This paper has reviewed current knowledge of clinical, biochemical, and morphological manifestations of extracranial GRH-producing tumors. Excessive GRH release stimulates pituitary somatotrophs causing elevation of blood GH levels and acromegaly. In some patients with GRH-containing tumor, blood GH concentrations are normal and no acromegaly develops. GRH-producing tumors associated with acromegaly are rare. Based on a critical analysis of the literature, 30 tumors are accepted as definitive. They possess unique features: occurrence in young age, female preponderance, foregut derivation, benign biological behavior, small secretory granules, and frequent association with MEN type I syndrome. The pancreas and lung are common primary sites. GRH-containing tumors unassociated with acromegaly include those of gut and thymus, small cell carcinoma of lung, and medullary carcinoma of thyroid. Several tumors are plurihormonal. In contrast to somatotroph adenoma seen in patients with classical acromegaly, the hypophysial lesion represents somatotroph hyperplasia in acromegalic patients with GRH-producing tumor. This finding indicates that GRH not only increases somatotroph secretory activity but causes somatotroph proliferation. Studies of GRH-producing tumors are of fundamental importance in obtaining a deeper insight into endocrine activity of pituitary somatotrophs and the pathogenesis of GH-secreting pituitary adenomas associated with acromegaly; the importance of GRH in the etiology of acromegaly is still unresolved. The relationship between GRH-secreting tumors and MEN type I syndrome is controversial; further studies are required to elucidate whether they represent two distinct entities or whether GRH-producing tumors accompanied by acromegaly are only forme fruste manifestations of MEN type I syndrome.

Growth Hormone-Releasing Hormone-Producing Tumors: Clinical, Biochemical, and Morphological Manifestations*

