Adrenal Activity in Anorexia Nervosa B. TIMOTHY WALSH, MD, JACK L. KATZ, MD, JOSEPH LEVIN, MRCP (ED.), JACOB KREAM, P H D , DAVID K. FUKUSHIMA, P H D , LEON D. HELLMAN, MD, HERBERT WEINER, M D ,
AND BARNETT ZUMOFF, MD
Adrenocortical activity was studied in 19 emaciated women with anorexia nervosa. Relative to body size the patients' mean cortisol production rates of 0.591 mg /kg /day and 16.4 mg m2 /day were significantly elevated compared to those of 0.322 mg/kg/day and 11.4 mg/m2/day forage and sex matched normal controls (p 0.10), in no case 502
TABLE 3.
Overnight Dexamethasone (1 mg) Suppression 8 AM Plasma cortisol concentration (/ig/dl)
Patient No.
Before dexamethasone
After dexamethasone
13.4 30.2 19.6
8.5 17.7 19.3
17 18 19
did a normal woman's UFC excretion exceed 100 /xg /day. Thus, it is unlikely that the patients' elevated UFC excretion is due solely to their increased urine flow. Since UFC excretion is thought to reflect the amount of unbound cortisol filtered by the kidneys (17,20,21), our data indicate there is a sustained elevation of unbound plasma cortisol in anorexia nervosa. Dexamethasone Suppression The ability of 1 mg of dexamethasone administered at 11 PM to suppress the 8 AM plasma cortisol concentration on the following morning was assessed in three patients (Table 3). The average 8 AM plasma cortisol concentration following dexamethasone in the three patients was 15.2 fig /dl, an average decrease of 26.5% from the previous day's 8 AM level. Normal subjects generally show a decrease of at least 60%, to values below 5 fig /dl (22).
DISCUSSION The current study shows that, while the absolute CPR is normal in anorexia nervosa, the CPR relative to body size is increased. Several lines of evidence suggest that body size is usually an important determinant of CPR.
Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
ADRENAL ACTIVITY IN ANOREXIA NERVOSA
1. Although the CPR rises several fold between infancy and adulthood, the CPR per m2 remains constant (23). 2. The difference in CPR between men and women disappears if CPR is expressed relative to body size (24). 3. Although the CPR is elevated in obesity, the CPR per kg is not (24, 25); similarly, in 30 normal and obese women we have found a strong correlation between CPR and body weight (r = 0.59, p < 0.001) and between CPR and body surface area (r = 0.60, p < 0.001) (26). 4. When obese patients lose weight their CPR's fall (27, 28) and when patients with uncomplicated malnutrition gain weight, their CPR's rise (18, 29). These findings imply that the CPR is normally proportional to body size, and, therefore, in comparing the CPR's of emaciated patients with anorexia nervosa to those of normal weight controls it is appropriate to express the CPR relative to body size. Since the CPR per m2 and per kg are clearly elevated in anorexia nervosa, this line of reasoning suggests that there is an increased rate of cortisol secretion in anorexia nervosa. The persistence of normal absolute rates of cortisol production in the face of elevated plasma cortisol levels, the increased UFC excretion, and the lack of normal responsiveness to dexamethasone are consistent with this hypothesis. These data suggest that in emaciated women with anorexia nervosa, the hypothalamic-pituitary mechanisms regulating adrenal activity are less sensitive than normal to negative feedback from circulating corticostefoids. The influence of altered thyroid function on adrenal activity in anorexia nervosa merits consideration. In common with patients suffering from a variety of acute and chronic medical illnesses, pa-
tients with anorexia nervosa have been found to have low serum triiodothyronine (T3) concentrations (8, 30). Probably as a result, the metabolic clearance rate of cortisol is slowed in anorexia nervosa (8). However, neither slowed cortisol metabolism nor a low serum T3 concentration is invariably associated with evidence of increased adrenal activity function such as we have found in anorexia nervosa. In hypothyroidism, the metabolic clearance rate is slowed but the plasma cortisol concentration is normal and the absolute CPR and the UFC excretion are diminished (31, 34). In acute starvation, the plasma cortisol concentration and the UFC excretion remain normal despite an abrupt fall in plasma T3 concentration (35). The effects of the low T3 concentration and of the slowed cortisol metabolism on dexamethasone suppression are not clear. However, the half-life of cortisol in anorexia nervosa is about 80 min (8); thus, there would be sufficient time for plasma cortisol to fall to less than 1 % of its 11 PM value by 8 AM if 1 mg of dexamethasone completely suppressed cortisol production. Although a functional hypothyroidism in anorexia nervosa probably accounts for the slowed cortisol metabolism, it is less clear that the abnormalities in the other measures of adrenal function can be explained on this basis. Additional studies of cortisol regulation in hypothyroidism and in conditions characterized by a low T3 concentration may clarify the extent to which these abnormalities contribute to the disturbances noted in anorexia nervosa. Many of the changes in adrenal function seen in anorexia nervosa have also been observed in uncomplicated malnutrition: decreased urinary excretion of adrenal corticosteroids (18, 36); diminished rates of cortisol metabolism (18, 29); elevated
Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
503
B. TIMOTHY WALSH, ET AL.
levels of plasma cortisol (18, 29, 37, 38); normal responses to ACTH (18, 29, 37); and incomplete suppression by dexamethasone (18, 29) have been reported. However, by several measures of adrenal function there appear to be differences between anorexia nervosa and uncomplicated malnutrition. First, the cortisol binding capacity has been found to be significantly reduced in uncomplicated malnutrition (38), but not in anorexia nervosa (8, 39). This probably reflects the more severe emaciation in the patients with uncomplicated malnutrition who, unlike most patients with anorexia nervosa (7), exhibited severe hypoalbuminemia and peripheral edema. Second, in the two studies of cortisol secretion rate in malnutrition (18,29), the plasma production rate has been found to be lower in the malnourished state than after refeeding; the data indicate that the production rate per kg is not elevated in malnutrition as it is in anorexia nervosa. Third, two Studies (18,40) have found that UFC excretion is approximately normal in malnutrition and does not change with weight gain. The UFC/creatinine clearance ratio was elevated in malnutrition in the one study in which it was reported (18), but not to the degree we have observed in anorexia nervosa. Comparison between the current study of adrenal function in
anorexia nervosa and studies of adrenal function in other forms of malnutrition is difficult because of major differences in the age, sex, diet, psychological state, and degree of malnutrition of the patients studied, as well as in the techniques used to assess adrenal function. Nonetheless, the marked elevation of CPR relative to body size and of UFC excretion in some patients with anorexia nervosa suggests that the increased activity of the hypothalamic-pituitary-adrenal system is out of proportion to their emaciation. What, in addition to malnutrition, might disturb the regulation of cortisol secretion in anorexia nervosa? A variety of stresses are associated with enhanced adrenal activity (41), and the emotional distress, the bizarre dieting, the sleep disturbance, and the increased physical activity observed in anorexia nervosa may constitute such stimuli. It has been proposed that an independent hypothalamic disturbance exists in anorexia nervosa (42) and it is possible that this disturbance includes decreased sensitivity to negative feedback from plasma cortisol. Finally, certain forms of psychological depression are associated with increased cortisol secretion (43), and, as others have noted (9,44), there are parallels between anorexia nervosa and depression.
REFERENCES 1. Palmer WL, Anorexia nervosa, in Cecil RL, A Textbook of Medicine. Philadelphia, WB Saunders, 1948, pp. 762-763 2. Thorn GW, Forsham PH, Frawley TF, Hill SR, Roche M, StaehelinD, WilsonDL: The clinical usefulness of ACTH and cortisone, N. Engl J Med 242:783-793, 1950 3. Perloff WH, Lasche EM, Nodine JH, Schneeberg NG, Vieillard CB: The starvation state and functional hypopituitarism. JAMA 155: 1307-1313, 1954 4. Bliss EL, Migeon CJ: Endocrinology of anorexia nervosa. J Clin Endocrinol Metab 17:766-776, 1957 5. Marks V, Bannister RG: Pituitary and adrenal function in undernutrition with mental illness (including anorexia nervosa). Br J Psychiat 109:480-484, 1963 6. Danowski TS, Livstone E, Gonzales AR, Jung Y, Khurana RC: Fractional and partial hypopituitarism in anorexia nervosa. Hormones 3:105-118, 1972 504
Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
