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Somatostatin: Hormonal and

Therapeutic Roles

SOMATOSTATIN, or growth hormone release

inhibitory hormone, was initially described as a

14-aminoacid peptide (somatostatin-14). Subsequentlya 28-aminoacid form (somatostatin-28) was found inman and this seems particularly prevalent in the

gastrointestinal tract. When pharmacological doses ofsomatostatin-14 are infused, the effects includeinhibition of endocrine secretions (growth hormone,thyroid-stimulating hormone, insulin, glucagon, andall the gut hormones), of exocrine secretions (gastricacid, pancreatic bicarbonate, and enzymes), and ofsmall intestinal absorption, and also depression ofsplanchnic blood flow.Somatostatin is present in many parts of the body in

both cells and nerves. Whether it works locally as aparacrine substance, which seems likely from theconnections of its cellular processes to cells of different

types,’ or whether it is a true hormone, has been muchdebated. The demonstration of somatostatin releaseafter a meal has strengthened the hormonal case, butthe quantities said to be released vary considerablyfrom one centre to another, with their different

radioimmunoassays; for example, Wass et all reporteda doubling of plasma concentrations after a standardbreakfast while O’Shaughnessy et aP reported no riseafter a standard breakfast and only a small rise after avery large meal. These small physiological plasma riseshave been reproduced in man by infusion of very low

1. Larsson LI, Goltermann N, Magistris LD, Rehfeld JF, Schwartz TW. Somatostatincell processes as pathways for paracrine secretion. Science 1979; 205: 1393-95.

2. Wass JAH, Penman E, Dryburgh JR, et al Circulating somatostatin after food andglucose in man. Clin Endocrinol 1980; 12: 569-74.

3. O’Shaughnessy DJ, Long RG, Adrian TE, et al. Somatostatin-14 modulates

postprandial glucose levels and release of gastrointestinal and pancreatic hormones.Digestion 1985; 31: 234-42.

doses of somatostatin, and meal-stimulated gastric acidsecretion and gut and pancreatic hormone release werethereby reduced.3,4 In dogs, plasma somatostatin roseafter a meal; and when somatostatin antiserum wasinfused during a fatty meal, plasma concentrations oftriglycerides, gastrin, pancreatic polypeptide, andinsulin were higher than on the control days.5 Thesedata suggest a hormonal role for somatostatin-14 in

controlling postprandial hormone and gastric acidsecretion. There is also evidence that somatostatin-28is released after meals6 but there are no published dataon the effects of infusion in physiological quantities.With its many actions, somatostatin-14 has been

tried therapeutically in various conditions, and thereported benefits include inhibition of tumoursecretions in patients with acromegaly, insulinomas,glucagonomas, the carcinoid syndrome, and VIPomas(the diarrhoea is also controlled in the last two, perhapspointing to an additional direct inhibitor effect onsmall and large intestinal secretion); improvement ofglycaemic control in non-insulin-dependent diabetesmellitus; improvement of the early and late dumpingsyndrome; and an antiarrhythmic effect in paroxysmalsupraventricular tachycardias. However, the

application of greatest potential clinical impact iscontrol of gastrointestinal bleeding. This is a commoncondition with a case-fatality rate of about 10%, and nodrug has an established place. Since somatostatin-14reduces gastric acid secretion, splanchnic blood flow,and portal vein pressure, it would seem theoreticallyideal. Initial small studies suggested that it might beeffective in the treatment of cimetidine-resistant

bleeding peptic ulcers’ and of oesophageal varices,where it was as effective as vasopressin and had fewerside-effects. Enthusiasm waned, however, when adouble-blind study in 534 patients showed no

significant effect in patients with bleeding ulcers.9 Alarge double-blind placebo-controlled trial in varicealbleeding would be worth while.

Somatostatin-14 has two main drawbacks as a

potential drug. Firstly, its actions are very non-specificand long-term use is likely to result in side-effects suchas intestinal malabsorption and glucose intolerance.Attempts have therefore been made to synthesiseanalogues that are more specific for individual effects.Two analogues proved to have relative glucagon andinsulin specificity in rats but not in man.10 Analogueswith special activity on rabbit and rat gut have been4 Loud FB, Holst JJ, Egense E, Petersen B, Christiansen J. Is somatostatin a hormonal

regulator of the endocrine pancreas and gastric acid secretion in man? Gut 1985; 26:445-49.

