance of Preexperimental Studies in the Psychosomatic Laboratory , Arch Neurol Psychiat 78:207-219, 1957.Crossref 5. Davis, J., et al: Apprehension and Elevated Serum Cortisol Levels , J Psychosom Res 6:83-86, 1962.Crossref 6. Fishman, J.R., et al: Emotional and Adrenal Cortical Responses to a New Experience: Effect of Social Environment , Arch Gen Psychiat 6:271-278, 1962.Crossref 7. Bliss, E.L., et al: Reaction of the Adrenal Cortex to Emotional Stress , Psychosom Med 18:56-76, 1956.Crossref 8. Persky, H., et al: Effect of Two Psychological Stresses on Adrenocortical Function: Studies on Anxious and Normal Subjects , Arch Neurol Psychiat 81:219-226, 1959.Crossref 9. Connell, A.M.; Cooper, J.; and Redfearn, J.W.: The Contrasting Effects of Emotional Tension and Physical Exercise on the Excretion of 17-Ketogenic Steroids and 17-Ketosteroids , Acta Endocr 27:179-194, 1958. 10. Hamburg, D.A.: " Plasma and Urinary Corticosteroid Levels in Naturally Occurring Psychologic Stresses ," in Korey, S.R.; Pope, A.; and Robins, E.: Ultrastructure and Metabolism of the Nervous System , Baltimore: The Williams and Wilkins Co., 1962, pp 406-413. 11. Wadeson, R.W., et al: Plasma and Urinary 17-OHCS Responses to Motion Pictures , Arch Gen Psychiat 9:146-156, 1963.Crossref 12. Mason, J.W.: Psychological Influences on the Pituitary-Adrenal Cortical System , Recent Progr Hormone Res 15:245-389, 1959. 13. Price, D.B.; Thaler, M.; and Mason, J.W.: Preoperative Emotional States and Adrenal Cortical Activity: Studies on Cardiac and Pulmonary Surgery Patients , Arch Neurol Psychiat 77:646-656, 1957.Crossref 14. Hill, S.R., Jr., et al: Studies on Adrenocortical and Psychological Response to Stress in Man , Arch Intern Med 97:269-298, 1956.Crossref 15. von Euler, U.S., et al: Cortical and Medullary Adrenal Activity in Emotional Stress , Acta Endocr 30:567-573, 1959. 16. Fox, H.M., et al: Adrenal Steroid Excretion Patterns in Eighteen Healthy Subjects , Psychosom Med 23:33-40, 1961.Crossref 17. Board, F.; Persky, H.; and Hamburg, D.A.: Psychological Stress and Endocrine Functions: Blood Levels of Adrenocortical and Thyroid Hormones in Acutely Disturbed Patients , Psychosom Med 18:324-333, 1956.Crossref 18. Board, F.; Wadeson, R.; and Persky, H.: Depressive Affect and Endocrine Functions , Arch Neurol Psychiat 78:612-620, 1957.Crossref 19. Bunney, W.E., Jr., and Hartmann, E.L.: Study of a Patient With 48-Hour Manic-Depressive Cycles: I. An Analysis of Behavioral Factors , Arch Gen Psychiat 12:611-618, 1963.Crossref 20. Bunney, W.E., Jr.; Mason, J.W.; and Hamburg, D.A.: Correlations Between Behavioral Variables and Urinary 17-Hydroxycorticosteroids in Depressed Patients , Psychosom Med 27:299-308, 1965.Crossref 21. Bunney, W.E., Jr., et al: A Psychoendocrine Study of Severe Psychotic Depressive Crises , Amer J Psychiat 122:72-80, 1965. 