J Chron Dis 1975, Vol. 28, pp. 91-100. Pergamon Press. Printed in Great Britain
EFFECT OF ILLNESS ON SERUM GROWTH HORMONE RESPONSE TO INTRAVENOUS GLUCOSE GEORGEN. SFAKIANAKIS, JACK M. GEORGE,XAVIERJ. RICCOBONO and MANUELTZAGOURNIS Departments of Radiology (Division of Nuclear Medicine) and Medicine, The Ohio State University Hospitals, Columbus, Ohio (Received 18 Decetnber 1973)
ORAL glucose administration has been shown to suppress human growth hormone (hGH) levels in normal subjects [ 1,2]. This phenomenon has been used to differentiate normal individuals from those who have an autonomous pituitary tumor secreting hGH [l-3]. An hGH rise 4-5 hr after oral glucose administration is a normal response to falling serum glucose [I], while an hGH rise 1 hr after oral glucose is considered abnormal and has been termed ‘paradoxical’ [2-4]. Several conditions, including malignant tumors, have been reported to be associated with a paradoxical rise in growth hormone levels 1 hr after oral glucose [4-131. Intravenous glucose administration leads to an earlier fall in blood sugar and resultant increase in hGH than oral glucose [l]. Several studies, however, have shown that 1 hr after quick intravenous glucose injection, plasma hGH levels are not elevated and commonly are lower than the basal levels in normal persons [14-161. An elevated plasma hGH 1 hr after intravenous glucose administration, equivalent to the paradoxical rise after oral GTT, has been reported in several conditions [14-191 and in a case of hepatoma [8]. Intravenous glucose has the advantage of bypassing any variability in ingestion or absorption and for this reason we chose it for the studies reported here. hGH responses to quick intravenous glucose injection in patients with malignancy were compared to those in asymptomatic controls and ill patients without malignancy. The results suggest that early glucose-induced hGH increases are not specific for malignancy and correlate best with the degree of stress associated with illness. MATERIALS
AND
METHODS
Twenty patients (13 males, 7 females) with a variety of malignancies with or without known metastasis were studied (Table 1). Sixteen ill patients (10 males, 6 females) without known neoplastic disease were also studied (Table 1). Nine hospitalized patients (1 male, 8 females) who were admitted for diagnostic studies served as the control group. The control group had no acute illness and no significant complaints although two of them had asymptomatic diabetes treated by diet. 91
92
GEORGEN.SFARIANARIS~~
al.
TABLE1. INDIVIDUALhGH RESPONSE TO RAPID INTRAVENOUS GLUCOSEINFUSION IN PATIENTSWITH MALIGNANCIES AND OTHER DISEASES (a) Correlation of paradoxical hGH response with tumor site and extent in patients with malignancy hGH rise Metastases at 1 hr Location Sex-age _~_. _ M M F M M M F F F F M M M M M M F F M M
Thyroid Thyroid Thyroid Lung Lung Tongue Breast Breast Breast Breast Stomach Liver Pancreas Pancreas Colon Kidney Cervix Rhabdomyosarcoma Lymphosarcoma Hodgkin’s (IV)
48 11 13 49 67 64 69 40 44 :; 58 71 52 85 53 52 40 II 29
+ + + +
+ + + + + + +
+ + + + + +
+ + + +
+ +
(b) Correlation of paradoxical hGH response with diagnosis in acutely ill patients without malignancy Sex-age
Diagnosis
M F F M M M F M M F F M F M M M
Pancreatitis-hepatitis Pancreatitis-hepatitis Cholangitis Anemia Pneumonia Pneumonia Pneumonia Pneumonia Osteomyelitis Pyelonephritis Pericarditis Pericardiotomy (1st day) Heart failure Heart failure Glossectomy (10th day) Glossectomy (3rd day)
52 50 56 68 81 51 54 63 68 42 62 41 61 63 64 71
hGH rise at 1 hr 1 + + + + +
+
+
The testing was performed in the morning after an overnight fast. Twenty-five grams of glucose were given intravenously in 2 min. Blood samples were obtained for serum glucose, hGH, insulin, plasma cortisol, and free fatty acid (FFA) determinations at 0, lo,60 and 120 min intervals. During the examination, the patients remained in bed or were sitting comfortably in a chair. All medications except antibiotics were withheld from midnight until the completion of the 2 hr test.
