Abstract:
EXOGENOUS GROWTH HORMONES IN ANIMAL PRODUCTION G.H. MC DOWELL Summary is now substantial evidence that exogenous hormones may be used There swine and to effect improvements in productivity of farm animals - poultry, ruminants. At present, steroids and related compounds are used widely throughout the World to improve growth of meat-producing animals Growth hormone and related hormones have been shown to principally cattle. improve productivity of farm animals and it is expected that growth hormone will be available for use in animal production systems, at least in the Major use of the hormone in dairy herds is Northern Hemisphere, by 1988. anticipated and the effects of growth and perhaps wool growth may be exploited as well. For the purpose of this overview on the use of 'growth hormones' in animal production it has been assumed the 'growth hormones' are hormones or hormone analogues which improve the productivity of farm animals or show Brief mention has been made of the potential for promise of doing so. immuno-manipulation of endogenous hormone secretion. I. INTRODUCTION To date most improvements in animal production have been achieved by improvement in husbandry/feeding practices and by deliberate selection/ breeding of superior animals. dramatic impr0vement.s In As a result, productivity have been obtained. In spite of this it 1s now clear that even improvements may be obtained either by manipulating the genomes of further in the shorter term, altering the hormonal animals (see Lockett 1985) or, status of the animal. Hormones regulate all body functions and accordingly body tissues of animals are controlled directly and/or indirectly by a complex of hormones. The potential for improving productivity of man's domestic animals has been appreciated for many years but exploitation of the stimulatory effects of hormones on animal productivity has not occurred until quite recently. Currently , a number of hormones and hormone analogues are being used in animal production systems and there is substantial interest in exploiting the use of other hormones. Much of the.commercial interest in using hormones to improve productivity has arisen from observations made during quite basic studies on the modes of actions of hormones in the animal body To some extent, the commercial application of hormones for improving productivity of farm animals has proceeded faster than research into physiological changes permitting increased productivity. l II. GROWTH HORMONE The importance of growth hormone for normal growth in mammals was recognised nearly 60 years ago and studies with rats conducted during the Dairy Research Unit, Department of Animal Husbandry, University of Sydney, Camden, New South Wales 2570 1930's showed that growth hormone stimulated growth (Evans and Simpson 1931) and increased the ratio of muscle protein:body fat (Lee and Schaffer 1934). Since that time it has been shown that growth hormone is required for normal in ruminants (Tindal and Yokayama 1964a, growth Vezinhet 1973). 1964b; Furthermore, the physiological effects of growth hormone have been studied extensively (see Table 1). Table 1. Biological activities of growth hormone (adapted from Machlin 1976) In short growth hormone promotes growth (stimulating cell division, skeletal growth and protein synthesis) exerts lipolytic effects (promotes release of fatty acids from adipose tissue and increases oxidation o-f fatty acids) and also exerts diabetogenic activity (induces peripheral insulin resistance and the transport of glucose into body tissues (see Hart and It appears that these effects of the hormone result in the Johnsson 1985). production responses induced by exogenous growth hormone - see below. Until recently the relative scarcity of purified hormone precluded extensive studies on the effects of exogenous growth hormone on productivity of farm animals. The recent resurgence of interest in use of growth hormone to improve productivity of farm animals, resulting from appreciation of the commercial applicability of exogenous hormone, has led to production of sufficient hormone of pituitary origin to allow meaningful studies on product ion responses in farm animals. The physiological bases for these responses also are being examined. Dev elopme nt 'genetica lly-en .gin et al. 1979) has effects of ex we severa lc Indeed, Australas ia ar e a . growth h,ormone next 2-3 years Wi (se of eered led nous ommer ctive 11 be e Mix procedures for If o r recombina to considerable growth hormon cial companies ly promoting re available for production of large quantities of nt DNA-derived growth hormone (Goeddel expansion of research effort on the e on productivity of farm animals. in North America, Britain, Europe and search in this area. It appears that extensive use in the field within the 1985). (a) Effects of growth hormone in growing animals Some effects of exogenous (homologous or heterologous) growth hormone on production parameters in domestic animals are summarised b e l o w . I n general, exogenous growth hormone has been found to increase liveweight gain, increase the proportion of lean tissues and decrease the proportion of Significantly, in most fatty tissue in the carcases of treated animals. studies with mammalian farm animals increases in the efficiency of utilisation of food for liveweight gain have been measured. Effects in chickens Although the role of growth hormone in 8 controlling growth in chickens remains unclear, available evidence suggests a similar role to that in mammalian species. It is clear that growth hormone is required for normal growth and other hormones interact with growth hormone to allow full expression of growth potential. There is however equivocal evidence that exogenous growth hormone increases