Clinical Endocrinology (1979) 10,575-581.
E F F E C T O F SOMATOSTATIN O N ABNORMAL GROWTH HORMONE A N D PROLACTIN SECRETION IN P A T I E N T S WITH T H E CARCINOID S Y N D R O M E A. GOMEZ-PAN,* M . F . S C A N L O N , * M. 0. T H O R N E R , ? L. H. REES,?. A. V. S C H A L L Y , S R . H A L L * A N D G. M. BESSER'f
*Endocrine Unit, Department of Medicine, Royal Victoria Infirmary, Newcastle upon Tyne, ?Departments of Endocrinology and. memica1 Pathology, St Bartholomew S Hospital, London, EClA 73E, and STulane University, New Orleans and VeteransA dm inis tra tion Hospital (Received 15 August 1978; revised 1 November 1978; accepted 13 November 1978)
SUMMARY
Growth hormone (GH) secretion has been studied in two patients with the carcinoid syndrome during glucose loading and growth hormone-release inhibiting hormone (GHRIH, somatostatin) infusion. Both patients had elevated fasting GH levels which were not suppressed by glucose; GH levels fell rapidly during GHRIH infusion. One patient also had hyperprolactinaemia with galactorrhoea and the prolactin (PRL) levels were unaltered by GHRIH. The association between carcinoid tumours and abnormalities of GH and PRL secretion is discussed. The hypothalamus regulates the secretion of growth hormone (GH) by means of two neurohurnoral agents, growth hormone-releasing factor (GH-RF), the structure of which is unknown and growth hormone-release inhibiting hormone (GHRIH; somatostatin), a cyclic tetradecapeptide Krulich et a/., 1968; Brazeau et al., 1973; Coy et al., 1973; Hall et al., 1973). There is now also firm evidence for the neurotransmitter control of GH secretion, perhaps through modulation of the release of GH-RF and somatostatin at a hypothalamic level. Pharmacological alpha adrenergic blockade suppresses the GH response to insulin hypoglycaemia (Blackard & Heidingsfelder, 1968), L-dopa (Kansal et al., 1972) and arginine (Buckler et al., 1969) whilst administration of alpha adrenoreceptor agonists causes GH release (Lal et al., 1975). Beta adrenergic blockade potentiates the GH response to both insulin hypoglycaemia (Parra et al., 1970) and L d o p a (Kansal et al., 1972). Administration of L-dopa, a carboxylated precursor of dopamine (Boyd et al., 1970), or dopamine receptor agonist drugs such as bromocriptine (Camanni et al., 1975; Tolis et al., 1975) or piribedil (Thorner et al., 1976) also causesGH release. 5-Hydroxytryptophan, a precursor of serotonin, Correspondence: Dr. M. F. Scanlon, Endocrine Unit, Department of Medicine, Royal Victoria Infirmary, Newcastle upon Tyne. 0300-0664/79/0600-0S75$02.00
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stimulates GH release (Imura et QZ., 1973; Lancranjan et QZ., 1977) whilst suppression of the GH response to arginine and 5-hydroxytryptamine by cyproheptadine (Nakai et ~ l . 1974) , might be due to the serotonin receptor blocking properties of the latter drug. It has also been reported recently that cyproheptadine lowers the elevated GH levels in acromegaly (Feldman er ~ l . 1976). , Some patients with the carcinoid syndrome may have elevated GH levels which are not suppressed by glucose loading (Feldman et ~ l . 1975) , and may even develop clinical acromegaly (Dabek, 1974; Sonksen e t QZ., 1976). In certain cases the tumour tissue itself may secrete a GH-like substance (Dabek, 1974) but there is also evidence for the secretion of biologically active substances with GH-releasing properties (Beck et ~ l . 1973; , Dabek, 1974; Sonksen et ~ l .1976). , Serotonin, dopamine and noradrenaline may each mediate such GH release and are known t o be produced in increased amounts by carcinoid tumours although it remains possible that other peptides or amines are involved. We report here the effects of glucose and somatostatin o n abnormal growth hormone secretion in two patients with the carcinoid syndrome. P A T I E N T S AND METHODS Two patients gave written consent to participate in the study. In the first patient, a 43year-old man, a diagnosis of carcinoid syndrome was made in 1970 on the basis of clinical and biochemical findings. Indeed, 3 years