Somatotropin Physiology

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 promotants 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 transmembrane 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 somatotropien 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 na geboorte en maksimum waardes in jong volwassenes bereik, vervoer. Op di6 manier belemmerdie hoe-affiniteitbindingsproteien die koppelingtussen somatotropien en sy reseptor.Die suiweringstempovan die gebondevorm is ongeveer1O-maal laer as di€ van die vrye vorm. Alhoewel soortgelykebindingsprotei'ene in die konyn, vark, muis en rot gevind is, kom daar min voor in skaap-en beesrasse. 'n Hierdie bindingsprotei'enword deur een van twee meganismesvervaardig: 6f proteolitieseafskeiding van die 'n reseptornaby die transmembraangedeelte,6fde novo-sintesevanaf verkorte mRNA. De eersgenoemdemeganisme 'n is in die mensen konyn aangetoon,en die tweedein die dragtigemuis en rot. De reseptorbehoort aan superfamilie wat, onder andere, die reseptorevir prolaktien, interleukiene,eritropoi'etien en die interferone insluit. Somatotropien- reseptoreis nou in talle weefselsbuiten die lewer gevind, bv. die nier, kardiovaskul6reen respiratoriesestelsels. Die verspreidingvan die reseptor is ook binne-in die sel beskryl selfs in die kern. Dit is voorgesteldat hierdie reseptor plaaslik vervaardig word om intrasellulOreveryoer van somatotropien te vergemaklik en/of om transkripsie van somatomedienete beheer.

Keywords: Growth hormone, mechanism, release, review, somatotropin,structure, synthesis.

Introduction also been shown to increase milk production in goats ffnight, The continuing search for improved efficiency has led to the 1992) and body mass in chickens (Johnson et al., 1993) and introduction of exogenous growth and lactation promotants to fish (Moriyama et al.,1993). enhance traditional animal production systems. Although the When administered to dairy cows, bST typically increases rolc of somatotropin in regulating growth has been known for milk production by 3 to 5 kg per cow per day, regardless of more than 50 years (Bauman et al., 1982), and its role in race or genetic potential, provided that the nutritional status of lactogenesis for more than 40 (Young, 1947), it is only over the cow is adequate. This translates to a proportional increase the last 10 years that modcm technology has given us the of about 15-207o, while productive efficiency is also im- means to apply that knowledge in a practical way. Various proved (kg milk per kg feed) by about l07o (Peel et al., 1981; species-limitcd somatotropins have becn synthesized by mears Bauman et al., 1985; Eppard et al., 1985; McCutcheon & of recombinant gene tcchnology (Seebcrg et al., 1983), Bauman, 1985; Richard et al., 1985; Sechen et al., 1985). thcreby allowing us to manipulate milk production in dairy Administration of pST to pigs typically increasesgrowth rate cattle (bovine somatotropin,bST), and lean meat production in by l0-12% and improves productive efficiency by about l5%. pigs (porcine somatotropin, pST), sheep (bST) and cattle At the same time, adipose tissue mass decreasesby up to 80Vo (bST). More specifically, somatotropintreatment may alter the and muscle growth increases by about 50Vo (Carnpbell et al., body composition of growing lambs (Mclaughlin et al., 1988; Evock et al, 1988). These applications have obvious 1993), as wcll as increase the milk production of primiparous implications for animal production, leading to not only ewes (Stelwagen et al., 1993), Furthermore, somatotropin has increased production and improved efficiency, but also to S.Afr.J.Anim.Sci., 199 4, 24(I) 3 products that may be more acceptable to consumers in terrns statin (14 residues, single disulphide bridge) and releasing of health risk. While there may be some resistance to the use hormone (GHRH, 44 residues) playing the major roles. Recent of exogenous hormones in production animals, that aspect will studies show that the most important factor controlling the not be dealt with in this review. Instead, I will outline the episodic release is the cyclic nature of GHRH relcase from the current information regarding the structure, mechanisms of hypothalamus flilehrenberg et al., 1984, Moore et al., 1992). release and the physiology of somatotropin. In the rat, somatostatin and GHRH are released in reciprocal 3-4 h cycles (about 180o out of phase) from the median Structure eminence into the hypophyseal portal blood, from whcre they Growth hormone may exist in plasma in several forms that act upon the pituitary somatotrophs to generate the observed (Tarurenbaum, range