12~392. Neuroregulation of GH secretion 131 BIRCE, C.A., PEAKE, G.T., MARIZ, I.K. & DAWGHADAY, W.H. (1967) Radioimmunoassayable growth hormone in the rat pituitary gland: effects of age, sex and hormonal state. Endocrinology, 81, 195-204. BLACKLAY, A. GROSSMAN, A , Ross, R.J.M., SAVAGE, M.O., DAVIES, P.S. W., PLOWMAN, P.N., COY, D.H. & BESSER, G.M. (1986) Cranial irradiation for cerebral and nasopharyngeal tumours in children: evidence for the production of a hypothalamic defect in growth hormone release. Journal ofEndocrinology, 108,25-29. BLOCH, B., LING, N., BENOIT, R., WEHRENBERG, W.B. & GUILLEMIN, R. (1984a) Specific depletion of immunoreactive growth hormone-releasing factor by monosodium glutamate in rat median eminence. Nature, 307,272-273. BLOCH, B., GAILLARD, R.C., BRAZEAU, P., LIN, H.D. &LING, N. (1984b) Topographical and ontogenetic study of the neurons producing growth hormone-releasing factor in human hypothalamus. Regulatory Peptides,B, 21-31. BORKENSTEIN, M. (1986) The effects of intranasal insufflation of growth hormone releasing factor analogue GRF (1-29) NH2 on growth hormone secretion in children with short stature. Acta Endocrinologica BOWERS, C.Y., MOMANY, F.A., REYNOLDS, G.A. & HONG, A. (1984) On the in vitro and in vivo activity of a new (SUPPI.), 279, 135-138. synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology, 114, 1537-1545. BRAMNERT, M. & HOKFELT, B. (1987) Naloxone enhances the increase in plasma growth hormone induced by a*adrenergic stimulation in healthy males. Acta Endocrinologica, 114, 308-3 13. BRESSON, J.L., CLAVEQUIN, M.C., FELLMAN, D. & BUGNON C. (1984) Ontogeny of the neuroglandular system revealed with hpGRF 44 antibodies in human hypothalamus. Neuroendocrinology, 39,68-73. BRUHN, T.O., MASON, R.T. & VALE W.W. (1985) Presence of growth hormone-releasing factor-like immunoreactivity in rat duodenum. Endocrinology, 117, 1710-1712. CABEZAS-CERRATO, J., PENALVA, , VIDAL, P., ICLESIAS, M., LADO, J. & ARAUXO, D. (1987) Pituitary response of normal subjects to fast sequential stimulus by the four hypothalamic releasing hormones before and after activation of GABA synapses by sodium valproate. 3rd Meering of the European Neuroendocrine Association. London, Abstract 67. CAMPBELL, P.J., BOLLI, G.B., CRYER, P.E. & GERICH, J.E. (1985) Pathogenesis of the dawn phenomenon in patients with insulin dependent diabetes mellitus. New England Journal of Medicine, 312, 1473-1479. CASANUEVA, F.F., BETTI, R., CELLA S.G., MULLER, E.E. & MANTEGAZZA, P. (1983) Effects of agonists and antagonists of cholinergic neurotransmission on growth hormone release in the dog. Acta Endocrinologica, CASANUEVA, F.F., VILLANUEVA, L., CABRANES, J.A., CABEZAS-CERRATO, J. & FERNANDEZ-CRUZ, A. (1984a) Cholinergic mediation of growth hormone secretion elicited by arginine, clonidine and physical exercise in man. Journal of Clinical Endocrinology and Metabolism, 59, 526-530. CASANUEVA, F.A., VILLANUEVA, L., PENALVA, ,, CABEZAS-CERRATO, J. (l984b) Depending on the stimulus, central serotoninergic activation by fenfluramine blocks or does not alter growth hormone secretion in man. Neuroendocrinology, 38,302-308. CASANUEVA, F.F., VILLANUEVA, L. DIEGUEZ, C., CABRANES, J.A., DIAZ, Y., SZOKE, B., SCANLON, M.F., SCHALLY A.F. & FERNANDEZ-CRUZ, A. (1986) Atropine blockade of growth hormone (GH)-releasing hormone-induced GH secretion in man is not exerted at pituitary level. Journal of Clinical Endocrinology and Metabolism, 62, 186-191. CASANUEVA, F.F., VILLANUEVA, L. DIEGUEZ, C., DIAZ, Y., CABRAMS, J.A., SZOKE, B., SCANLON, M.F., SCHALLY A.V. & FERNANDEZ-CRUZ, A. (1987) Free fatty acids (FFA) blockade of GHRH-induced GH secretion in man. Journal of Clinical Endocrinology and Metabolism, 65,634-640. CAVAGNINI, F., INVITTI, C., DI LANDRO, A., TENCONI, L., MARASCHINI, C. & GIROTTI, G. (1977) Effects of a GABA derivative baclofen, on growth hormone and prolactin secretion in man. Journal of Clinical Endocrinology and Metabolism, 45, 579-584. CEDA, G.P. &HOFFMAN, A.R. (1985) Growth hormone-releasing factor densensitisation in rat anterior pituitary cells in vitro. Endocrinology, 116, 13361340. CELLA, S.G., MORGESE, M., MANTEGAZA, P. & MULLER, E.E. (1984) Inhibitory action of the eel-adrenergic receptor on growth hormone secretion in the dog. Endocrinology, 114, 2406-2408. CHATELAIN, B., DAVID, M. & FRANCOIS, R. (1985) Effect of acute intravenous growth hormone-releasing factor on plasma prolactin in short children and patients with growth hormone deficiency. Hormone Research, 22, 4651 . CHIODINI, P.G., LIUZZI, A,, DALLABONZANA, D., OPPIZZI, G . & VERDE, G. (1985) Changes in growth hormone 103, 15-20. 