The Plasma Cortisol and Corticotropin Response to Hypoglycemia Following Adrenal Steroid and ACTH Administration R. A. DONALD AND E. A. ESPINER Department of Medicine, Christchurch Clinical School, Christchurch, New Zealand ABSTRACT. The plasma cortisol response to hypoglycemia is widely used as a test of hypothalamicpituitary-adrenal function. It was the aim of this study to determine whether this test gives a reliable indication of pituitary corticotropin (ACTH) release in patients recovering from adrenocortical suppression due to corticosteroid or ACTH therapy. The 16 patients who were studied (6 on more than one occasion) had received in excess of 5 mg prednisone or equivalent daily for over 12 months. The insulin tolerance tests were carried out 18 h after stopping steroid therapy. The tests were then repeated three to four days after adrenal function had been restored (as indicated by urinary oxogenic steroid excretion of greater than 35 mg/24 h) by zinc tetracosactrin administration. The ACTH response to hypoglycemia was signifi-
S
UDDEN withdrawal of prolonged or intensive steroid therapy may be hazardous and a number of deaths have been reported and attributed to adrenal insufficiency (1-3). However in many cases detailed documentation has been lacking and the evidence of adrenal failure has often been inconclusive. As several tests of hypothalamic-pituitary-adrenal function are available (4-7) accurate diagnosis should now be possible. The plasma cortisol response to insulin induced hypoglycemia is one such test and generally provides useful information about the integrity of the hypothalamic-pituitaryadrenal axis (5-11). In steroid or corticotropin-(ACTH) treated patients, however it is theoretically possible that the cortisol response might not be a good indication of endogenous ACTH release if adrenal size or function was altered by treatment and normal pituitary adrenal relationships were disturbed. Received January 23, 1975.
cantly impaired in the steroid-treated group. However with the exception of one patient who had persistently elevated resting ACTH levels there was a significant correlation (P < 0.01) between the maximum increments in plasma cortisol and ACTH during hypoglycemia. No significant difference in sensitivity to endogenous ACTH could be demonstrated between the steroid-treated group and 12 normal control subjects. Following ACTH administration the plasma ACTH and growth hormone responses to hypoglycemia were significantly reduced, but the response in plasma cortisol was not significantly affected. It is concluded that the plasma cortisol response to hypoglycemia gives a useful indication of ACTH release in steroid-treated patients provided that they have not recently received exogenous ACTH. (/ Clin Endocrinol Metab 41: 1, 1975).
It was therefore the aim of this study to see if the cortisol response to hypoglycemia gives a reliable indication of ACTH release in patients undergoing withdrawal of corticosteroid or ACTH therapy. Patients and Methods Sixteen steroid-treated subjects were studied on 22 occasions. There were 3 male and 13 female patients whose age range was 15 to 63 yr. Their diagnoses included asthma (4), ulcerative colitis (2), active chronic hepatitis (2), hirsutism (1), familial thrombocytopenia (1), glomerulonephritis (1), hypersensitivity angiitis (1), and rheumatoid arthritis (1). Three patients had been mistakenly diagnosed as having Addison's disease (2) or hypopituitarism (1). All had received in excess of 5 mg/day prednisone or equivalent for more than 12 months prior to testing. The maintenance doses ranged from 4-40 mg daily from 5 to 13 yr. Five patients had been noted to be floridly Cushingoid in appearance during the course of steroid therapy. The 12 control individuals (7 male, 5 female, ages 15-55 yr) had not received steroid or ACTH therapy and had no evidence of impaired hypothalamicpituitary-adrenal function.