from fragments to high molecular weight aggregates ultradian rhythm 1991). There is a delicate (Baumann, l99I), although a peptide monomer of 191 amino relationship between these two peptides, as exemplified by acids, with a molecular weight of 22 kDa is the most common the results of a trial in which rats were starvcd for 72 h. In form ([rwis, 1992). Another form that is commonly found in these animals, somatostatin did not inhibit the release but humans (but not yet in other animals) has a molecular mass of paradoxically enhanced the responsivenessof the somatotrophs (Tannenbaum 20 kDa and is lacking amino acids 32-46. The physiological to GHRH e/ al., 1989). The mechanism is not significance of the two forms is still not clear, although the clear, but may involve either an enhanced storage capacity, or smaller form has been linked to the immune status of an else thc down-regulation of the somatostatinreceptor. The net animal (Smal et al., 1985). Some of the fragments may be result is that st:rvation primes the system to optimally rclease possibly produced by proteolytic enzymes present in the plasma such as somatotropin when fecding recommences, thercby priming the system for compensatory growth. Pleasc note that plasmin, thrombin and chymotrypsin. Such fragments may considerable species differences probably occur, and that thcse have enhanced lactogenic and growth-promoting activities in patterns in all probability do not reflect the situation in humans (Ingram et al., 1992). The growth-promoting activity ruminants. For example, a pattern of fasting followed by may be associated with a slower clearance rate of the frag- refeeding causeschanges in concentrationof circulating ST in ments from the plasma. There is also considcrable structural rats which is the exact opposite of that found in all other overlap with placental lactogen and prolactin, which are phylo- species (Lapiene et al., 1992), in particular the cow. [n rats genetically related hormones (Thomas et al,1987). (Tannenbaum et al., 1976), fasting inhibits the secretion o[ The peptide is stabilized by two disulphide bridges, and is growth hormone, whereas elevated glucose, j.e. refecding, has folded into four a-helix regions which lie parallel and which little effect. In cattle (McAtee & Trenkle, 1971), on the other run up-up-down-down (instead of the more usual up-down-up- hand, fasting increasesthe concentration o[ circulating growth down where the regions are separated by short loop sections, hormone, chiefly by increasing the half-life. Thomas et al., 1987: Aston et al., 1991). The somatogenic While sexual dimorphism in the rcleasc of somatotropinhas region has now been mapped using antigenic analysis been clearly demonstrated in the rat, most studies in other (monoclonal antibodies) and has been shown to be associated specieshave concentratedon male animals. Male rats exhibit on the loops connecting helices I to 2 with three sites the typical ultradian rhythm, while in females the pulses are (residues 35-53) and 3 to 4 (residues 120-140 overlapping more frequcnt and of a lower amplitudc (Tannenbaum, 1991). site to overlap with 134-154). The lactogenic appears this The mechanism responsible for this difference is unknown, region, but is more stronglycentred on residues 18,21 and 25 although several possibilities have bcen proposed. Firstly, the in helix I and residues167, 168, 172, 174 and 176 of helix 4. neurons responsible for synthesizing and relcasing somato- These are not the only amino acids involved in binding, but statin have an intrin^sicsecrctory pattern that is different to that appear to be the most important, together with a Zn molecule exhibited by the neurons that release GHRH. These patterns which is necessary at this site (Cunningham & Wells, 1991). differ between the sexes. Secondly, the pattems may result This is, however, not the region which is involved with from neuronal interactions betwecn somatostatin and GHRH binding to the receptor site, which was recently defined for within the hypothalamus.Thirdly, the gonadal steroid eriviron- human somatotropin, where helices 2, 3 and 7 bind over a ment influences the release pattem. These suggestions are not centact area of 1230 A2 with the one receptor monomer via mutually exclusive, and probably reflect in some measure the nine hydrogen bonds while the N-terminus end binds with actual control mechanism. helices I and 6 via four hydrogen bonds over a contact area o[ The neuronal control of somatotropin release is diagram- 900 A (de Vos et al., 1992). There is some activity associated matically represented in Figure 1 (taken from