later he developed cardiac complications necessitating tricuspid and pulmonary valve replacement, and at the time of this study he had evidence of extensive hepatic metastases. There were no clinical features of acromegaly. In the second patient, a 23-year-old female, the carcinoid syndrome was diagnosed following thoracotomy in 1970 at which disseminated bronchial carcinoid tumour was found. Hepatic metastases were also present. In addition she suffered from the amenorrhoea-galactorrhoea syndrome and displayed mild clinical features of acromegaly, although there was no radiological evidence of enlargement of the sella turcica. Each patient had a standard 50 g oral glucose tolerance test (GTT) and on a different day, after fasting overnight and in the recumbent position, each received an infusion of somatostatin. Two indwelling venous cannulae (for somatostatin administration and blood sampling) were inserted under local anaesthesia at least 45 min before sampling commenced. Patient 1 had a 60-min infusion of 500 pg of somatostatin (rate 8.33 pglmin) and patient 2 received 500 pg of somatostatin over a 75-min period (rate 6.66 pg/min). Blood samples for GH, blood sugar (BS) and serum prolactin (PRL) (in patient 2) were drawn at intervals before, during and after administration of somatostatin and glucose. The cyclic somatostatin used in this study was synthesized by solid phase methods as described by Coy et ~ l (1973). . Serum GH was measured by radioimmunoassay (Hartog et ~ l . ,1964), using Medical Research Council (MRC) standard A (62/6). Serum PRL was estimated by radioimmunoassay (McNeilly, 1973) using MRC 71/222 as standard. BS was determined by a glucose oxidase method, using a Technicon autoanalyser. RESULTS Both patients had elevated fasting G H levels, which were not suppressed by an oral glucose load. Patient 1 had a diabetic GTT and showed a paradoxical GH rise after glucose load (Fig. 1). Administration of somatostatin resulted in a rapid reduction in serum GH levels in each
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10-
1’-
9-
87Glucose
4-
Fig. 1. Serum growth hormone and plasma glucose levels during an oral glucose tolerance
test in a patient with carcinoid syndrome (patient 1).
patient, though not to undetectable values (Figs 2 and 3). After discontinuation of the somatostatin infusion, GH levels remained suppressed for a further 30-min period in patient 1 (Fig. 2) and in patient 2 rebounded sharply to levels higher than basal (Fig. 3). Serum PRL levels were estimated during the somatostatin infusion in patient 2 . She was hyperprolactinaemic, with values ranging between 39 and 47 ng/ml (normal < 18 nglml), and these were unaltered by somatostatin. DISCUSSION Our results confirm previous observations that patients with the carcinoid syndrome may have elevated GH levels which are not suppressed by glucose loading (Feldman et al., 1975). It has been postulated that increased serotonin levels in these patients are responsible for the GH hypersecretion. This could also have explained the hyperprolactinaemia present in one of the patients reported here since pharmacological enhancement of serotoninergic pathways leads to increased secretion of prolactin as well as GH (Lancranjan et al., 1977). In the patient with hyperprolactinaemia, it is unlikely that increased circulating levels of dopamine and noradrenaline which might also have been produced by the carcinoid tumour, could have accounted for the GH hypersecretion since the catecholamines and dopamine in particular and inhibitors of prolactin secretion (for review see Thorner, 1977), and long-term administration of the dopamine agonist bromocriptine suppressed both GH and prolactin
A . Gomez-Pan et al.
5 78
H
-
m
5oOp4l Somatostatin
Fig. 2. Serum growth hormone and plasma glucose response. to somatostatin in a patient with carcinoid syndrome (patients 1).
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aJ v)
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Fig. 3. Serum growth hormone response to somatostatin in a patient with carcinoid syndrome (patient 2).
