S.Afr.J.Anim.Sci.,199 4, 24(1) Somatotropinphysiology - a review J.G.van der Walt Departmentof Physiology,Veterinary Science, University of Pretoria,Onderstepoort, 0110 Republicof SouthAf rica Received4 June 1993;accepted l5 November/,993 The continuing search for improved efficiency has led to the introduction of exogenousgrowth and lactation promo- tants to enhance traditional animal production systems.Various species-limitedsomatotropins have been synthesized by meansof recombinantgene technology,thereby allowing milk productionin dairy cattle,and lcan meat production in pigs, sheep and cattle to be manipulated.Growth hormone occurs in plasma in several forms, which overlap considerably with the structuresof placental lactogen and prolactin. The peptide is stabilized by two disulphidc bridges,and is folded into four a-helix regions.The somatogenicand lactogenicregions have been mapped,and two different binding sites found. Somatotropinis secretedepisodically from the anterior pituitary with a sniking ultradian rhythm in all mammals investigated thus far. The primary control over this release would appear to be neuro- endocrinological,with somatostatinand releasinghormone (GHRH) playing the major roles, with considerablespecics differences.Starvation primes the systemto optimally releasesomatotropin when feedingrecommences. While sexual dimorphism in the releaseof somatotropinhas been clearly demonstratedin the rat, most studiesin other specieshave concentratedon male animals. Although somatotropinexhibis negative feedback on its release,it does not appear to have a direct effect on the somatotroph.In the ruminantat lcast"somatotropin may also be involved in satietycontrol. Other systemsthat have been implicatedin the control of somatotropinrelease in ruminantsincludc cholecystokinin, serotonin,dopamine and cr-adrenergicreceptors and plasma glucoseconcentrations, all via regulatory mechanismsin the hypothalamus,which change from pre- to postweaning (glycogenic to gluconeogenic).Recently, GHRH analogues,consisting of a seriesof short (5-6 amino acids)peptides similar to encephalin,as well as a nonpeptidyl secretagoguehave been developed.Although GHRH normally contains40-44 residues,it is only the 29 amino acids.. at the amino terminal end that are associatedwith the releasingactivity. By replacing arginine residueswith agmatinS (decarboxylatedarginine), it is possible to create analoguesthat have an increasedpotency of more than 50-fold. The short-termresponse to somatotropinin high-yielding Holstein cows varies between 2 and 5 kglday. The dose responseappears to be curvilinear and is not affected by the pattern of administration.There is no increase in feed intake during short-termadministration of somatotropin,although in the long term increasesof 10-25% have been found, when measuredover the entire lactation. In such cases,feed intake increasedgradually to match the increased milk production, owing to an improvement of feed conversion.The lactogenic effect does not appearto be mediated by *y direct effect on the mammary gland. The most pronouncedeffect of somatotropinis the releaseof the insulin- like growth factors(IGF), chiefly from the liver, and to inhibit lipogenesis.Although somatotropindecreases body far, non-esterifiedfatty acids only increaseduring a negativeenergy balance. Although studiesin sheepgenerally support these contentions, the effect on growth is controversial.Average daily gain (ADG) and feed conversion efficiency (FCE) generally improve with treatment,accompanied by a fairly consistent l0 to 20qo decreasein carcassfat. The major effect in pigs is anabolic,leading in general to a 10-209o increasein ADG, a 15-357o improvement in FCE, a 30-407o decreasein lipid depositionand a 20-307o increasein protein dcposition.The optimum dose dependson whether optimal growth or maximal feed efficiency is required.Nile crocodiles(Crocodylus niloticus) also respond to treatment with human somatotropin, by increa-singfeed intake, gaining body weight and increasing body length. Somatotropinreleased into the blood strearnis bound by one of the two specific proteins found in plasma, one with high affinity and one with low affinity. In man, about 50Voof circulating somatotropinis complexed to binding proteins,which are low at birth, and increaseto reach maximum values in young aduls. By sequesteringsomato- tropin, the high affinity binding protein substantiallyinterferes with the interactionbetween somatotropinand its receptor.The clearancerate of the bound form is l0-fold lower than that of the free form. Although similar binding proteins are found in the rabbit, pig, mouse and rat, there is little in ovine and bovine species.The binding protein appears to be generatedby one of two mechanisms:either a