Tanncnbaum, with the hydrophobic region between helices I and 2 (residues 1991). It is currently thought that, in addition to the 80- 83) as well as glu33. There would also appear to be a somatostatin-containing projection to the median emincnce binding region on the loop between helices 3 and 4 (96-133). originating from the periventricular nucleus, lhere is probahll' The fact that there are at least two different binding sites has an additional collateral projection onto GHRH-containing been suggested by the observation that somatotropin binds to arcuate neurons from either the periventricular nucleus or the three structurally different receptors (binding to receptor 2 is local somatostatin neuronal network in the arcuate nucleus. calcium-independent,whereas binding with the other two is This implies that somatostatin may directly and, thcrefore, not, Astonet al.,l99l). cenrally regulate the infundibular release of GHRH into the portal circulation. Synthesls and release An aspect that is currently enjoying attention is the Somatotropin is secreted episodically from the anterior discovery of somatomammotrophic cells in several species pituitary with a striking ultradian rhythm in all mammals (Kineman et al., 1992) as well as a considerable heterogeneity investigated thus far. The primary control over this release in the function of so-called pure somatotrophs within a species would appear to be neuroendocrine in nature, with somato- (Takahashi, 1992). The fact that the same cell may produce S. -A fr.Tydskr.Veek., 199 4, 24(1)

Somatostatlnneuron Experiments using loxiglumide, an antagonist of CCK, (periventricularnucleus) suggested that the effect of CCK was independent of hypo- ./ thalamic somatostatin. Ftrthermore, pulses of luteinizing ,/ hormone appear to be positively conelated with the release of HYPOTHALAMUS somatotropin in foetal sheep (Albers e/ al., 1993). These Ventromedial nucleus findings imply that at least one other somatotropin-inhibiting GHRHneuron system exists in the hypothalamus of sheep, thereby support- (arcuate nucleus) ing the conclusions drawn from the pyridostigmine experiments fl(elijman& Frohman, 1991). Portal vessel Other systerns that have also been implicated in ruminants GHRH(+) Somatostatin (-) include serotonergic mechanisms that stimulate release, dopamine that inhibis release, and ct-adrenergic receptors that Pituitary potentiate release (Sartin et al., 1991), all via regulatory mechanisms in the hypothalamus. These mechanisms have been shown to change during the development of the animal ? from pre- to postweaning, when the hepatic metabolism GH changes from glycogenic to gluconeogenic. Figure 1 Hlpothalamic peptidergicneurons of the somatotropin The concentration of glucose in the plasma has also been neuroendocrineaxis. Taken from Tannenbaum(1991). shown to control the release of somatotropin, which suggests that some kind of glucoreceptor must be present in the central neryous system. Experiments were canied out on rats in which both somatotropin and prolactin aids in understandingsome of the aqueduct between the lateral ventricles and the fourth the apparent contradictions in earlier work. Furthermore, the ventricle was blocked. An inert glucose analogue, S-thio- age of the animal also affects the rate of synthesis and the glucose, was then injected either into a lateral or the fourth storage capacity of somatotropin within the somatroph ventricle, and the plasma glucose and somatotropin response (Console et al., 1993), and is an important component of the was followed. The results showed that receptors mediating the immunomodulation of hormone release (Lean et al., 1992), hyperglycaemic response to glucoprivation and the subsequent particularly in older animals (Farmer et al. 1993), and in decrease in the release of somatotropin are located in the animals under stress (Kclly & Dantzer, i990). However, hindbrain, and not in the forebrain (P6nicaud et al., 1990). experimental data obtained from cows do not seem to support A field of interest that has quietly grown over the last l0 this (Cole & Hansen, 1993). years, with sporadic bursts of activity from the drug The role of other factors in controlling the release of companies, is the development of GHRH analogues. Initial somatotropin from the pituitary has also been demorstrated. interest was generated by the dircovery that certain opiod Although somatotropin exhibits negative feedback on its peptides stimulated the release of somatotropin. This report led release, it does not appear to have a direct effect on the to the development of a series of short (5-6 amino acids) somatotroph