Effects of GHRIH in carcinoid syndrome
5 79
in this patient. However, we cannot exclude the possibility of secretion of ectopic GH o r GH-RF like material by the tumour tissue in these patients. A paradoxical GH rise after glucose administration as seen in one of our patients is normally present in the neonatal period (Cornblath et al., 1965) and is a common feature of acromegaly (Beck et al., 1966) but it can also be observed in a variety of metabolic disturbances such as chronic renal failure, Huntington’s chorea and Wilson’s disease (Martin, 1973). The mechanisms are unknown although it is possible that central neurotransmitter imbalances are involved in the mediation of these paradoxical GH responses or that there is an inappropriate pituitary response to an appropriate hypothalamic signal resulting from the rise in blood sugar. Administration of somatostatin produced a marked fall in circulating GH levels in both patients although suppression was not complete and GH levels remained detectable throughout the infusions. A similar pattern of inhibition of GH secretion by somatostatin has been reported in acromegaly (Hall et al., 1973; Besser e t al., 1974). Somatostatin had no effect on PRL levels in the patient with hyperprolactinaemia and the amenorrhoea-galactorrhoea syndrome. Lack of effect of somatostatin on PRLsecretion is in agreement with our previous observations in normals (Hall etal., 1973; Carr etal., 1975), and in patients with acromegaly (Besser e t al., 1974), but is in confict with reports from other workers (Grant e t al., 1974; Vale e t al., 1974). Association of the clinical features of acromegaly with bronchial carcinoid tumours has been reported previously (Dabek, 1974; Sonksen e t al., 1976) and this may represent a limited form of the pluriglandular syndrome (Rees & Ratcliffe, 1974). Gastrointestinal carcinoid tumours may be associated with abnormal GH secretion (Feldman e t al., 1975) but usually in the presence of widespread metastases, including hepatic. It may be possible that the anatomical location of each tumour type explains this phenomenon. Carcinoid tumours in general grow slowly but bronchial carcinoids secrete their products directly into the systemic circulation and thus chronic exposure to elevated GH levels may have accounted for the mild clinical features of acromegaly in patient 2. On the other hand the products of gastrointestinal carcinoid tumours are rapidly metabolized in the liver only reaching effective systemic concentrations in the presence of extensive metastases including hepatic. Life expectancy in this situation is short and thus chronic tissue exposure to elevated circulating GH levels does not occur. ACKNOWLEDGMENTS
We are grateful to the Research Committee of the Newcastle Area Health Authority (Teaching) for financial support. Dr M. F. Scanlon is a holder of an M.R.C. training fellowship in Endocrinology. REFERENCES BECK, C., LARKINS, R.G., MARTIN, T.J. & BURGER, H.G. (1973) Stimulation of growth hormone release from superfused rat pituitary by extracts of hypothalamus and of human lung tumours. Journal of Endocrinology, 59, 325-333. BECK, P., PARKER, M.L. & DAUGHADAY, W.H. (1966) Paradoxical hypersecretion of growth hormone in response to glucose. Journal of Clinical Endocrinology and Metabolism, 26, 463-469. BESSER, G.M., MORTIMER, C.H., CARR, D., SCHALLY, A.V., COY, D.H., EVERED, D.C., KASTIN, A.J., TUNBRIDGE, W.M.G., THORNER, M.O. & HALL, R. (1974) Growth hormone-release inhibiting hormone in acromegaly. British Medical Journal, i, 352-355.