Serum hGH After IV Glucose
93
Serum glucose levels were measured by autoanalyzer by the glucose oxidase method. Immunoassay measurements for hGH and insulin were done by the salt precipitation method described by Grodsky and Forsham [20]. Cortisol was determined by Mattingly’s fluorimetric method [21] and FFA by Dole’s titrimetric method [22]. Statistical analysis was performed using Student’s t-test and Pearson correlation.
F
60
120
Mln
patients with FIG. 1. Mean serumgrowthhormone (hGH) levels in controls (*-), malignancy (o - - - - o) and nonmalignant ill patients (= . . , . a) before and after 25 gm glucose infusion. Shaded area represents standard error of mean (SEM) of controls.
RESULTS
All nine of the asymptomatic controls showed normal growth hormone suppression 1 hr after intravenous glucose in con&-mation of previous studies [1416]. Mean basal hGH levels were not statistically different in the three groups (Fig. 1). One hour after glucose, mean hGH levels were 8.4 ng/ml in ‘tumor patients’ and 4.4 ng/ml in the ill patients without malignancy, both significantly higher than the 1.4 ngjml in the control group (p < 0.5). Although the tumor patients had a higher mean hGH level at 1 hr than the ill patients, the difference was not significant. As expected hGH rose slightly 2 hr after glucose in the control patients. Both groups of ill patients showed a decrease in hGH levels from the 1 hr level to the 2 hr level. Immunoassays of hGH were performed in serially diluted serum samples of four tumor patients with the paradox and three asymptomatic controls. The parallel dilution curves suggested that in both groups the growth hormone was immunologically identical to purified hGH standards (Fig. 2). Glucose
Mean serum glucose levels were not significantly different in the three groups at any time interval (Table 2). The disappearance rate of glucose as calculated from the values for blood glucose at 10 and 60 min was also very similar in all of the groups and could not account for differences noted in hGH responses. C
94
GEORGE
N. SFAKIANAKIS et al.
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FIG. 2. Growth
(-----)
hormone measurements in serial dilutions of serum from controls and patients with malignancy (- - - - -) compared to purified growth hormone (-).
Free fatty acids
Mean plasma free fatty acid levels of both groups of ill patients were not significantly different from those of asymptomatic controls (Table 2). The group with malignancy had a higher mean basal and 1 hr level than the group of ill patients without malignancy (p c 0.5). However, this difference did not seem to be related to the hGH responses, since a comparison of those patients with a paradoxical response and those showing normal suppression within each group revealed virtually identical free fatty acid levels at all times tested. Serum insulin
Mean serum insulin levels were not significantly different in the three groups at any time tested (Table 2). There was no correlation between hGH responses and serum insulin levels. Plasma cortisol
The mean cortisol levels in the three groups of the study are shown in Table 2. Significantly higher cortisol concentrations were found in the ill patients, with or without tumor, as compared to the asymptomatic controls (p < 0.05) (Table 2). Eight of the 45 subjects studied did not have cortisol determinations because they were previously treated with steroids or insufficient blood was available during the tests. There was a tendency toward higher hGH levels at all time intervals when basal cortisol levels were elevated (Table 3). Those patients with serum cortisol levels at 0 times exceeding 20 ug/lOO ml had significantly (~~0.01) higher hGH concentrations 1 hr after glucose (Fig. 3). Eight of the 10 patients with basal cortisol levels greater than 20 ug/lOO ml showed a paradoxical rise in hGH after glucose (four with and four without malignancy).