22. Bunney, W.E., Jr., and Fawcett, J.A.: Possibility of a Biochemical Test for Suicidal Potential , Arch Gen Psychiat 13:232-239, 1965.Crossref 23. Friedman, S.B.; Mason, J.W.; and Hamburg, D.A.: Urinary 17-Hydroxycorticosteroid Levels in Parents of Children with Neoplastic Disease , Psychosom Med 25:364-376, 1963.Crossref 24. Wolff, C.T.; Hofer, M.A.; and Mason, J.W.: Relationship Between Psychological Defenses and Mean Urinary 17-Hydroxycorticosteroid Excretion Rates: II. Methodologic and Theoretical Consideration , Psychosom Med 26:592-609, 1964.Crossref 25. Sachar, E.J., et al: Psychoendocrine Aspects of Acute Schizophrenic Reactions , Psychosom Med 25:510-537, 1963.Crossref 26. Reiss, M., et al: Regulation of Urinary Steroid Excretion: Effects of Dehydroisoandrosterone and of Anterior Pituitary Extract on Pattern of Daily Excretion in Man , Biochem J 44:632-635, 1949. 27. Rizzo, N.D., et al: Concurrent Observations of Behavior Changes and of Adrenocortical Variations in a Cyclothymic Patient During a Period of 12 Months , Ann Intern Med 41:798-815, 1954.Crossref 28. Bryson, R.W., and Martin, D.F.: 17-Ketosteroid Excretion in a Case of Manic-Depressive Psychosis , Lancet 267:365-367, 1954.Crossref 29. 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Henkin, R.I.; Gill, J.R., Jr.; and Bartter, F.C.: Effect of Adrenal Insufficiency and of Corticosteroids on Smell Threshold , J Clin Invest 45:1631-1633 ( (Oct) ) 1966.Crossref 83. Henkin, R.I.; Daly, R.L.; and Ojemann, G.A.: On the Action of Steroid Hormones on the Central Nervous System in Man , J Clin Invest 45:1021-1022 ( (June) ) 1966.Crossref 84. Porter, C.C., and Silber, R.H.: A Quantitative Color Reaction for Cortisone and Related 17, 21-Dihydroxy-20-Ketosteroids , J Biol Chem 185:201-207, 1950. 85. Peterson, R.E.; Karrer, A.; and Guerra, S.L.: Evaluation of Silber-Porter Procedure for Determination of Plasma Hydrocortisone , Anal Chem 29:144-149, 1957.Crossref 86. Weichselbaum, T.E.; Elman, R.; and Margraf, H.W.: Study of Potentially Active Adrenocortical Steroids in Peripheral Human Plasma After Various Stresses , J Clin Endocr 17:1158-1167, 1957.Crossref 87. Schultz, A.L.; Kerlow, A.; and Ulstrom, R.A.: Effect of Starvation on Adrenal Cortical Function in Obese Subjects , J Clin Endocr 24:1253-1257, 1964.Crossref 88. Jakobson, T., et al: The Excretion of Urinary 11-Deoxy and 11-Oxy-17-Hydroxy-Corticosteroids in Depressive Patients During Basal Conditions and During the Administration of Methopyrapone , J Psychosom Res 9:363-374, 1966.Crossref 89. Gallagher, T.F.: " Interrelation of Thyroid With Steroid Hormone Metabolism ," in Martini, L., and Pecile, A. (eds.): Hormonal Steroids, Biochemistry, Pharmacology, and Therapeutic Proceedings of the First International Congress on Hormonal Steroids , New York: Academic Press Inc., 1964, vol 1, pp 103-110. 90. Ceresa, F.: in discussion: " Ring A and Side-Chain Reduction Processes in Cortisol Metabolism ," in Martini, L., and Pecile, A. (eds.): Hormonal Steroids, Biochemistry, Pharmacology and Therapeutics Proceedings of the First International Congress on Hormonal Steroids , New York: Academic Press Inc., 1964, vol 1, pp 99-102. 