ADRENAL ACTIVITY IN ANOREXIA NERVOSA 7. Warren MP, Vande Wiele RL: Clinical and metabolic features of anorexia nervosa. Am J Obstet Gynecol 117:435^49, 1973 8. Boyar RM, Hellman LD, Roffwarg HP, Katz J, ZumoffB, O'Connor J, Bradlow HL, Fukushima DK: Cortisol secretion and metabolism in anorexia nervosa. N Engl J Med 296:190-193, 1977 9. Bethge H, Nagel AM, Solbach HG, Wiegelmann W, Zimmerman H: Zentrale regulationsstorung der nebennierenrinden funktion bei der anorexia nervosa. Mat Med Nordm 22:204-214, 1970 10. Frankel RJ, Jenkins JS: Hypothalamic-pituitary function in anorexia nervosa. Acta Endocrinol (Kbh) 78:209-221, 1975 11. Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R: Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26:57-63, 1972 12. DuBois D, DuBois EF: A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 17:863-871, 1916 13. Hellman L, Nakada F, Curti J, Weitzman ED, Kream J, Roffwarg HP, Ellman S, Fukushima DK, Gallagher TF: Cortisol is secreted episodically by normal man. J Clin Endocrinol Metab 30:411^422, 1970 14. Fukushima DK, Finkelstein JW, Yoshida K, Boyar RM, Hellman L: Pituitary-adrenal activity in untreated congenital adrenal hyperplasia. J Clin Endocrinol Metab 40:1-12, 1975 15. Murphy BEP: Some studies of the protein-binding of steroids and their application to the routine micro and ultramicro measurements of various steroids in body fluids by competitive protein-binding radioassay J Clin Endocrinol Metab 27:973-990, 1967 16. Kream J. Fukushima DK, Zumoff B: A rapid competitive protein-binding radioassay of urinary cortisol. Submitted for presentation. Tenth International Congress of Clinical Chemistry, Mexico City, 1978 17. Burke CW, Beardwell CG: Cushing's Syndrome. Q J Med 42:175-204, 1973 18. Smith SR, Bledsoe T, Chhetri MK: Cortisol metabolism and the pituitary-adrenal axis in adults with protein-calorie malnutrition. J Clin Endocrinol Metab 40:43-52, 1975 19. Baum CK, Davidson MJ, Landon J: Urinary free cortisol excretion by normal subjects. ] Endocrinol 63:47P-48P, 1974 20. Schedl HP, Chen PS, Greene G, Redd D: The renal clearance of plasma cortisol. J Clin Endocrinol Metab 19:1223-1229, 1959 21. Beisel WR, Cos JJ, Horton R, Chao PY, Forsham PH: Physiology of urinary cortisol excretion. J Clin Endocrinol Metab 24:887-893, 1964 22. Cryer PE, Sode J, Sabol JJ, Hines RC: The measurement of serum 11-hydroxycorticosteroids in the diagnosis of adrenal cortical disease. Medical Annals of the District of Columbia 39:570-573, 1970 23. Kenny FM, Preeyasombat C, Migeon CJ: Cortisol production rate. II. Normal infants, children, and adults. Pediatrics 37:34^12, 1966 24. Migeon CJ, Green OC, Eckert JP: Study of adrenocortical function in obesity. Metabolism 12:718-739, 1963 25. Mlynaryk P, Gillies RR, Murphy B, Pattee CJ: Cortisol production rates in obesity. J Clin Endocrinol Metab 22:587-591, 1962 26. Strain GW, Levin J, Fukushima DK, Kream J, Zumoff B: Cortisol production and plasma levels in obese women. Presented at the 60th Annual Meeting of the Endocrine Society, June, 1978. 27. Garces LY, Kenny FM, Drash A, Taylor FH: Cortisol secretion rate during fasting of obese adolescent subjects. J Clin Endocrinol Metab 28:1843-1847, 1968 28. Jackson IMD, Mowat JI: Hypothalamic-pituitary-adrenal function in obesity and the cortisol secretion rate following prolonged starvation. Acta Endocrinol (Kbh) 63:415^422, 1970 29. Alleyne GAO, Young VH: Adrenocortical function in children with severe protein-calorie malnutrition. Clin Sci 33:189-200, 1967 30. Miyai K, Yamamoto T, Azukizawa M, Ishibashi K, Kumahara Y: Serum thyroid hormones and thyrotropin in anorexia nervosa. J Clin Endocrinol Metab 40:334-338, 1975 31. Peterson RE: The influence of the thyroid on adrenal cortical function. J Clin Invest 37:736-743,1957 32. Kenny FM, Iturzaeta N, Preeyasombat C, Taylor FH, Migeon CJ: Cortisol production rate. VII. hypothyroidism and hyperthyroidism in infants and children. J Clin Endocrinol Metab 27:1616-1622, 1967 33. Havard CWH, Saldanha VF, Bird R, Gardner R: Adrenal function in hypothyroidism. Br Med J 1:337-339, 1970 Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