132 C. Dieguez et al. (GH) secretion induced by human pancreatic GHRH releasing hormone-44 in acromegaly: a comparison with thyrotropin-releasing hormone and bromocriptine. Journal ofClinical Endocrinology and Metabolism, 60,48-52. CH’NC, L.J.C., SANDLER, L.M., KRAENZLIN, M.E., BURRIN, J.M., JOPLIN, G.F. & BLOOM, S.R. (1985) Long term treatment of acromegaly with a long-acting analogue of somatostatin. British Medical Journal, 290,284285. CHIHARA, K., IWASAKI, J. MINAMITANI, ., KAJI, H., MATSUKURA, S. TAMAKI, N., MATSUMOTO, S. & FUJITA, T. (1982) Effect of vasoactive intestinal polypeptide on growth hormone secretion in perfused acromegalic pituitary adenoma tissues. Journal of Clinical Endocrinology and Metabolism, 54, 773-779. CHIHARA, K., KAJI, H., MINAMITANI, . KODAMA, H., KITA, T., GOTO, B., CHIRA, T., COY, D. & FUJITA, T. (1984) Stimulation of growth hormone by vasoactive intestinal polypeptide in acromegaly. Journal of Clinical Endocrinology and Metabolism, 58, 8 I--86. CHIHARA, K., KODAMA, H., KAJI, H., KITA, T., KASHIO, Y., OKIMURA. Y., ARE, H. & FUJITA, T. (l985a) Augmentation by propranolol of growth hormone-releasing hormone-( 1-44)-NHl-induced growth hormone release in normal short and normal children. Journal of Clinical Endocrinology and Metabolism, CHIHARA, K., KASHIO, Y., ARE, H., MINAMITANI, ., KAJI, H., KITA, T. & FUJITA, T. (1985b) Idiopathic growth hormone (GH) deficiency and GH deficiency secondary to hypothalamic germinoma: effect of single and repeated administration of human GH-releasing factor (hGRF) on plasma GH level and endogeneous hGRF-like immunoreactivity level in cerebro-spinal fluid. Journal of Clinical Endocrinology and Metabolism, 60,269-278. CHIHARA, K., KASHIO, Y., KITA, T., OKIMURA, Y., KAJI, H. ARE. H. & FUJITA, T. (1986) L-Dopa stimulates release of hypothalamic growth hormone-releasing hormone in humans. Journal of Clinical Endocrinology and Metabolism, 62,466-473. CLARK, R.G. & ROBINSON, I.C.A.F. (1985) Growth induced by pulsatile infusion of an amidated fragment of human growth hormone releasing factor in normal and GHRF-deficient rats. N a m e , 314, 28 1-283. CLAYTON, R.N. & BAILEY, L.C. (1987) Somatostatin partially reverses densensitization of somatotrophs induced by growth hormone-releasing factor. Journal of Endocrinology, 112, 69 76. COZZI, R., DALLABONZANA, D., OPPIZZI, G., VERDE, G., LIUZZI, A. & CHIODINI, P.G. (1986a) Bromocriptine does not alter growth hormone (GH) responsiveness to GH releasing hormone in acromegaly. Journal of Clinical Endocrinology and Metabolism, 62,60 1-604. Cozzr, R., LIUZZI, A., DALLABONZANO, D., OPPIZZI, G., VERDE, G., PETRONCINI, M., CHIODINI, P.G. & DEL POZO, E. (1986b) Chronic infusion of SMS 201 995 induces a stable normalisation of GH and SMC levels in acromegaly. European Neuroendocrine Association Conference on Somatostatin. Madrid, 1986, Abstract. DANIELPOUR, D. IKEDA, T., KUNKEL, M.W. & SIRRASKU, D.A. (1984) Identification of an autostimulatory growth factor in the extracts and conditioned medium of GH3/C14 rat pituitary cells in culture. Endocrinology, 114, 1221 -~1223. DAVIES, R.R., TURNER, S. & JOHNSTON, D. (1984) Oral glucose inhibits growth hormone secretion induced by human pancreatic growth hormone releasing factor 1 4 4 in normal man. Clinical Endocrinology, 21, 47748 1. DAVIS, J.R.E., SHEPPARD, M.C., SHAKESPEAR, .A., LYNCH, S.S. & CLAYTON, R.N. (1986) Does growth hormone-releasing factor densensitise the somatotroph? Interpretation of responses of growth hormone during and after 10-hour infusion of GRF 1-29 amide in man. Clinical Endocrinology, 24, 135.140. DELITALA, G., MAOUILI, M., PACIFICO, A,, BRIAUDA, S.A., PALERMO, M. & MANERELLI, M. (1983a) Cholinergic receptor control mechanisms for L-dopa apomorphine and clonidine-induced growth hormone secretion in man. Journal of Clinical Endocrinology and Metabolism, 57, 1145-1 149. DELITALA, G., GROSSMAN, A. & BESSER, G.M. (1983b) Opiate peptides control growth hormone through a cholinergic mechanism in man. Clinical Endocrinology, 18,401405. DELITALA, G., PALERMO, M., Ross, R., COY, D., BESSER, M. & GROSSMAN, A. (1987) Dopaminergic and cholinergic influences on the growth hormone response to growth hormone-releasing hormone in man. Neuroendocrinology, 45,243-247. DEL Pozo, E., NEUFELD, M., SCHLUTER, K., TORLOSA, F., CLARENBACH, P., BEIDER, E.. WENDEL, L., NUESCH, E., MARBACH, P., KRAMER, H. & VERP, L. (1986a) Endocrine profile of a long acting somatostatin derivative SMS 201 -995. Study in normal volunteers following subcutaneous administration. Acta Endocrinologia, 111,433439. DEL POZO, E. & LAMBERTS, S.W.J. (1986b) Effect of a long acting somatostatin analogue (SMS 201 995) on 61, 229--233. Neuroregulation of GH secretion 133 glucose homeostasis in type I diabetes and acromegaly. International Conference on Somatostatin. Washington, Abstract, p. 26. DIEGUEZ, C., FOORD, S.M., SHEWRING, ., EDWARDS, C.A., HEYBURN, P.J., PETERS, J.R., HALL, R. & SCANLON, M.F. (1984) The effects of long term growth hormone releasing factor (GRF 140) administration on growth hormone secretion and synthesis in vitro. Biochemical and Biophysical Research Communications, 121,111-117. DIEGUEZ, C., FOORD, S.M., PETERS, J.R., HALL, R. & SCANLON, M.F. (1985) The effe