5. Chiba T, Kadowaki S, Taminato T, et al. Effects of antisomatostatin gamma-globulinon gastrin release in rats. Gastroenterology 1981; 81: 321-26.

6. Polonsky KS, Shoelson SE, Docherty HM. Plasma somatostatin-28 increases inresponse to feeding in man. J Clin Invest 1983; 71: 1514-18.

7. Kayasseh L, Gyr K, Keller U, Stalder GA, Wall M Somatostatin and cimetidine inpeptic-ulcer haemorrhage. A randomised controlled trial. Lancet 1980; 1: 844-46.

8 Kravetz D, Bosch J, Teres J, Bruix J, Rimola A, Rodes J. Comparison of intravenoussomatostatin and vasopressin infusions in treatment of acute variceal haemorrhage.Hepatology 1984; 4: 442-46.

9. Somerville KW, Henry DA, Davies JG, Hine KR, Hawkey CJ, Langman MJS.Somatostatin in treatment of haematemesis and melaena Lancet 1985; i: 130-32.

10. Adrian TE, Barnes AJ, Long RG, et al. The effect of somatostatin analogs on secretionof growth, pancreatic and gastrointestinal hormones in man. J Clin EndocrinolMetab 1981; 53: 675-81

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described but have not been tested in man.11 Thesecond drawback of somatostatin-14 is its short plasmahalf-life (2-3 min); this means that it must be given bycontinuous intravenous infusion. Rebound effects

(such as severe flushing in patients with the carcinoidsyndrome) are sometimes seen a few minutes after theinfusion is stopped. A partial answer is provided bythree different long-acting analogues, of which two areoctapeptidesl2,13 and one a hexapeptide.14 The first ishydrophobic and is long-acting when given as a

subcutaneous injection; the others are more resistant todegradation. Twice daily injections of the long-actingoctapeptide SMS 201-995 are reported effective inreducing the high hormone concentrations and theirconsequences in patients with acromegaly, I 5 thecarcinoid syndrome, and pancreatic endocrinetumours.13 The dose regimens will vary greatly; forexample, severe acromegaly may require largeamounts. Two patients with profuse watery diarrhoeadue to VIP-secreting tumours were unresponsive tonumerous other treatments, but improved on

somatostatin for 3 and 14 months.’6," In the secondpatient there was also possible evidence of hepatictumour regression, suggesting that long-term long-acting somatostatin treatment, like bromocriptine inpatients with pituitary tumours, may have a directeffect on tumour size as well as on the secretion oftumour products.

What Triggers Autoimmunity?THE repertoire of antibodies that our B lymphocytes

can make includes many that are potentially reactivewith self components. So the first question to be askedmight be not "what triggers autoimmunity?" but"what prevents autoimmunity?". There are severalpossible answers. One is that B cells, early in theirdevelopment when they first express antibody at theirsurface membrane, can be switched off by contact withthe appropriate antigens provided that they meet theseat a sufficient concentration.’ Nevertheless, manypotentially self-reactive B cells escape. A second is thatmost B cells are not stimulated to secrete antibodywithout cooperation from T-helper (TH)lymphocytes; which must also recognise the same

11. Rosenthal LE, Yamashico DJ, Rivier J, et al Structure-activity relationships ofsomatostatin analogs in the rabbit ileum and the rat colon. J Clin Invest 1983; 71:840-49

12. Long RG, Barnes AJ, Adrian TE, et al. Suppression of pancreatic endocrine tumoursecretion by long acting somatostatin analogue. Lancet 1979; ii 764-67.

13 Wood SN, Kraenzlin ME, Adrian TE, Bloom SR. Treatment of patients withpancreatic endocrine tumours using a new long-acting somatostatin analogue:symptomatic and peptide responses. Gut 1985, 26: 438-44

14 Veber DF, Freidinger RM, Perlow DS, et al. A potent cyclic hexapeptide analogue ofsomatostatin Nature 1981; 292: 55-58.