505
B. TIMOTHY WALSH, ET AL. 34. Copinschi G, Leclercq R, Bruno OD, Cornil A: Effects of altered thyroid function upon cortisol secretion in man. Horm Metab Res 3:437^i42, 1971 35. Croxson MS, Hall TD, Kletzky OA, Jaramillo JE, Nicoloff JT: Decreased serum thyrotropin induced by fasting. J Clin Endocrinol Metab 45:560-568, 1977 36. Cooke JNC, James VHT, Landon ], Wynn V: Adrenocortical function in chronic malnutrition. Br Med ] 1:662-666, 1964 37. Rao KSJ, Srikantia SG, Gopalan C: Plasma cortisol levels in protein-calorie malnutrition. Arch Dis Child 43:365-367, 1968 38. Schonland MM, Shanley BC, Loening WEK, Parent MA, Coovadia HM: Plasma-cortisol and immunosuppression in protein-calorie malnutrition. Lancet 2:435-436, 1972 39. DeMoor P, Steeno O, Boosens I, Hendrikx A: Data on transcortin activity in human plasma as studied by gel filtration. J Clin Endocrinol Metab 26:71-78, 1966 40. Leonard PJ, MacWilliam KM: Cortisol binding in the serum in kwashiorkor. J Endocrinol 29:273-276, 1964 41. Mason JW: A review of psychoendocrine research on the pituitary-adrenal cortical system. Psychosom Med 30:576-607, 1968 42. Russell GFM: Metabolic aspects of anorexia nervosa. Proc R Soc Med 58:811-814, 1965 43. Sachar EJ, Hellman L, Fukushima DK, Gallagher TF: Cortisol production in depressive illness. Arch Gen Psychiatry 23:289-298, 1970 44. Cantwell DP, Sturzenberger S, Burroughs J, Salkin B, Green JK: Anorexia nervosa. an affective disorder? Arch Gen Psychiatry 34:1087-1093, 1977
506
Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
AND BARNETT ZUMOFF, MD
Adrenocortical activity was studied in 19 emaciated women with anorexia nervosa. Relative to body size the patients' mean cortisol production rates of 0.591 mg /kg /day and 16.4 mg m2 /day were significantly elevated compared to those of 0.322 mg/kg/day and 11.4 mg/m2/day forage and sex matched normal controls (p 0.10), in no case 502
TABLE 3.
Overnight Dexamethasone (1 mg) Suppression 8 AM Plasma cortisol concentration (/ig/dl)
Patient No.
Before dexamethasone
After dexamethasone
13.4 30.2 19.6
8.5 17.7 19.3
17 18 19
did a normal woman's UFC excretion exceed 100 /xg /day. Thus, it is unlikely that the patients' elevated UFC excretion is due solely to their increased urine flow. Since UFC excretion is thought to reflect the amount of unbound cortisol filtered by the kidneys (17,20,21), our data indicate there is a sustained elevation of unbound plasma cortisol in anorexia nervosa. Dexamethasone Suppression The ability of 1 mg of dexamethasone administered at 11 PM to suppress the 8 AM plasma cortisol concentration on the following morning was assessed in three patients (Table 3). The average 8 AM plasma cortisol concentration following dexamethasone in the three patients was 15.2 fig /dl, an average decrease of 26.5% from the previous day's 8 AM level. Normal subjects generally show a decrease of at least 60%, to values below 5 fig /dl (22).
DISCUSSION The current study shows that, while the absolute CPR is normal in anorexia nervosa, the CPR relative to body size is increased. Several lines of evidence suggest that body size is usually an important determinant of CPR.
Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
ADRENAL ACTIVITY IN ANOREXIA NERVOSA
1. Although the CPR rises several fold between infancy and adulthood, the CPR per m2 remains constant (23). 2. The difference in CPR between men and women disappears if CPR is expressed relative to body size (24). 3. Although the CPR is elevated in obesity, the CPR per kg is not (24, 25); similarly, in 30 normal and obese women we have found a strong correlation between CPR and body weight (r = 0.59, p < 0.001) and between CPR and body surface area (r = 0.60, p < 0.001) (26). 4. When obese patients lose weight their CPR's fall (27, 28) and when patients with uncomplicated malnutrition gain weight, their CPR's rise (18, 29). These findings imply that the CPR is normally proportional to body size, and, therefore, in comparing the CPR's of emaciated patients with anorexia nervosa to those of normal weight controls it is appropriate to express the CPR relative to body size. Since the CPR per m2 and per kg are clearly elevated in anorexia nervosa, this line of reasoning suggests that there is an increased rate of cortisol secretion in anorexia nervosa. The persistence of normal absolute rates of cortisol production in the face of elevated plasma cortisol levels, the increased UFC excretion, and the lack of normal responsiveness to dexamethasone are consistent with this hypothesis. These data suggest that in emaciated women with anorexia nervosa, the hypothalamic-pituitary mechanisms regulating adrenal activity are less sensitive than normal to negative feedback from circulating corticostefoids. The influence of altered thyroid function on adrenal activity in anorexia nervosa merits consideration. In common with patients suffering from a variety of acute and chronic medical illnesses, pa-
tients with anorexia nervosa have been found to have low serum triiodothyronine (T3) concentrations (8, 30). Probably as a result, the metabolic clearance rate of cortisol is slowed in anorexia nervosa (8). However, neither slowed cortisol metabolism nor a low serum T3 concentration is invariably associated with evidence of increased adrenal activity function such as we have found in anorexia nervosa. In hypothyroidism, the metabolic clearance rate is slowed but the plasma cortisol concentration is normal and the absolute CPR and the UFC excretion are diminished (31, 34). In acute starvation, the plasma cortisol concentration and the UFC excretion remain normal despite an abrupt fall in plasma T3 concentration (35). The effects of the low T3 concentration and of the slowed cortisol metabolism on dexamethasone suppression are not clear. However, the half-life of cortisol in anorexia nervosa is about 80 min (8); thus, there would be sufficient time for plasma cortisol to fall to less than 1 % of its 11 PM value by 8 AM if 1 mg of dexamethasone completely suppressed cortisol production. Although a functional hypothyroidism in anorexia nervosa probably accounts for the slowed cortisol metabolism, it is less clear that the abnormalities in the other measures of adrenal function can be explained on this basis. Additional studies of cortisol regulation in hypothyroidism and in conditions characterized by a low T3 concentration may clarify the extent to which these abnormalities contribute to the disturbances noted in anorexia nervosa. Many of the changes in adrenal function seen in anorexia nervosa have also been observed in uncomplicated malnutrition: decreased urinary excretion of adrenal corticosteroids (18, 36); diminished rates of cortisol metabolism (18, 29); elevated
Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
503
B. TIMOTHY WALSH, ET AL.
levels of plasma cortisol (18, 29, 37, 38); normal responses to ACTH (18, 29, 37); and incomplete suppression by dexamethasone (18, 29) have been reported. However, by several measures of adrenal function there appear to be differences between anorexia nervosa and uncomplicated malnutrition. First, the cortisol binding capacity has been found to be significantly reduced in uncomplicated malnutrition (38), but not in anorexia nervosa (8, 39). This probably reflects the more severe emaciation in the patients with uncomplicated malnutrition who, unlike most patients with anorexia nervosa (7), exhibited severe hypoalbuminemia and peripheral edema. Second, in the two studies of cortisol secretion rate in malnutrition (18,29), the plasma production rate has been found to be lower in the malnourished state than after refeeding; the data indicate that the production rate per kg is not elevated in malnutrition as it is in anorexia nervosa. Third, two Studies (18,40) have found that UFC excretion is approximately normal in malnutrition and does not change with weight gain. The UFC/creatinine clearance ratio was elevated in malnutrition in the one study in which it was reported (18), but not to the degree we have observed in anorexia nervosa. Comparison between the current study of adrenal function in
anorexia nervosa and studies of adrenal function in other forms of malnutrition is difficult because of major differences in the age, sex, diet, psychological state, and degree of malnutrition of the patients studied, as well as in the techniques used to assess adrenal function. Nonetheless, the marked elevation of CPR relative to body size and of UFC excretion in some patients with anorexia nervosa suggests that the increased activity of the hypothalamic-pituitary-adrenal system is out of proportion to their emaciation. What, in addition to malnutrition, might disturb the regulation of cortisol secretion in anorexia nervosa? A variety of stresses are associated with enhanced adrenal activity (41), and the emotional distress, the bizarre dieting, the sleep disturbance, and the increased physical activity observed in anorexia nervosa may constitute such stimuli. It has been proposed that an independent hypothalamic disturbance exists in anorexia nervosa (42) and it is possible that this disturbance includes decreased sensitivity to negative feedback from plasma cortisol. Finally, certain forms of psychological depression are associated with increased cortisol secretion (43), and, as others have noted (9,44), there are parallels between anorexia nervosa and depression.