Growth hormone neuroregulation and its alterations in disease states

THE clinical features of acromegaly result directly or indirectly from sustained hypersecretion of growth hormone.1 2 3 Somatotroph-cell adenomas, or in rare cases hyperplasia, constitute the pathologic pituitary lesions causing acromegaly.4 , 5 Also in rare cases, acromegaly may be caused by ectopic somatotroph-cell adenomas in the sphenoid or parapharyngeal sinuses.4 , 5 Attention has recently been focused on the elaboration of growth hormone–releasing factors by carcinoid6 and pancreatic islet-cell tumors7 causing acromegaly. The structure of human growth hormone–releasing factor was, in fact, first elucidated from two such pancreatic tumor extracts, which were shown to stimulate growth hormone release both in vitro and in vivo.8 , 9 Ectopic . . .

Acromegaly Due to Secretion of Growth Hormone by an Ectopic Pancreatic Islet-Cell Tumor

To assess the frequency with which acromegaly is caused by ectopic secretion of GRF, we collected plasma samples from 177 unselected acromegalic patients The samples together with those of three acromegalic patients with previously diagnosed tumors secreting GRF and of normal subjects were assayed in 3 independent GRF RIAs Plasma immunoreactive GRF (IR-GRF) levels in normal subjects were either undetectable or detectable at levels up to 625 pg/ml In none of the 177 specimens from acromegalic patients were IR-GRF values detectable in all assays, and in the most sensitive assay, the levels were similar to those in normal subjects, with the highest level measuring 82 pg/ml In contrast, plasma IR-GRF found in the 3 patients with tumors that secreted GRF ranged from 20-244 ng/ml These data suggest that extrahypothalamic GRF secretion is a rare cause of acromegaly However, it is important that this rare cause of acromegaly be diagnosed before the patient has unnecessary surgery and/or irradiat

Extrahypothalamic Growth-Hormone-Releasing Factor (GRF) Secretion Is a Rare Cause of Acromegaly: Plasma GRF Levels in 177 Acromegalic Patients*

/pdf/by-plasma-in-vitro-and-in-vivo-to-a-biologically-inactive-r7ynygykvc.pdf

by Plasma In Vitro and In Vivo to a Biologically Inactive Product Cleaved at the NH2 Terminus