91. Plager, J.E.; Schmidt, K.G.; and Staubitz, W.J.: Increased Unbound Cortisol in the Plasma of Estrogen-Treated Subjects , J Clin Invest 43:1066-1072, 1964.Crossref 92. Tait, J.F., et al: " Some Aspects of Steroid Dynamics ," in Martini, L., and Pecile, A. (eds.): Hormonal Steroids, Biochemistry, Pharmacology and Therapeutic Proceedings of the First International Congress on Hormonal Steroids , New York: Academic Press Inc., 1964, vol 1, pp 81-87. 93. DeMoor, P.; Steeno, O.; Hendrikx, A.: Clinical Features Observed in Patients With an Unexplained Low Cortisol Binding Capacity , Acta Endocr 48:272-282, 1965. 94. Selye, H.: The Story of the General Adaptation Syndrome , Montreal: Acta, Inc., 1946, p 140. 95. Genzell, C.A., and Notter, G.: Effect of Androgens on Plasma Levels on 17-Hydroxycorticosteroids , J Clin Endocr 16:483-488, 1956.Crossref 96. Edwards, K.M.; Jepson, R.P.; and Reece, M.W.: Corticosteroid Response to Surgery: Effect of Testosterone , J Clin Endocr 17:1460-1465, 1957.Crossref 97. Bush, I.E.: Methods of Paper Chromatography of Steroids Applicable to Study of Steroids in Mammalian Blood and Tissues , Biochem J 50:370-378, 1952. 98. Mason, J., et al: "Psychological Influences on Plasma Insulin Levels in the Monkey," in Abstracts of Presentations at the Annual Meeting of the American Psychosomatic Society, March, 1966. 99. Yates, F.E., and Urquhart, J.: Control of Plasma Concentrations of Adrenocortical Hormones , Physiol Rev 42:359-443, 1962. 100. Liddle, G.W.; Island, D.; and Meador, C.K.: Normal and Abnormal Regulation of Corticotropin Secretion in Man , Recent Progr Hormone Res 18:125-166, 1962. 101. 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Brodie, B.T.; Maichael, R.P.; and Westermann, E.D.: " Action of Reserpine on Pituitary-Adreno Cortical System Through Possible Action of Hypothalamus ," in Kety, S., and Elkes, J. (eds.): Regional Neurochemistry , New York: Pergamon Press, 1961, pp 351-361. 119. Gershon, S., and Yuwiler, A.: Lithium Ion: A Specific Psychopharmacological Approach to the Treatment of Mania , J Neuropsychiat 1:229-241, 1960. 120. Hartigan, G.P.: The Use of Lithium Salts in Affective Disorders , Brit J Psychiat 109:810-814, 1963.Crossref 121. Schou, M.: Lithium in Psychiatric Therapy , Psychopharmacologia 1:65-78, 1959.Crossref 122. Gill, J.R., Jr.; Mason, D.T.; and Bartter, F.C.: Adrenergic Nervous System in Sodium Metabolism: Effects of Guanethidine and Sodium-Retaining Steroids in Normal Man , J Clin Invest 43:177-184, 1964.Crossref 123. Kessell, A., and Holt, N.F.: Depression: An Analysis of a Follow-Up Study , Brit J Psychiat 111:1143-1153, 1965.Crossref 124. 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Pituitary Adrenal Function and Depression: An Outline for Research

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American Medical Association
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Copyright © 1967 American Medical Association. All Rights Reserved.