proteolytic cleavage of the receptor near the trans- membrane domain, or de novo synthesisfrom a truncated mRNA. The former mechanismhas been demonstratedin man and rabbit, and the latter in pregnant mouse and rat. The receptor belongs to a superfamily which include those for, inter alia, prolactin, the interleukins, erythropoietin and the interferons. Somatotropinreceptors have now been demonstratedin many tissuesother than the liver, such as kidney and the cardiovascularand respiratory systems.The disribution of the receptor has also been describedwithin the cell, even in the nucleus.It has been suggestedthat this receptoris synthesizedlocally to facilitate intracellulartransport of somatotropinand/or to regulatetranscription of IGF. Die volgehoue strewe na verbeterde doeltreffendheidhet gelei tot die toediening van eksogenegroei- en laktasie- stimulante om erkende diereproduksiestelselste bevorder. Verskeie spesiebeperktesomatotropiene is deur middel van rekombinantegeentegnologie gesintetiseer, om melkproduksiein melkbeesteen maervleisproduksiein varke, skapeen beestete manipuleer. Groeihormoon kom voor in plasma in verskillende vorms wat met die strukture van plasentale laktogeen en prolaktien ooreenstem.Die peptied word deur twee disulfiedbandegestabiliseer en in vier a-heliks- S.-A fr.Tydskr.Veek.,199 4, 24(l) gebiede gevou. Die somatogenieseen laktogeniesegebiede is gekarteeren twee verskillendebindingsplekke is ontdek. In alle soogdierewat tot dusver ondersoekis word somatotropienepisodies vanuit die anterior pituitOreklier afgeskei 'n met opmerklike ultradieseritme. Die prim6re beheeroor hierdievrystelling is neuro-endokrinologies,waar somato- statienen vrystellingshormoon(GHRH) die belangriksterol speel,met aansienlikespesieverskille. Uithongering berei die stelsel voor vir optimale vrystelling van somatotropiensodra voer weer beskikbaar word. Terwyl geslagstwee- vormigheid in die vrystelling van somatotropienduidelik uitgewys is in die rot" is die meerderheidstudies met ander 'n spesiesop manlike diere uitgevoer. Alhoewel somatotropiensy vrystelling negatief beheer, het dit nie regstreekse 'n invloed op die somatotroofnie. In die herkouer, tenminste,speel somatotropienook rol in die beheer van 'n versadiging.Ander stelselswat ook rol in die beheervan somatotropienvrystellingin die herkouerspeel, sluit in cholesistokinien,serotonien, dopamien en a-adrenergiesereseptore sowel as plasmaglukosekonsentrasies,almal deur behercndemeganismes in die hipotalamuswat van voor- tot naspeen(glikogenies tot glukoneogenies)verander. 'n Onlangseis GHRH-analoewat uit reekskort peptiedes(5-6 aminosure)soortgelyk aan enkefalienbestaan, asook 'n nie-peptiedverbindingontwikkel. Alhoewel GHRH uit 44 aminosurebestaan, is net die terminale 29 aminosure biologies aktief. Deur arginicn met agmatien(gedekarboksileerde arginien) te verplaas,is dit moontlik om analodmet 'n 50-maal verhoogde docltreffendheid te sintetiseer.Die korttermynreaksietot somatotropien in hoEproduserende Holsteinkoeievarieer vanaf 2-5 kgldag. Die reaksie is kromlynig en word nie deur die patroon van toediening beinvlocd nie. Voerinname sryg nie tydens hierdie korttermynbehandelingnie, alhoewel dit met tussen l0-?57o tydenslangtermyntoediening kan toeneem,gemeet oor die volle laktasie.In sulke gevalle sal die voerinnamegeleide- 'n lik toeneem om die verhoogde melkproduksie te volg, as gevolg van verbeterde voeromset. De laktogeniese invloed word nie deur enige regstreekseeffek op die melkklier uitgeoefennie. Die vemaamsteinvloed van somato- tropien is die vrystelling van somatomedienedeur die lewer, en die vermoe om lipogenesete beperk. Alhoewel 'n somatotropienliggaamsvet verminder, neem vryevetsuretoe slegs tydens negatiewe energiebalans.Alhoewel navorsingby skape hierdie opmerkingsondersteun, bly die uitwerking op groei onduidelik.Die algemenedaaglikse toenarne(ADT) en die doeltreffendheidvan voeromset (VOD) verbeter oor die algemeenmet behandeling,gepaard- 'n gaande met redelik konstante 10-20qo vermindering in karkasvet. Die belangriksteuitwerking in varke is 'n 'n 'n anabolies,wat in die algemeenlci lot verhogingvan 10-20Voin AUf, verbeteringvan l5-35Vo in VOD, 'n afname van 30-40Vo in vetneerleggingen styging van 20-307o in protei'ensintese.Die optimum toediening is van die verlangde effek afhanklik, naamlik optimale groei of maksimum doeltreffendheidvan voeromset.Die Nylkokodil 'n (Crocodylus niloticus) reageer ook op toediening van menslike somatotropien deur toename in voerinname, liggaamsmassaen lengte te toon. Somatotropienwat in die bloed vrygestel is, word deur een van twee bindings- proteieneopgeneem, een met hod en een met lae affiniteit.In die mens word ongeveer50Vo vur sirkulerendesomato- tropien s6 deur bindingsproteiene,wat lae waardes pas