Pathophysiology and clinical aspects of the ectopic GH‐releasing hormone syndrome

GH secretion is under the control of two hypothalamic hormones, somatostatin and GH-releasing hormone (GHRH). In addition, a group of synthetic GH-releasing peptides has been discovered, which are potent GH-secretagogues (Bowers, 1993). Their receptor, which is distinct from the GHRH receptor, has been characterized but the endogenous ligand remains elusive. The first evidence of the existence of GHRH came from the work of Reichlin (1960), who demonstrated that bilateral damage to the ventromedial hypothalamus of rats caused impairment of linear growth. A few years later the presence of a bioassayable GH-releasing activity in extracts of hypothalamus was reported by Deuben & Meites (1964). However, the paucity of available tissue, the lack of sensitivity of the bioassays to detect a GH-releasing activity and, most importantly, the difficulty in removing interfering substances, such as somatostatin, precluded the isolation and characterization of human GHRH. The solution to the problem came from an old clinical observation. In fact, it had been noted since the 1960s that in rare cases carcinoids, especially of the bronchial tree, were associated with acromegaly (Buse et al., 1961; Dabek, 1974). A few years later, So ̈nskenet al. (1976) reported for the first time that removal of a bronchial carcinoid resulted in remission of active disease in two acromegalic patients and proposed that the tumours contained a GH-releasing activity. This hypothesis was later confirmed by demonstrating that extracts of bronchial carcinoid tumours removed from acromegalic patients were able to stimulate GH secretion in a rat anterior pituitary cell monolayer culture in a dose-dependent manner (Shalet et al., 1979; uz Zafaret al., 1979). Following this line of research, Frohman and co-workers (1980, 1984) analysed other tumours removed from acromegalic patients and succeeded in partially purifying the long sought-after peptide. Successful isolation and chemical characterization of the peptide were achieved almost simultaneously in 1982 by two different research groups who had received large amounts of pancreatic endocrine tumours excised from two acromegalic patients (Guilleminet al., 1982; Rivier et al., 1982). The group of Guillemin (1982) reported the presence of three different molecular forms of GHRH, the longest of which was GHRH1–44NH2. Two other shorter peptides were also sequenced from the same tumour extract, GHRH 1–40OH and GHRH1–37NH2 (Guillemin et al., 1982). In the other tumour, Rivier et al. (1982) found only one molecular form of GHRH to be present, namely GHRH 1–40OH. The biological activity of the three molecular forms of GHRH was indistinguishable in a variety of in vitro systems (Brazeau et al., 1982a; Spiess et al., 1982). It was later demonstrated that full biological activity was retained by a fragment as short as GHRH 1–29 (Ling et al., 1984a), whereas further removal of C-terminal amino acids caused almost complete loss of biological activity. Furthermore, only minor modifications of the N-terminal end of GHRH caused a complete loss of GH-releasing activity of the peptide, suggesting that the first amino acids are essential for biological activity (Ling et al., 1984b). It remained to be demonstrated that the peptides extracted from the pancreatic tumours were identical to human hypothalamic GHRH. Spiess et al. (1983) demonstrated that extracts of human hypothalami exhibited elution patterns on HPLC and tryptic digests similar to GHRH1–44NH2 and GHRH1–40OH. Ling et al. (1984c), working with sufficient amounts of human brain, could identify unequivocally and sequence both forms of hypothalamic GHRH, showing that they had the same amino acid sequence as the GHRHs obtained from the pancreatic tumours. Using both extracted and subsequently synthetic GHRH, the mechanisms of action of the peptide on somatotrophs could be clarified. Upon binding to a specific membrane receptor, GHRH triggers the activation of the adenylate cyclase system, causing an immediate increase in both extraand intracellular cAMP levels (Brazeauet al., 1982b; Bilezikjian & Vale, 1983). Moreover, GHRH has been shown to produce a rapid and dosedependent stimulation of calcium efflux (Login et al., 1986).