REFERENCES 1. Palmer WL, Anorexia nervosa, in Cecil RL, A Textbook of Medicine. Philadelphia, WB Saunders, 1948, pp. 762-763 2. Thorn GW, Forsham PH, Frawley TF, Hill SR, Roche M, StaehelinD, WilsonDL: The clinical usefulness of ACTH and cortisone, N. Engl J Med 242:783-793, 1950 3. Perloff WH, Lasche EM, Nodine JH, Schneeberg NG, Vieillard CB: The starvation state and functional hypopituitarism. JAMA 155: 1307-1313, 1954 4. Bliss EL, Migeon CJ: Endocrinology of anorexia nervosa. J Clin Endocrinol Metab 17:766-776, 1957 5. Marks V, Bannister RG: Pituitary and adrenal function in undernutrition with mental illness (including anorexia nervosa). Br J Psychiat 109:480-484, 1963 6. Danowski TS, Livstone E, Gonzales AR, Jung Y, Khurana RC: Fractional and partial hypopituitarism in anorexia nervosa. Hormones 3:105-118, 1972 504
Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
ADRENAL ACTIVITY IN ANOREXIA NERVOSA 7. Warren MP, Vande Wiele RL: Clinical and metabolic features of anorexia nervosa. Am J Obstet Gynecol 117:435^49, 1973 8. Boyar RM, Hellman LD, Roffwarg HP, Katz J, ZumoffB, O'Connor J, Bradlow HL, Fukushima DK: Cortisol secretion and metabolism in anorexia nervosa. N Engl J Med 296:190-193, 1977 9. Bethge H, Nagel AM, Solbach HG, Wiegelmann W, Zimmerman H: Zentrale regulationsstorung der nebennierenrinden funktion bei der anorexia nervosa. Mat Med Nordm 22:204-214, 1970 10. Frankel RJ, Jenkins JS: Hypothalamic-pituitary function in anorexia nervosa. Acta Endocrinol (Kbh) 78:209-221, 1975 11. Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R: Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26:57-63, 1972 12. DuBois D, DuBois EF: A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 17:863-871, 1916 13. Hellman L, Nakada F, Curti J, Weitzman ED, Kream J, Roffwarg HP, Ellman S, Fukushima DK, Gallagher TF: Cortisol is secreted episodically by normal man. J Clin Endocrinol Metab 30:411^422, 1970 14. Fukushima DK, Finkelstein JW, Yoshida K, Boyar RM, Hellman L: Pituitary-adrenal activity in untreated congenital adrenal hyperplasia. J Clin Endocrinol Metab 40:1-12, 1975 15. Murphy BEP: Some studies of the protein-binding of steroids and their application to the routine micro and ultramicro measurements of various steroids in body fluids by competitive protein-binding radioassay J Clin Endocrinol Metab 27:973-990, 1967 16. Kream J. Fukushima DK, Zumoff B: A rapid competitive protein-binding radioassay of urinary cortisol. Submitted for presentation. Tenth International Congress of Clinical Chemistry, Mexico City, 1978 17. Burke CW, Beardwell CG: Cushing's Syndrome. Q J Med 42:175-204, 1973 18. Smith SR, Bledsoe T, Chhetri MK: Cortisol metabolism and the pituitary-adrenal axis in adults with protein-calorie malnutrition. J Clin Endocrinol Metab 40:43-52, 1975 19. Baum CK, Davidson MJ, Landon J: Urinary free cortisol excretion by normal subjects. ] Endocrinol 63:47P-48P, 1974 20. Schedl HP, Chen PS, Greene G, Redd D: The renal clearance of plasma cortisol. J Clin Endocrinol Metab 19:1223-1229, 1959 21. Beisel WR, Cos JJ, Horton R, Chao PY, Forsham PH: Physiology of urinary cortisol excretion. J Clin Endocrinol Metab 24:887-893, 1964 22. Cryer PE, Sode J, Sabol JJ, Hines RC: The measurement of serum 11-hydroxycorticosteroids in the diagnosis