Apomorphine-Stimulated Growth Hormone Release
JOHN T. LA ROSSA, M.D. RICHARD AGRIN. M.D. JAMES
C. MELBY.
M.D.
Boston, Massachusetts
Apomorphine, a dopaminergic receptor stimulant, was tested and compared in subemetic doses (0.75 mg subcutaneously) to levodopa (500 mg orally) as a stimulant of growth hormone release in 10 normal volunteer subjects (five male, five female). The administration of levodopa failed to cause a normal increment in serum growth hormone levels (>5 ng/ml from base line) in four patients, produced a borderline normal response in two patients and a normal response in four patients. Apomorphine stimulation produced a borderline normal response in one patient and a normal response in the remaining nine patients. The peak response to apomorphine administration was 26.94 f 6.60 ng/ml and to levodopa 9.76 f 2.67 ng/ml (p 5 ng/ml in four patients, a borderline response in two patients (Cases 8 and 9) and no response in four patients. The mean peak following the administration of levodopa was 9.76 + 2.67 ng/ml. The individual peak occurred at 60 minutes in four patients, at 90 minutes in five patients and at 120 minutes in one patient. The individual peak was > 10 ng/ml in only four of 10 patients. The mean increment of rise (Jmax) following the administration of levodopa was 7.31 f 2.26 ng/ml. Nausea and vomiting occurred in three of 10 patients, all of whom had similar side effects after apomorphine administration. The mean peak for apomorphine was significantly different (p 5 ng/ml increment) but one patient (Case #6) had a borderline response of 4.8 ng/ml. This patient was obese; further
ET AL.
experience with apomorphine may indicate the need to use larger doses in such patients. Levodopa, on the other hand, failed to elicit any response in four patients; two others had a borderline response and four had a normal response. This is in agreement with previous work demonstrating the inadequacy of levodopa stimulation [24] and in contradistinction to those reporting on the reliability of levodopa stimulation [ 111. Previous experience with levodopa testing has been attractive because of oral administration, relatively minor side effects and ability to utilize levodopa testing as an outpatient procedure. Our results with apomorphine testing compare favorably to those obtained with levodopa testing in regards to severity and frequency of side effects. Apomorphine produced nausea and vomiting in four of 10 patients, whereas levodopa produced the same effects in three of 10 patients; the three patients who reacted to levodopa also reacted to apomorphine. The nausea and vomiting developed within 20 minutes of administration of apomorphine and lasted up to 40 minutes. No patients tested with apomorphine complained of lightheadedness as previously reported in one series [25], although all noted transient drowsiness in our study. Peak apomorphine-stimulated values occurred at 30 minutes in three patients and at 45 minutes in seven patients. Thus, apomorphine testing could be carried out for 60 minutes as opposed to levodopa testing which would require 120 minutes. Further testing utilizing apomorphine in hospitalized patients may establish that apomorphine-stimulated growth hormone release may be safely utilized as both an in- and outpatient procedure, and that is is the most reliable provocative test of growth hormone release to the clinician.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
912
Roth J, Glick SM, Yallow RS: et al.: Hypoglycemia: A potent stimulus to secretion of growth hormone. Science 140: 987, 1963. Merimee TJ, Lillicrap DA, Rabinowitz D: Effect of arginine on serum levels of human growth hormone. Lancet 2: 668, 1965. Frohman LA, Horton ES, Lebowitz HE: Growth hormone releasing action of a pseudomonas endotoxin (Piromen). Metabolism 16: 67, 1967. Mitchell ML. Bryne MJ, Sanchez Y, et al.: Detection of growth hormone deficiency. The glucagon stimulation test. N Engl J Med 282: 539, 1970. Gagliardino JJ, Bailey JD, Martin JM: Effect of vasopressin on serum levels of human growth hormone. Lancet 1: 1357, 1967. Zahnd GR, Nadeau A, Von Muhlendahl K: Effect of corticotrophin on plasma levels of human growth hormone. Lancet 2: 1278, 1969. Kunita H, Takebe K, Nakagawa K: Effect of metyrapone on secretion of growth hormone in man. J Clin Endocrinol Metab 31: 301, 1970. Boyd AE Ill, Lebowitz HE, Pfeiffer JB: Stimulation of human
December 1977
The American Journal of Medicfne
9.
10.
11.
12.
13. 14.
15.