Administration of human pancreatic tumor growth hormone (GH) releasing factor (hpGRF[1-40]) as a single injection to normal human subjects stimulates the secretion of GH in a dose-responsive manner. In the present studies, hpGRF(1-40) was infused in a graded stepwise manner over a 6-h period in order to determine whether the GH secretory response would be sustained. Normal adult males received four consecutive 90-min infusions of hpGRF(1-40) at doses of 1, 3.3, 10, and 33 ng/kg per min, preceded and followed by a 90-min saline infusion; and the plasma GH responses were compared with those during a separate control infusion. Plasma GH levels were significantly elevated by each hpGRF(1-40) infusion; and dose responsiveness was evident for the lowest three doses. Mean integrated GH secretory rates for the four doses were 1.95, 3.29, 4.29, and 3.65 times those of the respective control study. Plasma GH responses exhibited considerable variability, frequently decreasing during the latter part of each infusion; and at the highest dose, they decreased continuously beginning shortly after the onset of infusion. Episodic GH secretion occurred in individual subjects during each of the infusion periods. The possible contribution of hypothalamic somatostatin secretion to the diminished GH responsiveness was evaluated by determining plasma thyroid stimulating hormone (TSH) levels during the infusions and the TSH responses to thyrotropin-releasing hormone (500 micrograms i.v.) during a separate hpGRF(1-40) infusion of 2 ng/kg per min. Neither basal nor stimulated TSH levels differed between GRF-infused and control groups. The results indicate that GH secretion is dose responsive to hpGRF(1-40) infusions, though the response to hpGRF(1-40) infusions, though the response is complex. The absence of impaired TSH secretion provides evidence against a mediating role of somatostatin. The explanation for the loss of GH responsiveness remains undetermined but could include GRF-induced receptor down-regulation, a postreceptor effect, or, in spite of our negative results, a somatostatin-mediated inhibition.

/pdf/plasma-growth-hormone-responses-to-constant-infusions-of-46yndrxia2.pdf

Plasma growth hormone responses to constant infusions of human pancreatic growth hormone releasing factor. Intermittent secretion or response attenuation.

The metabolic clearance rate (MCR) and plasma disappearance rate (t1/2) of human pancreatic tumor growth hormone releasing factor [hpGRF(1-40)] was determined in normal adult male subjects by single injection and constant infusion techniques. Single injections of 1, 3.3, and 10 micrograms/kg hpGRF(1-40) were administered intravenously, plasma immunoreactive (IR) GRF levels were measured during the subsequent 180 min, and biexponential curve analysis was performed. Graded, dose-constant infusions of hpGRF(1-40) at rates of 1, 3.3, 10, and 33 ng/kg per min were administered and the MCR was calculated from measurement of steady state plasma IR-GRF levels at each infusion rate. The postinfusion disappearance rate was determined by linear regression analysis of plasma IR-GRF levels during the 120-min period after cessation of the infusion. The calculated MCR during the single injection study was 194 +/- 17.5 liters/m2 per d and was not significantly different from the calculated value during the constant infusion study (202 +/- 16 liters/m2 per d). The disappearance rate during the single injection study was subdivided into two linear phases: an initial equilibration phase (7.6 +/- 1.2 min) and a subsequent elimination phase (51.8 +/- 5.4 min). The latter was similar to the linear disappearance rate observed (41.3 +/- 3.0 min) after cessation of the constant infusion. The chromatographic and biologic characteristics of plasma IR-GRF, 30 min after injection, were similar to those of synthetic hpGRF(1-40). The results have been discussed in relation to the MCR of other hypothalamic hormones and have been used to extrapolate secretion rates of GRF in patients with ectopic GRF production.

/pdf/metabolic-clearance-and-plasma-disappearance-rates-of-human-3lr7pk39z1.pdf

Metabolic clearance and plasma disappearance rates of human pancreatic tumor growth hormone releasing factor in man.

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Plasma growth hormone responses to constant infusions of human pancreatic growth hormone releasing factor. Intermittent secretion or response attenuation.

Metabolic clearance and plasma disappearance rates of human pancreatic tumor growth hormone releasing factor in man.