15 Plewe G, Beyer J, Krause U, Neufeld M, del Pozo E. Long-acting and selectivesuppression of growth hormone secretion by somatostatin analogue SMS 201-995in acromegaly Lancet 1984; ii: 782-84

16. Maton PN, O’Dorisio TM, Howe BA, et al. Effect of a long-acting somatostatinanalogue (SMS 201-995) in a patient with pancreatic cholera N Engl J Med 1985;312: 17-21

17 Kraenzlin ME, Ch’ng JLC, Wood SM, Carr DH, Bloom SR Long-term treatment of aVIPoma with somatostatin analogue resulting in remission of symptoms and

possible shrinkage of metastases. Gastroenterology 1985; 88: 185-871. Nossal GJV. Cellular mechanisms of immunologic tolerance. Ann Rev Immunol 1983;

1: 33-62

antigen, and that the necessary TH cells that couldrecognise self antigens are not available.2 A third is thatsuppressor T cells and even anti-antibodies developthat prevent the B cells from functioning.3 All thesemechanisms probably play their part, but absence ofappropriate TH cells has been regarded as the mostimportant. However this raises the separate question ofwhy potentially self-reactive TH cells are apparentlynot available. To this the answer is that they mayindeed be present, but are not normally stimulated byself antigens because of the special nature of T cellantigen receptors, which are at last beginning to beunderstood.T cell antigen receptors (Ti), like immunoglobulins,

are made up of two linked glycoprotein molecules,coded for by genes that control variable, D, J, andconstant regions, and these can be joined in an

enormous variety of ways, so enabling the T cell

population to recognise very many extrinsic but alsoself antigens. However, unlike immunoglobulins, Tiare intimately associated with one of two othermolecules identified in man by the monoclonalantibodies T4 and T8.4 T4 is on T helper cells and T8on cytotoxic/suppressor Tc cells. For stimulation ofthese T cells to take place the Ti/T4 or Ti/T8

complexes need to interact with antigens in associationwith molecules of the major histocompatibilitycomplex (MHC). TH cells recognise antigens whenthey are associated with MHC class II and Tc cells withMHC class I. A further requirement is that resting THcells be first activated by the accessory factorinterleukin-1, which is produced by macrophages.5Resting Tc cells require the accessory factor

interleukin-2, which is produced by TH cells—ie, theyalso require TH help—before they can proliferate.Such a complex arrangement must have some

biological explanation, and this may well be to avoidthe development of autoimmunity. The argument goesas follows. T cell precursors, which in adults arise fromstem cells in the bone marrow, do not express antigenreceptors. This is inferred from the fact that their Ti

genes are in the germ line configuration, and notrearranged as they are found to be in mature T cells.Consequently at this stage they must be indifferent toantigens, whether extrinsic or self. The T cell

precursors migrate to the thymus, where they multiplyextensively and gene rearrangement takes place—ie,antigen receptors become expressed there.6 However,nine-tenths of the T cells die within the thymus beforemature T cells emerge. It is generally supposed thatthis destruction reflects elimination of T cells capableof reacting with such self components as are accessible

2. Allison AC. Autoimmune diseases: concepts of pathogenesis and control in

autoimmunity. In: Talal N, ed. Autoimmunity: genetic, immunologic, virologicand clinical aspects New York: Academic Press, 1977: 92-139.

3 Green DR, Flood PM, Gershon RK. Immunoregulatory T-cell pathways. Ann RevImmunol 1983, 1: 423-38

4 Reinherz EL, Meuer SC, Schlossman SF. The delineation of antigen receptors onhuman T lymphocytes Immunol Today 1983; 4: 5-8.

5. Smith KA Interleukin-2. Annu Rev Immunol 1984, 2: 319-33.6. Snodgrass HR, Kisielow P, Kiefer M, Steinmetz M, von Boehmer H. Ontogeny of the

T-cell antigen receptor within the thymus. Nature 1985; 313: 592-95.