Volume 63
growth hormone secretion by L-Dopa. N Engl J Med 283: 1425, 1970. Roth J Glick SM,Yallow RS, et al.: Secretion of human growth hormone: physiologic and experimental modifications, Metabolism 12: 577, 1963. Lin T. Tucci JR: Provocative tests of growth hormone release. A comparison of results with seven stimuli. Ann Intern Med 80: 464, 1974. Eddy RL, Gilliand PF, lbarra JD. et al.: Human growth hormone release. Comparison of provocative test procedures. Am J Med 56: 179, 1974. Brown WA, VanWoeri MH, Ambani LM: Effect of apomorphine on growth hormone release in humans. J Clin Endocrinol Metab 37: 463, 1973. Maany I, Frazer A, Mendels J: Apomorphine: effect on growth hormone. J Clin Endocrinol Metab 40: 162, 1975. Brown WA, Krieger DT. VanWoert MH, et al.: Dissociation of growth hormone and cortisol release following apomorphine. J Clin Endocrinol Met 38: 1127, 1974. Lal S, Martin JB, de la Vega CE, et al.: Comparison of the effect of apomorphine and Idopa on serum growth hormone levels in normal men. Clin Endocrinol 4: 277, 1975.
APOMORPHINE-STIMULATED
16. 17.
18.
19
20.
Frohman LA: Diseases of hypothalamic releasing factors. Disease-a-Month 22: 6, 1976. Everett GM, Barcherding JW: L-Dopa: effect on concentrations of dopamine, norepinephrine and serotonin in brains of mice. Science 168: 848, 1970. Muller EE, dal Pra P, Pecile A: Influence of brain neurohumors injected into the lateral ventricle of the rat on growth hormone release. Endocrinology 83: 893, 1968. Frohman LA, Stachura ME: Neuropharmacologic control of neuroendocrine function in man. Metabolism 24: 211, 1975. Hokfelt T, Fuxe K: Brain-endocrine interaction. Median eminence: structure and function. International Symposium, Munich, Karger, Basel, 1971, p 181.
December
2 1.
22.
23.
24.
1977
GROWTH HORMONE RELEASE-L4
ROSSA ET AL.
Anden NE, Rubenson A, Fuxe K, et al.: Evidence for dopamine receptor stimulation by apomorphine. J Pharm Pharmacol 19: 627, 1967. Roos BE: Decrease in homovanillic acid as evidence for dopamine receptor stimulation by apomorphine in the neostriatum of rats. J Pharm Pharmacol 21: 263, 1969. Butcher LL. Anden NE: Effects of apomorphine and amphetamine on schedule-controlled behavior: reversal of tetrabenazine suppression and dopaminergic correlates. Eur J Pharm 6: 255, 1989. Gomez-Sanchez C, Kaplan NM: Apparent inadequacy of Ldopa stimulation as a clinical test of growth hormone release. J Clin Endocrinol Metab 34: 1105, 1972.
The American
Journal of Medicine
Volume 63
913
JOHN T. LA ROSSA, M.D. RICHARD AGRIN. M.D. JAMES
C. MELBY.
M.D.
Boston, Massachusetts
Apomorphine, a dopaminergic receptor stimulant, was tested and compared in subemetic doses (0.75 mg subcutaneously) to levodopa (500 mg orally) as a stimulant of growth hormone release in 10 normal volunteer subjects (five male, five female). The administration of levodopa failed to cause a normal increment in serum growth hormone levels (>5 ng/ml from base line) in four patients, produced a borderline normal response in two patients and a normal response in four patients. Apomorphine stimulation produced a borderline normal response in one patient and a normal response in the remaining nine patients. The peak response to apomorphine administration was 26.94 f 6.60 ng/ml and to levodopa 9.76 f 2.67 ng/ml (p 5 ng/ml in four patients, a borderline response in two patients (Cases 8 and 9) and no response in four patients. The mean peak following the administration of levodopa was 9.76 + 2.67 ng/ml. The individual peak occurred at 60 minutes in four patients, at 90 minutes in five patients and at 120 minutes in one patient. The individual peak was > 10 ng/ml in only four of 10 patients. The mean increment of rise (Jmax) following the administration of levodopa was 7.31 f 2.26 ng/ml. Nausea and vomiting occurred in three of 10 patients, all of whom had similar side effects after apomorphine administration. The mean peak for apomorphine was significantly different (p 5 ng/ml increment) but one patient (Case #6) had a borderline response of 4.8 ng/ml. This patient was obese; further
ET AL.