in thc pituitary (Kraicer et al., 1988). This peptides based on enkephalin (Momany et al, l98l; Swart & observation implies that the mechanism must involve central Van der Walt, 1986; Bowers et al., l99l: Robinson et al., control, which has subsequently been demonstrated to be 1992). Development of these compounds was initiated shortly mediated by acetylcholinergic receptors (Kelijman & before the structure of the naturally-occurring GHRH was Frohman, 1991). Another likely interpretation may lie in the elucidated in 1982. Interest in these compounds has continued observation that exogenous pST increases the number of to the present time, although apparently restricted to certain somatotrophs in the pituitary (Andres et al., 1993). Moreover, pharmaceuticalcompanies (Bowers et al., l99l; Robinson er somatotropin exerts a direct, negative control over the gene al., 1992). Recently, a nonpeptidyl secretagogue has been expression of GH-releasing hormone in rats, independent of reported (Smith et al., 1993), which suggeststhat interest in any influence from peripheral IGF-1 (Sato & Frohman, 1993). this line of research has not altogether waned. ln the rat, treatment with pyridostigmine, an acetylcho- Another approach has been to manufacture structural linesterase inhibitor, enhances the release of somatotropin, analogues of the naturally-occurring GHRH. Although GHRH suggestingthat somatostatinrelease is inhibited. However, this normally contains N-M residues, it is only the 29 amino enhancement effect of pyridostigmine appears to operate via a acids at the amino terminal end that are associated with the different mechanism to that responsible for the feedback effect releasing activity (Ling et al., 1984). By replacing arginine of somatotropin, which involves the increase of somatostatin residues with agmatine (decarboxylated arginine, or 4-guani- in the hypothalamus. This effect has not been reported in the dinobutylamine), it is possible to create analogues that have an ruminant. increased potency of more than SO-fold (Zarandi et al., 1992: Another factor that has recently been implicated in the Roberge et al., 1992). It has been suggested that this increase ccntral control of somatotropin relcase is cholecystokinin in potency may be due to either an increased receptor affinity (CCK). This peptide is found not only in the gut, but also in (Zarandi et al., 1992) or a greater biological stability, i.e. a the central nervous system, where it contributes to the control greater resistance to proteolytic degradation (Roberge et al., of satiety. It is possiblc that, in the ruminant at least, 1992). somatotropin may also be involved in the responseto satiety (Driver & Forbes, 1981; Tindal et al., 1985). Intravenous Physiologyof action administration of CCK in man and rat stimulates release of Any discussionof the physiologyof somatotropinmust be somatotropin, whilc in sheep CCK was only active when based on a species approach, owing to the wide variability of administered intracercbroventricularly(Spencer et al., 1991). the response to this hormone across different species. S.Afr.J.Anim.Sci., 199 4, 24(l) 5

Although many of the mechanisms have been elucidated using Shcep the rat, this review will concentrate on the action of this Although not of any great economic importance from a milk hormone in productive domestic animals. producing viewpoint, sheep have been used as a model for studies on the effect of somatotropin. Snrdies on the role of Cattle adipose tissue in sheep have supported the contention that The dairy cow has been used extensively as a model for somatotropin chiefly affects the lipogenic side of the substrate research as a result of the lactogenic effect of somatotropin in cycle (Vernon, 1978; Vernon, 1979; Vernon et dl., 1981; that animal. The effect of somatotropin administration, both Vernon, 1982; Vernon & Finley, 1985). The effect on growth short and long term, on the lactation response has been well is controversial, although in most cases there is an improve- documented and has been extensively reviewed (Peel & ment in average daily gain (ADG) and feed conversion effi- Bauman, 1987). Briefly, the short-term response varies ciency. A fairly consistent l0 to 2O7o decrease in carcass fat between 2 and 5 kg/day in high-yielding Holstein cows, was observed in most studies (Prosser et al., 1991; Heird & regardless of the stage of lactation. The dose response appears Hallford, 1991; Johnssonet al., 1985). One study (Johnssoner to be curvilinear although the pattern in which the hormone is al., 1985) showed recombinant bovine hormone to increase administered does