623 _t46
8
l2
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FFA (@q/L)
Insulin (N/ml)
Cortisol (icd100 ml)
11.2 11.5
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289 ~26
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24 16
398 176
115 116
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EFFECT OF ILLNESS ON SERUM GROWTH HORMONE RESPONSE TO INTRAVENOUS GLUCOSE GEORGEN. SFAKIANAKIS, JACK M. GEORGE,XAVIERJ. RICCOBONO and MANUELTZAGOURNIS Departments of Radiology (Division of Nuclear Medicine) and Medicine, The Ohio State University Hospitals, Columbus, Ohio (Received 18 Decetnber 1973)
ORAL glucose administration has been shown to suppress human growth hormone (hGH) levels in normal subjects [ 1,2]. This phenomenon has been used to differentiate normal individuals from those who have an autonomous pituitary tumor secreting hGH [l-3]. An hGH rise 4-5 hr after oral glucose administration is a normal response to falling serum glucose [I], while an hGH rise 1 hr after oral glucose is considered abnormal and has been termed ‘paradoxical’ [2-4]. Several conditions, including malignant tumors, have been reported to be associated with a paradoxical rise in growth hormone levels 1 hr after oral glucose [4-131. Intravenous glucose administration leads to an earlier fall in blood sugar and resultant increase in hGH than oral glucose [l]. Several studies, however, have shown that 1 hr after quick intravenous glucose injection, plasma hGH levels are not elevated and commonly are lower than the basal levels in normal persons [14-161. An elevated plasma hGH 1 hr after intravenous glucose administration, equivalent to the paradoxical rise after oral GTT, has been reported in several conditions [14-191 and in a case of hepatoma [8]. Intravenous glucose has the advantage of bypassing any variability in ingestion or absorption and for this reason we chose it for the studies reported here. hGH responses to quick intravenous glucose injection in patients with malignancy were compared to those in asymptomatic controls and ill patients without malignancy. The results suggest that early glucose-induced hGH increases are not specific for malignancy and correlate best with the degree of stress associated with illness. MATERIALS
AND
METHODS
Twenty patients (13 males, 7 females) with a variety of malignancies with or without known metastasis were studied (Table 1). Sixteen ill patients (10 males, 6 females) without known neoplastic disease were also studied (Table 1). Nine hospitalized patients (1 male, 8 females) who were admitted for diagnostic studies served as the control group. The control group had no acute illness and no significant complaints although two of them had asymptomatic diabetes treated by diet. 91
92
GEORGEN.SFARIANARIS~~
al.
TABLE1. INDIVIDUALhGH RESPONSE TO RAPID INTRAVENOUS GLUCOSEINFUSION IN PATIENTSWITH MALIGNANCIES AND OTHER DISEASES (a) Correlation of paradoxical hGH response with tumor site and extent in patients with malignancy hGH rise Metastases at 1 hr Location Sex-age _~_. _ M M F M M M F F F F M M M M M M F F M M
Thyroid Thyroid Thyroid Lung Lung Tongue Breast Breast Breast Breast Stomach Liver Pancreas Pancreas Colon Kidney Cervix Rhabdomyosarcoma Lymphosarcoma Hodgkin’s (IV)
48 11 13 49 67 64 69 40 44 :; 58 71 52 85 53 52 40 II 29
+ + + +
+ + + + + + +
+ + + + + +
+ + + +
+ +
(b) Correlation of paradoxical hGH response with diagnosis in acutely ill patients without malignancy Sex-age
Diagnosis
M F F M M M F M M F F M F M M M
Pancreatitis-hepatitis Pancreatitis-hepatitis Cholangitis Anemia Pneumonia Pneumonia Pneumonia Pneumonia Osteomyelitis Pyelonephritis Pericarditis Pericardiotomy (1st day) Heart failure Heart failure Glossectomy (10th day) Glossectomy (3rd day)
52 50 56 68 81 51 54 63 68 42 62 41 61 63 64 71
hGH rise at 1 hr 1 + + + + +
+
+
The testing was performed in the morning after an overnight fast. Twenty-five grams of glucose were given intravenously in 2 min. Blood samples were obtained for serum glucose, hGH, insulin, plasma cortisol, and free fatty acid (FFA) determinations at 0, lo,60 and 120 min intervals. During the examination, the patients remained in bed or were sitting comfortably in a chair. All medications except antibiotics were withheld from midnight until the completion of the 2 hr test.
Serum hGH After IV Glucose
93
Serum glucose levels were measured by autoanalyzer by the glucose oxidase method. Immunoassay measurements for hGH and insulin were done by the salt precipitation method described by Grodsky and Forsham [20]. Cortisol was determined by Mattingly’s fluorimetric method [21] and FFA by Dole’s titrimetric method [22]. Statistical analysis was performed using Student’s t-test and Pearson correlation.