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BLACKARD, W.G. & HEIDINGSFELDER, S.A. (1968) Adrenergic receptor control mechanism for growth hormone secretion. Journal of Clinical Investigation, 47, 1407-1414. BOYD, A.E., LEBOVITZ, H.E. & PFEIFFER, J.B. (1970) Stimulation of human-growth-hormone secretion by L-dopa. New England Journal of Medicine, 283, 1425-1429. BRAZEAU, P., VALE, W., BURGUS, R., LING, N., BUTCHER, M., RIVIER, J. & GUILLEMIN, R. (1973) Hypothalamic polypeptide that inhibits the secretion of immunoreactive growth hormone. Science, 179, 77-79. BUCKLER, J.M.H., BOLD, A.M., TABERNER, M. & LONDON, D.R. (1969) Modification of hormonal response to arginine by a-adrenergic blockade. British Medical Journal, iii, 153-154. CAMANNI, F., MASSARA, F., BELFORTE, L. & MOLINATTI, G.M. (1975) Changes in plasma growth hormone levels in normal and acromegalic subjects following administration of 2-bromo-a-ergocriptine. Journal of Clinical Endocrinology and Metabolism, 40, 363-366. CARR, D., GOMEZ-PAN, A., WEIGHTMAN,D.R., ROY, V.C.M., HALL, R., BESSER, G.M., THORNER, M.O., McNEILLY, A.S., SCHALLY, 4.V., KASTIN, A.J. & COY, D.H. (1975) Growth hormonerelease inhibiting hormone; actions on thyrotrophin and prolactin secretion after thyrotrophin releasing hormone. British Medical Journal, iii, 67-69. CORNBLATH, M., PARKER, M.L., REISNER, S.H., FORBES, A.E. & DAUGHADAY, W.H. (1965) Secretion and metabolism of growth hormone in premature and full term infants. Journal of Clinical Endocrinology, 25, 209-218. COY, D.H., COY, E.J., ARIMURA, A. & SCHALLY, A.V. (1973) Solid phase synthesis of growth hormone-release inhibiting factor. Biochemical and Biophysical Research Communications, 54, 12671273. DABEK, J.T. (1974) Bronchial carcinoid tumour with acromegaly in two patients. Journal of Clinical Endocrinology and Metabolism, 28, 329-333. FELDMAN, J.M., PLONK, J.W. & BIVENS, C.H. (1976) Inhibitory effect of serotonin antagonists on growth hormone release in acromegalic patients. Clinical Endocrinology, 5, 7 1-78. FELDMAN, J.M., PLONK, J.W., BIVENS, C.H., LEBOVITZ, H.E. & HANDWERGER, S. (1975) Growth hormone and prolactin secretion in the carcinoid syndrome. American Journal of the Medical Sciences, 269, 333-348. GRANT, N.H., SARANTAKIS, D. & YARDLEY, J.P. (1974) Actions of growth hormone-release inhibiting hormone on prolactin release in rat pituitary cell cultures. Journal ofEndocrinology, 61, 163164. HALL, R., BESSER, G.M., SCHALLY, A.V., COY, D.H., EVERED, D.C.,GOLDIE, D.J.,KASTIN, A.J., McNEILLY, A.S., MORTIMER, C.H. PHENEKOS, C., TUNBRIDGE, W.M.G. & WEIGHTMAN, D.R. (1973) Actions of growth hormone-release inhibiting hormone in healthy men and in acromegaly. Lancet, ii, 581-584. HARTOG, M., GAAFAR, M.A., MEISSER, B. & FRASER, T.R. (1964) Immunoassay of serum growth hormone in acromegalic patients. British MedicaZ Journal, ii, 1229-1232. IMURA, H., NAKAI, Y. & YOSHIMA, T. (1973) Effect of 5-hydroxytryptophan on growth hormone and ACTH release in man. Journal of Clinical Endocrinology and Metabolism, 36,204-206. KANSAL, P.C., BUSE, J., TALBERT, O.R. & BUSE, M. (1972) The effect of Ldopa on plasma growth hormone, insulin, and thyroxine. Journal of Clinical Endocrinology and Metabolism, 34, 99-1 05. KRULICH, L., DHARIWAL, A.P.S. & McCANN, S.M. (1968) Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology, 83,783-790. LAL, S., TOLIS, G., MARTIN, J.B., BROWN, G.M. & GUYDA, H. (1975) Effect of Clonidine on growth hormone, prolactin, luteinizing hormone, follicle stimulating hormone and thyroid stimulating hormone in the serum of normal men. Journal of Clinical Endocrinology and Metabolism, 41, 827832. LANCRANJAN, I., WIRZ-JUSTICE, A., PUHRINGER, W. & DEL POZO, E. (1977) Effect of 1-5 Hydroxytryptophan infusion on growth hormone and prolactin secretion in man. Journal of Clinical Endocrinology and Metabolism, 45,588-593. MARTIN, J.B. (1973) Neural regulation of growth hormone secretion. New England Journal of Medicine. 288,1384-1393. McNEILLY, A.S. (1973) Radioimmunoassay of human prolactin. Proceedings of the Royal Society of Medicine, 66, 863-864.