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DONALD AND ESPIMER
JCE & M • 1975 V o l 4 1 • No 1
trations were considered. The correlation between the maximum plasma ACTH and cortisol increments is shown in Fig. 1. It will be seen that the mean maximum ACTH increment is significantly less (P < 0.001) in the steroid treated group as compared with the control subjects. However there is a good correlation between plasma ACTH and cortisol increments whether the steroid treated group is considered alone (r = 0.78) or in combination with the normal controls (r = 0.90). Either correlation coefficient is significant (P < 0.01). In calculating these correlation coefficients the value obtained in one patient (result indicated by brackets) has been disregarded. This was the only steroid treated patient who was observed to have resting plasma ACTH levels of greater than 150 pg/ml on a number of occasions. Even when the patient's results are included no significant difference could be demonstrated in the adrenal responsiveness of the steroid treated group and the controls. This was analyzed by comparing the mean of the ratio of maximum cortisol increment to maximum ACTH increment in the two groups (t = 1.788, P > 0.05). The mean maximum plasma growth hormone increment of the steroid treated patients (24.39 ng/ml ± 4.29 SE) was significantly less (P < 0.05) than that of the controls (47.17 ng/ml ± 9.54 SE). Results The effect of short-term ACTH adminisIn order to assess the plasma ACTH and tration on the endogenous plasma ACTH, cortisol response to hypoglycemia maximum cortisol and GH response to hypoglycemia increments above baseline resting concen- was then studied in the steroid-treated group (see Fig. 2 and Table 2). The administration of ACTH had no significant effect on TABLE 1. Testing procedure for ACTH-treated patients the hypoglycemic stimulus as indicated by Days 1 the mean minimum blood sugar level. Howand 2 Previous steroid therapy discontinued. ever, it will be evident from Fig. 2 that the Dexamethasone 0.5 mg at 8 AM and 3 PM substituted. maximum endogenous plasma ACTH response was reduced after ACTH adminisDay 3 Dexamethasone discontinued. tration in 8 out of the 9 subjects tested. This Day 4 First insulin tolerance test. reduction in the mean plasma ACTH Day 5 Zinc synacthen 0.5-1.0 mg daily for 2 to 4 response was statistically significant (P days until urinary OGS excretion greater < 0.05). The total amount of ACTH secreted than 35 mg/day. (as indicated by the area under the ACTH 2 - 3 days later second insulin tolerance test. response curve) was also significantly
Insulin tolerance tests were carried out between 10 and 11 AM and the morning prednisone or dexamethasone dose was withheld until after the test had been completed. The dose of insulin given was 0.15 U/kg body weight. Nine patients were studied in greater detail both before and after ACTH administration. Tetracosactrin zinc phosphate complex (Synacthen depot CIBA) 0.5-1.0 mg/day was administered im for 2-4 days. This duration of therapy was designed to restore adrenal function to normal as indicated by a rise in urinary oxogenic steroid excretion to 35 mg/day or greater. An interval of between 2 and 3 days was allowed between the last dose of ACTH and the second insulin tolerance test. Details of the investigation procedure are given in Table 1. The insulin tolerance test procedure has been described previously (11). Plasma cortisol was estimated by a fluorimetric method (12) and urinary oxogenic steroids by the method described by Metcalf (13). Plasma growth hormone (14) and ACTH (15) were measured by radioimmunoassay. The sensitivity of the ACTH assay when 2 ml plasma is extracted is generally 10 pg/ml (11). In this present study however, repeated sampling was necessary and therefore the plasma volume was reduced to 1 ml with a consequent halving of sensitivity. The specificity (16) and accuracy (17) of the ACTH assay have been described elsewhere. In the studies which follow, all samples from the same patient were measured in the same assay. Statistical analyses were carried out by Student's t test.
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CORTISOL AND ACTH RESPONSE TO HYPOGLYCEMIA 35 T
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UDDEN withdrawal of prolonged or intensive steroid therapy may be hazardous and a number of deaths have been reported and attributed to adrenal insufficiency (1-3). However in many cases detailed documentation has been lacking and the evidence of adrenal failure has often been inconclusive. As several tests of hypothalamic-pituitary-adrenal function are available (4-7) accurate diagnosis should now be possible. The plasma cortisol response to insulin induced hypoglycemia is one such test and generally provides useful information about the integrity of the hypothalamic-pituitaryadrenal axis (5-11). In steroid or corticotropin-(ACTH) treated patients, however it is theoretically possible that the cortisol response might not be a good indication of endogenous ACTH release if adrenal size or function was altered by treatment and normal pituitary adrenal relationships were disturbed. Received January 23, 1975.
cantly impaired in the steroid-treated group. However with the exception of one patient who had persistently elevated resting ACTH levels there was a significant correlation (P < 0.01) between the maximum increments in plasma cortisol and ACTH during hypoglycemia. No significant difference in sensitivity to endogenous ACTH could be demonstrated between the steroid-treated group and 12 normal control subjects. Following ACTH administration the plasma ACTH and growth hormone responses to hypoglycemia were significantly reduced, but the response in plasma cortisol was not significantly affected. It is concluded that the plasma cortisol response to hypoglycemia gives a useful indication of ACTH release in steroid-treated patients provided that they have not recently received exogenous ACTH. (/ Clin Endocrinol Metab 41: 1, 1975).