F
60
120
Mln
patients with FIG. 1. Mean serumgrowthhormone (hGH) levels in controls (*-), malignancy (o - - - - o) and nonmalignant ill patients (= . . , . a) before and after 25 gm glucose infusion. Shaded area represents standard error of mean (SEM) of controls.
RESULTS
All nine of the asymptomatic controls showed normal growth hormone suppression 1 hr after intravenous glucose in con&-mation of previous studies [1416]. Mean basal hGH levels were not statistically different in the three groups (Fig. 1). One hour after glucose, mean hGH levels were 8.4 ng/ml in ‘tumor patients’ and 4.4 ng/ml in the ill patients without malignancy, both significantly higher than the 1.4 ngjml in the control group (p < 0.5). Although the tumor patients had a higher mean hGH level at 1 hr than the ill patients, the difference was not significant. As expected hGH rose slightly 2 hr after glucose in the control patients. Both groups of ill patients showed a decrease in hGH levels from the 1 hr level to the 2 hr level. Immunoassays of hGH were performed in serially diluted serum samples of four tumor patients with the paradox and three asymptomatic controls. The parallel dilution curves suggested that in both groups the growth hormone was immunologically identical to purified hGH standards (Fig. 2). Glucose
Mean serum glucose levels were not significantly different in the three groups at any time interval (Table 2). The disappearance rate of glucose as calculated from the values for blood glucose at 10 and 60 min was also very similar in all of the groups and could not account for differences noted in hGH responses. C
94
GEORGE
N. SFAKIANAKIS et al.
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70-
I I ," E
60-
: L:
50-
$
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/
I’
,**’
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,/' ,,'I ,$:' ,' #' g I / ,I ,$ ,* #' ;/ ,' ,,;P'/ /,,/ 8,' /'#' / I' I' /.' ,/ , ,;:* ,' I' :' /
3020'
002
0.05 Serum
01
0.150.2025 0.4
dilutions
FIG. 2. Growth
(-----)
hormone measurements in serial dilutions of serum from controls and patients with malignancy (- - - - -) compared to purified growth hormone (-).
Free fatty acids
Mean plasma free fatty acid levels of both groups of ill patients were not significantly different from those of asymptomatic controls (Table 2). The group with malignancy had a higher mean basal and 1 hr level than the group of ill patients without malignancy (p c 0.5). However, this difference did not seem to be related to the hGH responses, since a comparison of those patients with a paradoxical response and those showing normal suppression within each group revealed virtually identical free fatty acid levels at all times tested. Serum insulin
Mean serum insulin levels were not significantly different in the three groups at any time tested (Table 2). There was no correlation between hGH responses and serum insulin levels. Plasma cortisol
The mean cortisol levels in the three groups of the study are shown in Table 2. Significantly higher cortisol concentrations were found in the ill patients, with or without tumor, as compared to the asymptomatic controls (p < 0.05) (Table 2). Eight of the 45 subjects studied did not have cortisol determinations because they were previously treated with steroids or insufficient blood was available during the tests. There was a tendency toward higher hGH levels at all time intervals when basal cortisol levels were elevated (Table 3). Those patients with serum cortisol levels at 0 times exceeding 20 ug/lOO ml had significantly (~~0.01) higher hGH concentrations 1 hr after glucose (Fig. 3). Eight of the 10 patients with basal cortisol levels greater than 20 ug/lOO ml showed a paradoxical rise in hGH after glucose (four with and four without malignancy).
623 _t46
8
l2
11.4 Ikl.1
FFA (@q/L)
Insulin (N/ml)
Cortisol (icd100 ml)
11.2 11.5
38 &lO
289 ~26
10.3 il.1
24 16
398 176
115 116
*0.2
1.4
10.5 11.3
11 i3
541 i72
91 +12
1,l.l
3.5
120
20.5* kl.9
10 12
757 --,67
96 16
$0.6
2.9
18.7* hl.8
32 _C5
269 516
16.6* I2.0
27 i6
473 It53
153 512
“2.2
8.4*
Patients with malignancy (n=20) 0 10 60
*p