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NAKAI, Y., IMURA, H., SAKURAI, H., KURCHACHI, H. & YOSHIMA, T. (1974) Effect of cyproheptadine on human growth hormone secretion. Journal of Clinical Endocrinology and Metabolism, 38,446-449. PARRA, A., SCHULTZ, R.B., FOLEY, T.P. Jr & BLIZZARD, R.M. (1970) Influence of epinephrinepropranolol infusion on growth hormone release in normal and hypopituitary patients. Journal of Clinical Endocrinology and Metabolism, 30, 134-131. REES, L.H. & RATCLIFFE, J.G. (1974) Ectopic hormone production by nonendocrine tumours. Clinical Endocrinology, 3, 26 3-299. SONKSEN, P.H., AYRES, A.B., BRAIMBRIDGE, M., CORRIN, B., DAVIES, D.R., JEREMIAH, G.M., OATEN, S.W., LOWY, C. & WEST, T.E.T. (1976) Acromegaly caused by pulmonary carcinoid tumours. Clinical Endocrinology, 5, 503-5 13. THORNER, M.O. (1977) Dopamine mechanism and the endocrine system-clinical implications. Advanced Medicine, Vol. 13 (ed. G.M. Besser) pp. 99-114. Pitman Medical, England. THORNER, M.O., WASS, J.A.H., JONES, A., BLOOM, S.R. & MACLEOD, R.M. (1976) Effect of piribedil infusion on circulating growth hormone (GH), insulin, glucagon, cortisol and blood sugar in man. In: Proceedings of the Vth International Congress of Endocrinology, Abstract 59, p. 24. Hamburg, Germany. TOLIS, G., PINTER, E.J. & FRIESEN, H.G. (1975) The acute effect of 2-Bromoa-ergocryptine (CB 154) on anterior pituitary hormones and free fatty acids in man. International Journal of Clinical Pharmacology, 12, 28 1-283. VALE, W., RIVIER, C., BRAZEAU, P. & GUILLEMIN, R. (1974) Effects of somatostatin on the secretion of thyrotropin and prolactin. Endocrinology, 95,968-977.
E F F E C T O F SOMATOSTATIN O N ABNORMAL GROWTH HORMONE A N D PROLACTIN SECRETION IN P A T I E N T S WITH T H E CARCINOID S Y N D R O M E A. GOMEZ-PAN,* M . F . S C A N L O N , * M. 0. T H O R N E R , ? L. H. REES,?. A. V. S C H A L L Y , S R . H A L L * A N D G. M. BESSER'f
*Endocrine Unit, Department of Medicine, Royal Victoria Infirmary, Newcastle upon Tyne, ?Departments of Endocrinology and. memica1 Pathology, St Bartholomew S Hospital, London, EClA 73E, and STulane University, New Orleans and VeteransA dm inis tra tion Hospital (Received 15 August 1978; revised 1 November 1978; accepted 13 November 1978)
SUMMARY
Growth hormone (GH) secretion has been studied in two patients with the carcinoid syndrome during glucose loading and growth hormone-release inhibiting hormone (GHRIH, somatostatin) infusion. Both patients had elevated fasting GH levels which were not suppressed by glucose; GH levels fell rapidly during GHRIH infusion. One patient also had hyperprolactinaemia with galactorrhoea and the prolactin (PRL) levels were unaltered by GHRIH. The association between carcinoid tumours and abnormalities of GH and PRL secretion is discussed. The hypothalamus regulates the secretion of growth hormone (GH) by means of two neurohurnoral agents, growth hormone-releasing factor (GH-RF), the structure of which is unknown and growth hormone-release inhibiting hormone (GHRIH; somatostatin), a cyclic tetradecapeptide Krulich et a/., 1968; Brazeau et al., 1973; Coy et al., 1973; Hall et al., 1973). There is now also firm evidence for the neurotransmitter control of GH secretion, perhaps through modulation of the release of GH-RF and somatostatin at a hypothalamic level. Pharmacological alpha adrenergic blockade suppresses the GH response to insulin hypoglycaemia (Blackard & Heidingsfelder, 1968), L-dopa (Kansal et al., 1972) and arginine (Buckler et al., 1969) whilst administration of alpha adrenoreceptor agonists causes GH release (Lal et al., 1975). Beta adrenergic blockade potentiates the GH response to both insulin hypoglycaemia (Parra et al., 1970) and L d o p a (Kansal et al., 1972). Administration of L-dopa, a carboxylated precursor of dopamine (Boyd et al., 1970), or dopamine receptor agonist drugs such as bromocriptine (Camanni et al., 1975; Tolis et al., 1975) or piribedil (Thorner et al., 1976) also causesGH release. 5-Hydroxytryptophan, a precursor of serotonin, Correspondence: Dr. M. F. Scanlon, Endocrine Unit, Department of Medicine, Royal Victoria Infirmary, Newcastle upon Tyne. 0300-0664/79/0600-0S75$02.00
0 1979 Blackwell Scientific Publications