It was therefore the aim of this study to see if the cortisol response to hypoglycemia gives a reliable indication of ACTH release in patients undergoing withdrawal of corticosteroid or ACTH therapy. Patients and Methods Sixteen steroid-treated subjects were studied on 22 occasions. There were 3 male and 13 female patients whose age range was 15 to 63 yr. Their diagnoses included asthma (4), ulcerative colitis (2), active chronic hepatitis (2), hirsutism (1), familial thrombocytopenia (1), glomerulonephritis (1), hypersensitivity angiitis (1), and rheumatoid arthritis (1). Three patients had been mistakenly diagnosed as having Addison's disease (2) or hypopituitarism (1). All had received in excess of 5 mg/day prednisone or equivalent for more than 12 months prior to testing. The maintenance doses ranged from 4-40 mg daily from 5 to 13 yr. Five patients had been noted to be floridly Cushingoid in appearance during the course of steroid therapy. The 12 control individuals (7 male, 5 female, ages 15-55 yr) had not received steroid or ACTH therapy and had no evidence of impaired hypothalamicpituitary-adrenal function.
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DONALD AND ESPIMER
JCE & M • 1975 V o l 4 1 • No 1
trations were considered. The correlation between the maximum plasma ACTH and cortisol increments is shown in Fig. 1. It will be seen that the mean maximum ACTH increment is significantly less (P < 0.001) in the steroid treated group as compared with the control subjects. However there is a good correlation between plasma ACTH and cortisol increments whether the steroid treated group is considered alone (r = 0.78) or in combination with the normal controls (r = 0.90). Either correlation coefficient is significant (P < 0.01). In calculating these correlation coefficients the value obtained in one patient (result indicated by brackets) has been disregarded. This was the only steroid treated patient who was observed to have resting plasma ACTH levels of greater than 150 pg/ml on a number of occasions. Even when the patient's results are included no significant difference could be demonstrated in the adrenal responsiveness of the steroid treated group and the controls. This was analyzed by comparing the mean of the ratio of maximum cortisol increment to maximum ACTH increment in the two groups (t = 1.788, P > 0.05). The mean maximum plasma growth hormone increment of the steroid treated patients (24.39 ng/ml ± 4.29 SE) was significantly less (P < 0.05) than that of the controls (47.17 ng/ml ± 9.54 SE). Results The effect of short-term ACTH adminisIn order to assess the plasma ACTH and tration on the endogenous plasma ACTH, cortisol response to hypoglycemia maximum cortisol and GH response to hypoglycemia increments above baseline resting concen- was then studied in the steroid-treated group (see Fig. 2 and Table 2). The administration of ACTH had no significant effect on TABLE 1. Testing procedure for ACTH-treated patients the hypoglycemic stimulus as indicated by Days 1 the mean minimum blood sugar level. Howand 2 Previous steroid therapy discontinued. ever, it will be evident from Fig. 2 that the Dexamethasone 0.5 mg at 8 AM and 3 PM substituted. maximum endogenous plasma ACTH response was reduced after ACTH adminisDay 3 Dexamethasone discontinued. tration in 8 out of the 9 subjects tested. This Day 4 First insulin tolerance test. reduction in the mean plasma ACTH Day 5 Zinc synacthen 0.5-1.0 mg daily for 2 to 4 response was statistically significant (P days until urinary OGS excretion greater < 0.05). The total amount of ACTH secreted than 35 mg/day. (as indicated by the area under the ACTH 2 - 3 days later second insulin tolerance test. response curve) was also significantly
Insulin tolerance tests were carried out between 10 and 11 AM and the morning prednisone or dexamethasone dose was withheld until after the test had been completed. The dose of insulin given was 0.15 U/kg body weight. Nine patients were studied in greater detail both before and after ACTH administration. Tetracosactrin zinc phosphate complex (Synacthen depot CIBA) 0.5-1.0 mg/day was administered im for 2-4 days. This duration of therapy was designed to restore adrenal function to normal as indicated by a rise in urinary oxogenic steroid excretion to 35 mg/day or greater. An interval of between 2 and 3 days was allowed between the last dose of ACTH and the second insulin tolerance test. Details of the investigation procedure are given in Table 1. The insulin tolerance test procedure has been described previously (11). Plasma cortisol was estimated by a fluorimetric method (12) and urinary oxogenic steroids by the method described by Metcalf (13). Plasma growth hormone (14) and ACTH (15) were measured by radioimmunoassay. The sensitivity of the ACTH assay when 2 ml plasma is extracted is generally 10 pg/ml (11). In this present study however, repeated sampling was necessary and therefore the plasma volume was reduced to 1 ml with a consequent halving of sensitivity. The specificity (16) and accuracy (17) of the ACTH assay have been described elsewhere. In the studies which follow, all samples from the same patient were measured in the same assay. Statistical analyses were carried out by Student's t test.
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CORTISOL AND ACTH RESPONSE TO HYPOGLYCEMIA 35 T
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