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0003-990X
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10.1001/archpsyc.1967.01730230001001
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Abstract

Abstract OVER the past two decades, since Selye1 introduced the concept of the "general adaptation syndrome," an impressive body of psychoendocrine studies has described increased 17-hydroxycorticosteroid (17-OHCS) excretion and elevated plasma 17-OHCS levels in association with psychological responses to both naturally occurring and experimentally contrived stress situations. Relatively greater and more sustained increases in indices of pituitary adrenal function have been well documented in some severely depressed patients. The potential now exists to pursue a new level of investigation of the role of pituitary adrenal function in depression, and perhaps in a broader sense, in human behavior. This paper reviews current data relating depression and pituitary adrenal function and proposes an outline for future research in this field. A consideration of the relationship of steroid metabolism to depression suggests three overall questions. (1) Is there evidence that a consistent significant alteration References 1. The test is based on the fact that dexamethasone, a potent glucocorticoid, acts like cortisol to inhibit the anterior pituitary. It is not measured, however, as 17-OHCS in urine. When normal individuals are given 2 mg of dexamethasone daily, adrenal function is suppressed to the extent that urinary 17-OHCS levels are decreased to less than half of the baseline levels within two days. Patients with adrenal hyperplasia fail to suppress to this extent. 2. Methopyrapone acts by inhibiting the formation of cortisol from 11-deoxycortisol by temporary enzyme inhibition, as shown in Fig 1. As stated previously, cortisol is the major compound involved in the feedback mechanism which inhibits the output of ACTH from the anterior pituitary. Methopyrapone blocks this feedback inhibition and provokes increased ACTH secretion. As shown in Fig 1, ACTH stimulates the adrenal cortex, which results in an increase in the precursor of cortisol, 11-deoxycortisol. Increases in 11-deoxycortisol are reflected in measurements of urinary 17-OHCS. Therefore, an increase in the activity of the anterior pituitary and in ACTH will be reflected as an increase in urinary 17-OHCS. 3. Selye, H.: Stress and General Adaptation Syndrome (Heberden Oration) , Brit Med J 1:1383-1392, 1950.Crossref 4. Sabshin, M., et al: Significance of Preexperimental Studies in the Psychosomatic Laboratory , Arch Neurol Psychiat 78:207-219, 1957.Crossref 5. Davis, J., et al: Apprehension and Elevated Serum Cortisol Levels , J Psychosom Res 6:83-86, 1962.Crossref 6. Fishman, J.R., et al: Emotional and Adrenal Cortical Responses to a New Experience: Effect of Social Environment , Arch Gen Psychiat 6:271-278, 1962.Crossref 7. Bliss, E.L., et al: Reaction of the Adrenal Cortex to Emotional Stress , Psychosom Med 18:56-76, 1956.Crossref 8. Persky, H., et al: Effect of Two Psychological Stresses on Adrenocortical Function: Studies on Anxious and Normal Subjects , Arch Neurol Psychiat 81:219-226, 1959.Crossref 9. Connell, A.M.; Cooper, J.; and Redfearn, J.W.: The Contrasting Effects of Emotional Tension and Physical Exercise on the Excretion of 17-Ketogenic Steroids and 17-Ketosteroids , Acta Endocr 27:179-194, 1958. 10. Hamburg, D.A.: " Plasma and Urinary Corticosteroid Levels in Naturally Occurring Psychologic Stresses ," in Korey, S.R.; Pope, A.; and Robins, E.: Ultrastructure and Metabolism of the Nervous System , Baltimore: The Williams and Wilkins Co., 1962, pp 406-413. 11. Wadeson, R.W., et al: Plasma and Urinary 17-OHCS Responses to Motion Pictures , Arch Gen Psychiat 9:146-156, 1963.Crossref 12. Mason, J.W.: Psychological Influences on the Pituitary-Adrenal Cortical System , Recent Progr Hormone Res 15:245-389, 1959. 13. Price, D.B.; Thaler, M.; and Mason, J.W.: Preoperative Emotional States and Adrenal Cortical Activity: Studies on Cardiac and Pulmonary Surgery Patients , Arch Neurol Psychiat 77:646-656, 1957.Crossref 14. Hill, S.R., Jr., et al: Studies on Adrenocortical and Psychological Response to Stress in Man , Arch Intern Med 97:269-298, 1956.Crossref 15. von Euler, U.S., et al: Cortical and Medullary Adrenal Activity in Emotional Stress , Acta Endocr 30:567-573, 1959. 16. Fox, H.M., et al: Adrenal Steroid Excretion Patterns in Eighteen Healthy Subjects , Psychosom Med 23:33-40, 1961.Crossref 17. Board, F.; Persky, H.; and Hamburg, D.A.: Psychological Stress and Endocrine Functions: Blood Levels of Adrenocortical and Thyroid Hormones in Acutely Disturbed Patients , Psychosom Med 18:324-333, 1956.Crossref 18. Board, F.; Wadeson, R.; and Persky, H.: Depressive Affect and Endocrine Functions , Arch Neurol Psychiat 78:612-620, 1957.Crossref 19. 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Journal

Archives of General PsychiatryAmerican Medical Association

Published: May 1, 1967

References

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