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stimulates GH release (Imura et QZ., 1973; Lancranjan et QZ., 1977) whilst suppression of the GH response to arginine and 5-hydroxytryptamine by cyproheptadine (Nakai et ~ l . 1974) , might be due to the serotonin receptor blocking properties of the latter drug. It has also been reported recently that cyproheptadine lowers the elevated GH levels in acromegaly (Feldman er ~ l . 1976). , Some patients with the carcinoid syndrome may have elevated GH levels which are not suppressed by glucose loading (Feldman et ~ l . 1975) , and may even develop clinical acromegaly (Dabek, 1974; Sonksen e t QZ., 1976). In certain cases the tumour tissue itself may secrete a GH-like substance (Dabek, 1974) but there is also evidence for the secretion of biologically active substances with GH-releasing properties (Beck et ~ l . 1973; , Dabek, 1974; Sonksen et ~ l .1976). , Serotonin, dopamine and noradrenaline may each mediate such GH release and are known t o be produced in increased amounts by carcinoid tumours although it remains possible that other peptides or amines are involved. We report here the effects of glucose and somatostatin o n abnormal growth hormone secretion in two patients with the carcinoid syndrome. P A T I E N T S AND METHODS Two patients gave written consent to participate in the study. In the first patient, a 43year-old man, a diagnosis of carcinoid syndrome was made in 1970 on the basis of clinical and biochemical findings. Indeed, 3 years later he developed cardiac complications necessitating tricuspid and pulmonary valve replacement, and at the time of this study he had evidence of extensive hepatic metastases. There were no clinical features of acromegaly. In the second patient, a 23-year-old female, the carcinoid syndrome was diagnosed following thoracotomy in 1970 at which disseminated bronchial carcinoid tumour was found. Hepatic metastases were also present. In addition she suffered from the amenorrhoea-galactorrhoea syndrome and displayed mild clinical features of acromegaly, although there was no radiological evidence of enlargement of the sella turcica. Each patient had a standard 50 g oral glucose tolerance test (GTT) and on a different day, after fasting overnight and in the recumbent position, each received an infusion of somatostatin. Two indwelling venous cannulae (for somatostatin administration and blood sampling) were inserted under local anaesthesia at least 45 min before sampling commenced. Patient 1 had a 60-min infusion of 500 pg of somatostatin (rate 8.33 pglmin) and patient 2 received 500 pg of somatostatin over a 75-min period (rate 6.66 pg/min). Blood samples for GH, blood sugar (BS) and serum prolactin (PRL) (in patient 2) were drawn at intervals before, during and after administration of somatostatin and glucose. The cyclic somatostatin used in this study was synthesized by solid phase methods as described by Coy et ~ l (1973). . Serum GH was measured by radioimmunoassay (Hartog et ~ l . ,1964), using Medical Research Council (MRC) standard A (62/6). Serum PRL was estimated by radioimmunoassay (McNeilly, 1973) using MRC 71/222 as standard. BS was determined by a glucose oxidase method, using a Technicon autoanalyser. RESULTS Both patients had elevated fasting G H levels, which were not suppressed by an oral glucose load. Patient 1 had a diabetic GTT and showed a paradoxical GH rise after glucose load (Fig. 1). Administration of somatostatin resulted in a rapid reduction in serum GH levels in each
Effects of GHRIH in carcinoid syndrome
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10-
1’-
9-
87Glucose
4-
Fig. 1. Serum growth hormone and plasma glucose levels during an oral glucose tolerance
test in a patient with carcinoid syndrome (patient 1).
patient, though not to undetectable values (Figs 2 and 3). After discontinuation of the somatostatin infusion, GH levels remained suppressed for a further 30-min period in patient 1 (Fig. 2) and in patient 2 rebounded sharply to levels higher than basal (Fig. 3). Serum PRL levels were estimated during the somatostatin infusion in patient 2 . She was hyperprolactinaemic, with values ranging between 39 and 47 ng/ml (normal < 18 nglml), and these were unaltered by somatostatin. DISCUSSION Our results confirm previous observations that patients with the carcinoid syndrome may have elevated GH levels which are not suppressed by glucose loading (Feldman et al., 1975). It has been postulated that increased serotonin levels in these patients are responsible for the GH hypersecretion. This could also have explained the hyperprolactinaemia present in one of the patients reported here since pharmacological enhancement of serotoninergic pathways leads to increased secretion of prolactin as well as GH (Lancranjan et al., 1977). In the patient with hyperprolactinaemia, it is unlikely that increased circulating levels of dopamine and noradrenaline which might also have been produced by the carcinoid tumour, could have accounted for the GH hypersecretion since the catecholamines and dopamine in particular and inhibitors of prolactin secretion (for review see Thorner, 1977), and long-term administration of the dopamine agonist bromocriptine suppressed both GH and prolactin
A . Gomez-Pan et al.