experience with apomorphine may indicate the need to use larger doses in such patients. Levodopa, on the other hand, failed to elicit any response in four patients; two others had a borderline response and four had a normal response. This is in agreement with previous work demonstrating the inadequacy of levodopa stimulation [24] and in contradistinction to those reporting on the reliability of levodopa stimulation [ 111. Previous experience with levodopa testing has been attractive because of oral administration, relatively minor side effects and ability to utilize levodopa testing as an outpatient procedure. Our results with apomorphine testing compare favorably to those obtained with levodopa testing in regards to severity and frequency of side effects. Apomorphine produced nausea and vomiting in four of 10 patients, whereas levodopa produced the same effects in three of 10 patients; the three patients who reacted to levodopa also reacted to apomorphine. The nausea and vomiting developed within 20 minutes of administration of apomorphine and lasted up to 40 minutes. No patients tested with apomorphine complained of lightheadedness as previously reported in one series [25], although all noted transient drowsiness in our study. Peak apomorphine-stimulated values occurred at 30 minutes in three patients and at 45 minutes in seven patients. Thus, apomorphine testing could be carried out for 60 minutes as opposed to levodopa testing which would require 120 minutes. Further testing utilizing apomorphine in hospitalized patients may establish that apomorphine-stimulated growth hormone release may be safely utilized as both an in- and outpatient procedure, and that is is the most reliable provocative test of growth hormone release to the clinician.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
912
Roth J, Glick SM, Yallow RS: et al.: Hypoglycemia: A potent stimulus to secretion of growth hormone. Science 140: 987, 1963. Merimee TJ, Lillicrap DA, Rabinowitz D: Effect of arginine on serum levels of human growth hormone. Lancet 2: 668, 1965. Frohman LA, Horton ES, Lebowitz HE: Growth hormone releasing action of a pseudomonas endotoxin (Piromen). Metabolism 16: 67, 1967. Mitchell ML. Bryne MJ, Sanchez Y, et al.: Detection of growth hormone deficiency. The glucagon stimulation test. N Engl J Med 282: 539, 1970. Gagliardino JJ, Bailey JD, Martin JM: Effect of vasopressin on serum levels of human growth hormone. Lancet 1: 1357, 1967. Zahnd GR, Nadeau A, Von Muhlendahl K: Effect of corticotrophin on plasma levels of human growth hormone. Lancet 2: 1278, 1969. Kunita H, Takebe K, Nakagawa K: Effect of metyrapone on secretion of growth hormone in man. J Clin Endocrinol Metab 31: 301, 1970. Boyd AE Ill, Lebowitz HE, Pfeiffer JB: Stimulation of human
December 1977
The American Journal of Medicfne
9.
10.
11.
12.
13. 14.
15.
Volume 63
growth hormone secretion by L-Dopa. N Engl J Med 283: 1425, 1970. Roth J Glick SM,Yallow RS, et al.: Secretion of human growth hormone: physiologic and experimental modifications, Metabolism 12: 577, 1963. Lin T. Tucci JR: Provocative tests of growth hormone release. A comparison of results with seven stimuli. Ann Intern Med 80: 464, 1974. Eddy RL, Gilliand PF, lbarra JD. et al.: Human growth hormone release. Comparison of provocative test procedures. Am J Med 56: 179, 1974. Brown WA, VanWoeri MH, Ambani LM: Effect of apomorphine on growth hormone release in humans. J Clin Endocrinol Metab 37: 463, 1973. Maany I, Frazer A, Mendels J: Apomorphine: effect on growth hormone. J Clin Endocrinol Metab 40: 162, 1975. Brown WA, Krieger DT. VanWoert MH, et al.: Dissociation of growth hormone and cortisol release following apomorphine. J Clin Endocrinol Met 38: 1127, 1974. Lal S, Martin JB, de la Vega CE, et al.: Comparison of the effect of apomorphine and Idopa on serum growth hormone levels in normal men. Clin Endocrinol 4: 277, 1975.
APOMORPHINE-STIMULATED
16. 17.
18.
19
20.
Frohman LA: Diseases of hypothalamic releasing factors. Disease-a-Month 22: 6, 1976. Everett GM, Barcherding JW: L-Dopa: effect on concentrations of dopamine, norepinephrine and serotonin in brains of mice. Science 168: 848, 1970. Muller EE, dal Pra P, Pecile A: Influence of brain neurohumors injected into the lateral ventricle of the rat on growth hormone release. Endocrinology 83: 893, 1968. Frohman LA, Stachura ME: Neuropharmacologic control of neuroendocrine function in man. Metabolism 24: 211, 1975. Hokfelt T, Fuxe K: Brain-endocrine interaction. Median eminence: structure and function. International Symposium, Munich, Karger, Basel, 1971, p 181.
December
2 1.
22.
23.
24.
1977
GROWTH HORMONE RELEASE-L4
ROSSA ET AL.
Anden NE, Rubenson A, Fuxe K, et al.: Evidence for dopamine receptor stimulation by apomorphine. J Pharm Pharmacol 19: 627, 1967. Roos BE: Decrease in homovanillic acid as evidence for dopamine receptor stimulation by apomorphine in the neostriatum of rats. J Pharm Pharmacol 21: 263, 1969. Butcher LL. Anden NE: Effects of apomorphine and amphetamine on schedule-controlled behavior: reversal of tetrabenazine suppression and dopaminergic correlates. Eur J Pharm 6: 255, 1989. Gomez-Sanchez C, Kaplan NM: Apparent inadequacy of Ldopa stimulation as a clinical test of growth hormone release. J Clin Endocrinol Metab 34: 1105, 1972.
The American
Journal of Medicine
Volume 63
913