not affect the resporse. There is no increase wool growth, whereas other studies $ilallace, 1979 Wynn, in feed intake during short-term administration of somato- 1982) using the ovine form purified from the pituitary initially tropin. On the other hand, long-term administration of the suppresseswool growth, followed by a rebound after cessation hormone may lead to an increase of between l07o and 257o in of treatment. Whethcr this is due to a difference betwe€n the high-yielding dairy cows, when measured over the entire ovine and bovine forms, which is unlikely due to the single lactation. In such cases, feed intake increased gradually to amino acid difference, or whether it is some other factor in a match the increased milk production, owing to an improve- possibly unpure version of the ovine hormone, is not clear. If ment of feed conversion. The lactogenic effect does not appear it is due to a species difference, then recombinant DNA to be mediated by any direct effect on the marrunary gland, as technology may be used to enginecr a chimaeric somatotropin no-one has been able to demonstrate the presence of somato- molecule with wool growth-promoting activity. tropin receptors in the gland (Akers, 1983). The most As in cattle, the major anabolic effects of somatotropin pronounced effect of somatotropin is the release of the appear to be mediated by the IGF family. This somatotropin/ somatomedins or insulin-like growth factors (IGF) (Cohick er IGF axis is dose-dependent and is sensitive to nutritional al, 1987; Davis et al., 1987), chiefly from the liver, and there status(Bass et al., 1987). Although diet affected the amount of is some evidence to suggest that some of the lactogenic effect somatotropin binding to liver membranes, as well as the of bST may be mediated via these hormones (Prosser et al., concentration of IGF-I in plasma, that did not reflect in the 1991). While the direct effect of these IGF hormones on the growth rate or carcass composition of lambs (Mclaughlin er udder is still not clear, they would seem to coordinate the al.,1993). metabolism of a number of tissues in such a way as to provide Another potential use for somatotropin may lie in improving the substrates necessary for the synthesis of the key consti- the reproductive response of ewe lambs. It is well known that (McCutcheon tuents of milk, thereby promoting lactation & ewe lambs that grow at faster rates and mature earlier, Bauman, 1985). For example, cardiac output rises by lWo, conceive sooner (Southam et al., l97l). Unfortunately, even while blood flow to the mammary gland increases by 35Vo after four months of treatment, the resporlse of these lambs to et al., 1988). The coordination of these various @avis treatment was disappointing, with only marginally enhanced metabolic activities has been referred to as homeorhesis reproductive and growth responses (Heird & Hallford, 1991). (Bauman & Currie, 1980). Similar studies showed that somatotropin does not in fact However, the most striking effect of somatotropin in cattle provide any direct clues for the normal timing of newo- is the ability to inhibit lipogenesis and possibly to increase endocrine maturity in female sheep (Suttie et a1.,1991). lipolysis (Bauman, 1992), thereby exerting a major effect on lactogenesis. Although a decrease in body fat accompanies the Pigs administration of somatotropin, an increase in non-esterified fatty acids is only seen when the cows are in a negative energy The major effect in pigs is anabolic, leading in general to a balance, which suggests that the major effect is on lipogenesis l0-207o increase in daily gain, a 15 to 357o improvement in (Ingle et al., 19721' Eppard et al., 1985; McCutcheon & feed conversion efficiency, a 30 to 4O7o decrease in lipid Bauman, 1986). One of the mechanisms responsible for this deposition and a 2O to 3Wo increase in protein deposition effect may be a reversal of the effect of insulin on adipose (Chung et al., 1985; Evock et al., 1988; Campbcll et al., tissue (Etherton et al., 1987). Insulin promotes lipogenesis 1988). The optimum dose depends on which growth variable through increasing the uptake of glucose via specific one wishes to encourage. For example, optimal growth is transmembrane carriers (Birnbaum, 1992; Robinson & James, obtained at a lower dose than required for maximal feed 1992), through the inhibition of hormone-sensitive lipase efficiency (Boyd et al., i986). It is possible,in the light of the (Scow & Blanchette-Mackie, 1991), and by acting as substrate effect on body composition, that even greater effects may be for glycerol-3-phosphate synthesis (Dominguez & Henera, obtained by careful rebalancing of the diet, to provide the 1976). Adipocytes take up and hydrolyse insulin via a non- necessaryextra protein. However, a word of caution should be lysosomal pathway (Olefsky et al., 1982), and somatotropin sounded; the action of somatotropin in pigs may also lead to has been shown to modulate the activity of the protease some systemic abnormalities such as liver and kidney respornible for this hydrolysis (Marinchenko er al., 1992). degeneration, oedema and an arthritis-like condition @vock ef However, note that the effect of insulin on lipolysis and a/., 1988). In the end, the dosage chosen will have to reflect protein synthesis in adipose tissue is not altered by the the economic realities of gain balanced against loss. In pigs, it IGFs. would appear that the anabolic effect of somatotropin is also 6 S. -A fr.Tydskr.Veek., 1994, 24(l>

mediated by circulating IGF-I, rather than in a paracrine binding of the hormone, and it therefore also brings together 'second fashion (Grant et a|.,1991). the intracellular domains that are responsible for the messenger' portion of activation pe Meys, 1992) (see Figure Reptiles 2). Although somatotropin receptors were originally thought to Nile crocodiles (Crocodylus nilotictu) also responded to treat- be associated mainly with the liver, they have now been demonstrated in many other tissues, such as kidney and the ment (0.325 1uglg twice a week for 4 weeks) with human (Lobie somatotropin, by increasing feed intake from 2.8 glkg to 29.8 cardiovascular and respiratory systems et al., 1992). glkg, gaining 8.l%o body weight (while control animals lost The distribution of the receptor has also been described within 6.37o) and increasing body length by 3.93Vo (none in control the cell, where it has been found not only on the cell animals, Kimwele et al., 1992). In this case, the treatment was membrane, but also within the cell, even in the nucleus. It has given to correct for anorexia, but there may be commercial therefore been suggested that this receptor is synthesized applicatiors resulting from this report. locally to facilitate intracellular transport of somatotropin and/ or to regulate transcription of presumably the IGF in a variety lvlechanism of action of tissues (Lobie et al., 1992). An example of this is the demonstration of receptors in the canine renal proximal tubule, Somatotropin released into the blood stream is bound by one where the hormone promotes ammoniagenesis (Chobanian et of the two specific proteins found in plasma, the one with a al., 1992). Since somatotropin promotes rapid growth which is high affinity and the other with a low affinity (Baumann et al., often accompanied by a metabolic acidosis owing to an 1988). Either of the binding proteins will bind one molecule of increase in circulating fatty acids and ketone bodies, an abiliry somatotropin, to form complexes of 83 kDa = about 246 to provide ammonia for acid-base balance in the kidney is residues (high affinity) or 125 kDa (low affinity). The high required. affinity protein corresponds to the extracellular portion of the hepatic somatotropin receptor (Baumann, 1990). fn man, about 5O7o of circulating somatotropin is complexed to binding proteins, which are low at birth, and increase to reach maximum values in yorurg adults (Fontoura et al., 1991). By sequestering somatotropin, the high affinity binding protein substantially interferes with the interaction between somatotropin and its receptor (Mannor et al., 1991). The clearance rate of the bound form is lO-fold lower than that of the free form of the hormone. The bound form is distributed in almost double the intravascular space compared to the distribution of the free form in a volume equal to the entire extracellular space. Although this complex inhibits the binding of somatotropin to the cellular receptor by competition in vitro, it actually enhances the activity of the hormone in vivo, owing mainly to its effect on half-life and persistence (Baumann, 1991). These binding proteins also appear to exhibit a diurnal rhythm, in which the nadir occurs at night (Carlsson et al., 1e93). Similar binding proteins arc found in many mammals, those closest to man are the rabbit, pig, mouse and rat. On the other hand, ovine and bovine species appear to have little binding protein (Shaw & Baumann, 1988). The binding protein appears to be generated by one of two mechanisms, either a Figure 2 Ribbon diagram of human somalotropin (white) in proteolytic near the transmembrane domain, or de cleavage complex with two molecules of the exracellular domain of iis novo synLhesisfrom