5 78
H
-
m
5oOp4l Somatostatin
Fig. 2. Serum growth hormone and plasma glucose response. to somatostatin in a patient with carcinoid syndrome (patients 1).
700 -
600 -
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c
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\
3
E 500-
I
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aJ v)
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Fig. 3. Serum growth hormone response to somatostatin in a patient with carcinoid syndrome (patient 2).
Effects of GHRIH in carcinoid syndrome
5 79
in this patient. However, we cannot exclude the possibility of secretion of ectopic GH o r GH-RF like material by the tumour tissue in these patients. A paradoxical GH rise after glucose administration as seen in one of our patients is normally present in the neonatal period (Cornblath et al., 1965) and is a common feature of acromegaly (Beck et al., 1966) but it can also be observed in a variety of metabolic disturbances such as chronic renal failure, Huntington’s chorea and Wilson’s disease (Martin, 1973). The mechanisms are unknown although it is possible that central neurotransmitter imbalances are involved in the mediation of these paradoxical GH responses or that there is an inappropriate pituitary response to an appropriate hypothalamic signal resulting from the rise in blood sugar. Administration of somatostatin produced a marked fall in circulating GH levels in both patients although suppression was not complete and GH levels remained detectable throughout the infusions. A similar pattern of inhibition of GH secretion by somatostatin has been reported in acromegaly (Hall et al., 1973; Besser e t al., 1974). Somatostatin had no effect on PRL levels in the patient with hyperprolactinaemia and the amenorrhoea-galactorrhoea syndrome. Lack of effect of somatostatin on PRLsecretion is in agreement with our previous observations in normals (Hall etal., 1973; Carr etal., 1975), and in patients with acromegaly (Besser e t al., 1974), but is in confict with reports from other workers (Grant e t al., 1974; Vale e t al., 1974). Association of the clinical features of acromegaly with bronchial carcinoid tumours has been reported previously (Dabek, 1974; Sonksen e t al., 1976) and this may represent a limited form of the pluriglandular syndrome (Rees & Ratcliffe, 1974). Gastrointestinal carcinoid tumours may be associated with abnormal GH secretion (Feldman e t al., 1975) but usually in the presence of widespread metastases, including hepatic. It may be possible that the anatomical location of each tumour type explains this phenomenon. Carcinoid tumours in general grow slowly but bronchial carcinoids secrete their products directly into the systemic circulation and thus chronic exposure to elevated GH levels may have accounted for the mild clinical features of acromegaly in patient 2. On the other hand the products of gastrointestinal carcinoid tumours are rapidly metabolized in the liver only reaching effective systemic concentrations in the presence of extensive metastases including hepatic. Life expectancy in this situation is short and thus chronic tissue exposure to elevated circulating GH levels does not occur. ACKNOWLEDGMENTS
We are grateful to the Research Committee of the Newcastle Area Health Authority (Teaching) for financial support. Dr M. F. Scanlon is a holder of an M.R.C. training fellowship in Endocrinology. REFERENCES BECK, C., LARKINS, R.G., MARTIN, T.J. & BURGER, H.G. (1973) Stimulation of growth hormone release from superfused rat pituitary by extracts of hypothalamus and of human lung tumours. Journal of Endocrinology, 59, 325-333. BECK, P., PARKER, M.L. & DAUGHADAY, W.H. (1966) Paradoxical hypersecretion of growth hormone in response to glucose. Journal of Clinical Endocrinology and Metabolism, 26, 463-469. BESSER, G.M., MORTIMER, C.H., CARR, D., SCHALLY, A.V., COY, D.H., EVERED, D.C., KASTIN, A.J., TUNBRIDGE, W.M.G., THORNER, M.O. & HALL, R. (1974) Growth hormone-release inhibiting hormone in acromegaly. British Medical Journal, i, 352-355.
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