of adrenal cortical disease. Medical Annals of the District of Columbia 39:570-573, 1970 23. Kenny FM, Preeyasombat C, Migeon CJ: Cortisol production rate. II. Normal infants, children, and adults. Pediatrics 37:34^12, 1966 24. Migeon CJ, Green OC, Eckert JP: Study of adrenocortical function in obesity. Metabolism 12:718-739, 1963 25. Mlynaryk P, Gillies RR, Murphy B, Pattee CJ: Cortisol production rates in obesity. J Clin Endocrinol Metab 22:587-591, 1962 26. Strain GW, Levin J, Fukushima DK, Kream J, Zumoff B: Cortisol production and plasma levels in obese women. Presented at the 60th Annual Meeting of the Endocrine Society, June, 1978. 27. Garces LY, Kenny FM, Drash A, Taylor FH: Cortisol secretion rate during fasting of obese adolescent subjects. J Clin Endocrinol Metab 28:1843-1847, 1968 28. Jackson IMD, Mowat JI: Hypothalamic-pituitary-adrenal function in obesity and the cortisol secretion rate following prolonged starvation. Acta Endocrinol (Kbh) 63:415^422, 1970 29. Alleyne GAO, Young VH: Adrenocortical function in children with severe protein-calorie malnutrition. Clin Sci 33:189-200, 1967 30. Miyai K, Yamamoto T, Azukizawa M, Ishibashi K, Kumahara Y: Serum thyroid hormones and thyrotropin in anorexia nervosa. J Clin Endocrinol Metab 40:334-338, 1975 31. Peterson RE: The influence of the thyroid on adrenal cortical function. J Clin Invest 37:736-743,1957 32. Kenny FM, Iturzaeta N, Preeyasombat C, Taylor FH, Migeon CJ: Cortisol production rate. VII. hypothyroidism and hyperthyroidism in infants and children. J Clin Endocrinol Metab 27:1616-1622, 1967 33. Havard CWH, Saldanha VF, Bird R, Gardner R: Adrenal function in hypothyroidism. Br Med J 1:337-339, 1970 Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
505
B. TIMOTHY WALSH, ET AL. 34. Copinschi G, Leclercq R, Bruno OD, Cornil A: Effects of altered thyroid function upon cortisol secretion in man. Horm Metab Res 3:437^i42, 1971 35. Croxson MS, Hall TD, Kletzky OA, Jaramillo JE, Nicoloff JT: Decreased serum thyrotropin induced by fasting. J Clin Endocrinol Metab 45:560-568, 1977 36. Cooke JNC, James VHT, Landon ], Wynn V: Adrenocortical function in chronic malnutrition. Br Med ] 1:662-666, 1964 37. Rao KSJ, Srikantia SG, Gopalan C: Plasma cortisol levels in protein-calorie malnutrition. Arch Dis Child 43:365-367, 1968 38. Schonland MM, Shanley BC, Loening WEK, Parent MA, Coovadia HM: Plasma-cortisol and immunosuppression in protein-calorie malnutrition. Lancet 2:435-436, 1972 39. DeMoor P, Steeno O, Boosens I, Hendrikx A: Data on transcortin activity in human plasma as studied by gel filtration. J Clin Endocrinol Metab 26:71-78, 1966 40. Leonard PJ, MacWilliam KM: Cortisol binding in the serum in kwashiorkor. J Endocrinol 29:273-276, 1964 41. Mason JW: A review of psychoendocrine research on the pituitary-adrenal cortical system. Psychosom Med 30:576-607, 1968 42. Russell GFM: Metabolic aspects of anorexia nervosa. Proc R Soc Med 58:811-814, 1965 43. Sachar EJ, Hellman L, Fukushima DK, Gallagher TF: Cortisol production in depressive illness. Arch Gen Psychiatry 23:289-298, 1970 44. Cantwell DP, Sturzenberger S, Burroughs J, Salkin B, Green JK: Anorexia nervosa. an affective disorder? Arch Gen Psychiatry 34:1087-1093, 1977
506
Psychosomatic Medicine Vol. 40, No. 6 (October 1978)