a truncated mRNA. The former mech- receptor,shown as binding protein I (black) and binding protein 2 anism has been demonstrated in man and rabbit. and the latter (grey).Taken from De Meys (1992). in pregnant mouse and rat (Baumann, 1990). The low affinity binding protein has a greater affinity for the smaller somatotropin, a finding for which there is as yet no physiological function. The somatotropin receptor consists of a single poly- The ontogeny of these receptors in bovine hepatocytes has peptide chain of 620 residues, with a single transmembrane been investigated, and it was shown that the number of these domain (see Figure 2). It has been shown to belong to a receptors increased with age during the first six months of superfamily of receptors which include those for, inter alia, growth, in parallel with plasma concentrations of IGF-I, prolactin, the interleukins, erythropoietin and the interferons whereafter both declined slightly (Badinga et al., l99l). It is, (Kelly et al., 1991; De Meyts, 1992). The binding of the therefore, suggested that increasing receptor numbers in hormone to its receptor exhibits several unique features. The bovine liver contribute significantly to postnatal growth in receptor exists as a dimer, but it binds only one molecule of a cattle (Breier & Gluckman, 1991). In rats, however, receptor non-symmetrical hormone. What is remarkable is that the two mRNA in the brain declines with age, in contrast to the identical faces of the receptor bind to two different sites on increase in these receptors in peripheral tissues (Lobie et al., opposite sides of the four-helical bundle of the hormone. The 1993), thereby suggesting that a specific somatotropin-IGF-l dimerization of the receptor is probably induced by the axis influences brain growth and maturity. S.Afr.J.Anim.Sci., 199 4, 24(1) 1

Concluslons BIRNBAUM, M.J., 1992.\\e insulin-sensitiveglucose transporter. Int. Rev. Cytol. 137A, 239. While there have been startling advances over the past few BOWERS, C.Y., SARTOR, A.O., REYNOT,DS,G.A. & BADGER, T.M., years, there is still much to learn about the mechanism and 1991. On the actions of the growth hormone-releasinghexapeptide, physiology of somatotropin. The fact that there are so many GIIRP. Endocrinology 128, 2O27. different forms of the hormone in circulation (the so-called BOYD, R.D., BAUMAN, D.8., BEERMAN, D.II., DENEERGARD, dominant form, the 22 kDa molecule, constitutes only about A.F., SOUZA, L. & BUTLER, W.R., 1986.Titration of the porcine 2IVo of the total immunoreactivity in the plasma), complicates growth hormone dose which maximizes growth performance and lean depositionin swine.J. Anim. Sci. 63 (Supl. the interpretation of results, and leads to the confusion l), 218. BREIER, B.H. & GI-UCKMAN, P.D., 1991.The regulationof postnatal surrounding the assay of somatotropin. The puzzle of the growth: nutritional influenceson endocrinepathways and function of marilnary gland still needs to be solved, as does the role of the somatotrophicaxis. LivestkProd. 5ci.27,77. the different forrns of binding proteins. I have not attempted to CAMPBEI-L, R.G., STEELE, N.C., CAPERNA, T.J., MCMLRIY. J.P., describe the role of the IGF hormones, although it is difficult SOLOMON, M.B. & MITCI{ELL, 4.D., 1988.Interrelatiarships to understand the action of somatotropin without them. It is betweenenergy intake and exogenousporcine growth hormone obvious that any future description of somatotropin action will administratisr on the performance,hndy comynsition and prcrein and energymetabolism of growing pigs weighing25 to 55 kilogramsbody have to include the role of the IGF proteins. There are many weight.J. Anim. Sci.66, 1643. avenues open for exploration, particularly itr the domestic CARLSSON, L.M.S., ROSBERG, S., VITANGCOL, R.V., WONG, animals. Most of what we know is derived from the rat and W.l.T. & ALBERTSSONWIKLAND, K., 1993.Analysis of 24-hour the human, and, as pointed out above, there are known to be plasmaprofiles of growth hormone(GIl)-bindingprotein, GII Gfl- major differences between species. Although most of the binding protein complex, and GII in healthy children. J. clin. Etdocr. research to date has concentrated on the role of somatotropin Metab.77,356. CHOBANIAN, M.C., JULIN, C.M., MOLTI]NI, itself, it is possible that exotic releasing factors, modificd K.II. & BRAZY, P.C., 1992. Growth hormone regulatesammoniagenesis in canine renal forms of binding protein, or genetically engineered receptors proximal tubule segments.Am. J. Physiol.262,878. may play important roles in the future. 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