Diffuse Hormonal Systems

The birth of endocrinology was in the gastrointestinal tract! Figure 1 shows the progression from the discovery of the first hormone secretin when Bayliss and Starling instilled acid into the denervated duodenum of a dog and observed the flow of pancreatic secretions and said this must be due to a hormone which is a word derived from the Greek to “excite”. Subsequently gastrin was identified by Edkins as a potent gastric acid secretogogue in 1905 and Zollinger and Ellison in 1955 recognized it as the principal culprit for the Zollinger Ellison syndrome due to gastric acid overproduction. These discoveries led to a focus on pancreatic and gastric secretion. In 1925 Oberg and Ivy discovered CCK which contracted the gallbladder and it took eons to recognize a clinical syndrome associated with gastric hypersecretion by Jens Rehfeld. Meanwhile Verner and Morrison discovered VIP in 1972 which identified the culprit behind the watery diarrhea , hypokalemia acidosis syndrome (WDHHA) . A flurry of activity in the 60s and 70s led to the discovery of a host of peptides including gastric Inhibitory polypeptide (GIP) by John Brown who renamed it as glucose dependent insulin releasing peptide which has conferred upon it much greater notoriety. Advances in this field were catapulted with the development of radioimmunoassay by Berson and Yalow in 1959 led to the ability of quantification of hormones in the circulation in picomolar amounts and the application of the assay to glucagon by Roger Unger. The advances in immunological techniques and protein chemistry led to intensive progress with the purification and sequencing of a host of other peptides such as motilin, gastric inhibitory peptide somatostatin, leptin and ghrelin. Thus, grew the interest in physiologic mechanisms of action of these hormones digestive glandular secretion, gastrointestinal motility, visceral blood flow and tissue growth and proliferation as well as dedifferentiation of cells into their malignant counterparts. This era was recognized for the discovery of molecules without known biological function such as pancreatic polypeptide (PP), physiologic activity without known peptide regulators, hormones with dual function or as in the case of somatostatin discovered by Schally and Guillemin which was the second peptide captured for a role in peptide therapy. The ability to derive molecules from the parent molecule and its precursor enhanced the capacity to exploit its actions in controlling physiology as a virtual inhibitor of all secretions, to radiolabel the peptide in the development of imaging techniques such as the Octreoscan and the formation of long-acting analogs cable of restricting cell growth and proliferation. Further refinements have seen the evolution of peptide receptor radiotherapy (PRRT) and more potent Gallium DOTATOC and TATE scanning. This age has been referred to as Theranostics by Baum to reflect on the diagnostic capabilities as well as the therapeutic potential. The original recognition of Karzinoid as a tumor of the GI tract in 1907 led to the description by Feyrter of the cell type as Helle Zellen or transparent cells because of their characteristics gave birth to the recognition of the LC cell which is the grandfather of a far-reaching neuroendocrine tumor potential and expanded the role of the gut from pancreas and intestinal tract to a gut brain axis from which a number of disorders have blossomed. This theranostic era has witnessed the implications of tyrosine kinase inhibitors, MTOR involvement in tumor growth and therapy and these last few years have been party to a plethora of new discoveries of old hormones. New discoveries of new hormones and new discoveries of new functions for older peptides and new discoveries of actions outside of the GI tract for established GI hormones.Endocrine tumors of the gastroenteropancreatic (GEP) axis consist of cells that are capable of amine precursor uptake and decarboxylation and therefore have been named APUDomas (1). The morphologic similarity of the APUD cells suggested a common embryologic origin, which was believed to be the neural crest but was later revised to include the neuroectoderm or, in the case of endocrine cells, the dorsal placoderm. However, most investigators agree that these tumors should be classified according to their secretory products (i.e., carcinoid, gastrinoma, insulinoma, somatostatinomas, glucagonoma, vasoactive intestinal peptide [VIPoma] and pancreatic polypeptide [PPoma] (2) (3) (4). Before presenting their clinical characteristics we will briefly review the currently held views on the embryologic origin of these cells and the factors regulating their growth, differentiation and apoptosis, that serve to maintain homeostatic balance. We will also indicate the derangements that result in tumor formation.