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Human pancreatic tumor GH-releasing factor

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Summary

Within the past year, three similar peptides with specific growth hormone (GH) releasing effects have been extracted from human tissue, identified, and synthesized. Human pancreatic tumor GH releasing factor (1–40)-OH (hpGRF-40) was the sole hpGRF isolated from the pancreatic tumor of a patient in Charlottesville and was the predominant peptide isolated from the pancreatic tumor of a patient in Lyon. The Lyon tumor also contained hpGRF(1–37)-OH and hpGRF(1–44)-NH2. Both immunological and biochemical data suggest that hpGRF-40 and hpGRF-44 are present in the human hypothalamus and may be the human GH releasing hormone(s) (GHRH).

In cultures of rat pituitary cells, hpGRF stimulates GH but affects neither basal and dopamine-inhibited prolactin release nor basal and gonadotropin releasing hormone (GnRH)-stimulated luteinizing hormone (LH) release. hpGRF stimulates cyclic AMP production within seconds, an effect which is blocked by somatostatin. In contrast, while hpGRF stimulates phosphatidylinositol turnover in the pituitary, the effect is not inhibited by somatostatin.

In the human, hpGRF-40 (1 μg/kg) given intravenously (i.v.) stimulates GH release within 5 minutes. hpGRF-40 does not elevate serum prolactin levels, thyrotropin (TSH), LH, or corticotropin (measured indirectly through plasma cortisol), or blood glucose or plasma concentrations of insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastrin, gastric inhibitory peptide, motilin, or somatostatin. When graded doses of hpGRF (0.1–10 μg/kg) are given i.v., no differences are noted in the maximal levels of serum GH achieved. Doses of 1, 3.3 and 10 μg/kg hpGRF-40 elicits a prolonged and biphasic pattern of GH release. Twenty-four hours after hpGRF-40 administration, serum somatomedin C is increased in 66% of subjects tested. Side effects including a feeling of warmth and facial flushing are observed in 66% (3.3 gmg/kg) and 100% (10 μg/kg) of men given hpGRF-40. hpGRF-40 (3.3 μg/kg, i.v.) selectively stimulates GH release and somatomedin C production in normal women, although no differences are found in GH responsivity during the menstrual cycle. hpGRF-40 given intranasally to normal men (30 μg/kg) stimulates GH release within 30 minutes. The calculated metabolic clearance rate for hpGRF-40 is 194±17.51/m2/d; the disappearance rate occurs as two phases: an initial equilibration phase (7.6±1.2 minutes) and a subsequent elimination phase (51.8±5.4 minutes). hpGRF-40 administered i.v. stimulates the release of GH in some adult patients with GH deficiency documented in childhood. Serum somatomedin C concentrations may increase in patients in whom hpGRF-40 fails to stimulate GH release. If patients with GH deficiency who do not respond to hpGRF-40 administration (10 μg/kg i. v.) are given the peptide (0.33 μg/kg i. v. every 3 hours) for five days, some will respond to a subsequent 10 μg/kg challenge. Of those who do respond initially, the response to the subsequent challenge may be greater. Serum somatomedin C increases significantly following the 5 days of intermittent administration of hpGRF-40.

hpGRF-40 and/or hpGRF-44 may be the long sought GHRH. Clinical studies with hpGRF suggest that GH deficiency may often result from hypothalamic GHRH deficiency rather than pituitary disease. hpGRF and its analogues and antagonists may find therapeutic application in the treatment of GH deficiency and in other disorders in which an increase or decrease in the secretion of GH would be beneficial.

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Author notes

  1. M. O. Thorner

    Present address: Departments of Internal Medicine, Pharmacology, and Pediatrics, University of Virginia Medical Center, Charlottesville, Virginia

Authors and Affiliations

  1. Departments of Internal Medicine, Pharmacology, and Pediatrics, University of Virginia Medical Center, Charlottesville, Virginia

    W. S. Evans, M. Vance, J. L. C. Borges, R. M. Blizzard, A. D. Rogol, R. M. MacLeod, M. J. Cronin, L. A. Frohman, J. L. Thominet, R. Furlanetto, J. Rivier & W. Vale

  2. Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio

    M. O. Thorner, W. S. Evans, M. Vance, J. L. C. Borges, R. M. Blizzard, A. D. Rogol, R. M. MacLeod, M. J. Cronin, L. A. Frohman, J. L. Thominet, R. Furlanetto, J. Rivier & W. Vale

  3. Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

    M. O. Thorner, W. S. Evans, M. Vance, J. L. C. Borges, R. M. Blizzard, A. D. Rogol, R. M. MacLeod, M. J. Cronin, L. A. Frohman, J. L. Thominet, R. Furlanetto, J. Rivier & W. Vale

  4. Peptide Biology Laboratory, Salk Institute, San Diego, California

    M. O. Thorner, W. S. Evans, M. Vance, J. L. C. Borges, R. M. Blizzard, A. D. Rogol, R. M. MacLeod, M. J. Cronin, L. A. Frohman, J. L. Thominet, R. Furlanetto, J. Rivier & W. Vale

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Thorner, M.O., Evans, W.S., Vance, M. et al. Human pancreatic tumor GH-releasing factor. Acta neurochir 75, 72–80 (1985). https://doi.org/10.1007/BF01406325

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