growth in the chicken once optimal growth has been obtained. This may be due to the use of heterologous (ovine or bovine) growth hormone, but in most studies purified (either where chicken pituitary-derived growth hormone or 'genetically-engineered') has been used, effects on growth have not been recorded. Table 2. Effects of intravenous injection of purified chicken growth old at hormone on body weight gain (g) on, cockerels 4 weeks of treatment. Values are percentage increases in commencement body weight relative to saline-treated birds (adapted from Leung 1985 > There are a limited number of exceptions where growth responses have been observed following treatment of chickens with purified chicken growth hormone. Marsh and Scanes (1984) noted significant increases of 10020% in body weights of chickens given daily injections of purified chicken hormone and similarly a significant increase (8%) i n body weights of chickens injected with chicken growth hormone plus thyroid hormone. More recently Leung (1985) reported results of studies with cockerels 4 weeks of age, ' Intravenous injections of 5 pg/d or 10 chicken growth hormone significantly No effects of treatment (Table 2). food utilisation were recorded in this pg/d, but not 50 ug/d, of purified growth but transiently stimulated on body composition nor efficiency of study. In most studies with pigs exogenous growth hormone ii) Effects in pigs has been found to stimulate growth, alter body composition and improve the efficiency of food utilisation in young pigs growing rapidly (see Table 3). Table 3. Summary of some effects of exogenous porcine growth hormone on growth, feed conversion efficiency (FCE) and carcase composition of growing pigs (adapted data presented by Hart and Johnsson and cited from various sources) Machlin (1972) noted `toxic' effects of doses of growth hormone PO.22 mg/kg liveweight but did not define the nature or bases of these effects. Possibly, the above report of toxic effects of porcine growth hormone In studies with influenced later researchers to use lower doses of hormone. doses ranging from 0.015-0.06 mg/kg of genetically-engineered human hormone small decreases in Baile e t a l . (1983b) obs erved small effects on growth, of feed conversion and no changes in carcase composition. the efficiency Similarly, Chung et al. (1985) recorded only small (but signif icant) positive effects on growth and feed conversion efficiency and no change in composition in pigs treated with 0.022 mg/kg/d porcine growth carcase hormone. further research is required to resolve optimum doses and Clearly, Furthermore, potential problems with toxicity of growth hormone in pigs. the observation o f Machlin `(1972) that relative growth responses and improvements in efficiency of food utilisation were higher for pigs offered restricted than adequate amounts of food deserves further study. iii) Effects in c a t t l e Early studies on the effects of growth hormone on Since that time Sejrsen et growing cattle were reported by Brumby (1959). al. (1983) and Bauman (1984) have reported effects of exogenous bovine growth hormone on growth and body composition in young dairy cattle. Long-term treatment (12 to 21 weeks) with exogenous growth hormone Preliminary results increased growth rate by about 10% in all studies. reported by Bauman (1984) indicated a marked improvement in the efficiency of food utilisation together with greater protein and lower fat contents of carcases of treated than control calves. There is now limited data on metabolic/physiological effects of exogenous growth hormone in growing cattle. Eisemann et al. (1984a) measured e f f e c t s o f daily injections, over 12 days, of bovine growth hormone on plasma concentrations and whole body irreversible losses of non-esterified fatty acids in growing Hereford heifers and Eisemann et al. (1984b) reported In this study there was no data on nitrogen retention in the same study. significant effect on growth rate but plasma concentrations of and whole I body irreversible losses for non-esterified fatty acids as well as nitrogen Similar observations retention were significantly increased by treatment. on nitrogen retention and growth rate had been reported previously by Car et (1982) for Holstein al. (1967) for S immental steers and by Moseley et al. steers. (1985) examined the e f f e c t s o f More recently Leenanuruksa et al. exogenous growth hormone on arterial concentrations and arterio-venous differences across leg muscle tissue of metabolites together with blood flow Arterial concentrations of to muscle tissue in growing dairy heifers. glucose a n d POH-butyrate tended to increase and of non-esterified fatty A signifiacids increased significantly during growth hormone treatment. cant increase in blood flow to leg muscle tissue occurred following treatment and marked changes in arterio-venous differences of metabolites were Growth hormone decreased arterio-venous difference for glucose, measured. caused a change from increased arterio-venous difference for 3-OH-butyrate, uptake to output of non-esterified fatty acids and increased lactate release. Effects of growth hormone on exchanges of amino acids across hind limb muscle tissue have been measured in growing calves (Jois et al. 1985a, 1985b). Treatment with growth hormone did not affect markedly plasma concentrations nor arterio-venous differences of plasma and blood free amino acids but significantly increased arterial concentrations of blood free amino acids. Most interesting effects of growth hormone on arterio-venous differences of peptide-associated amino acids in both plasma and blood were Whereas peptide-associated amino acids in plasma and blood were measured. released from muscle tissue during control (saline) periods, growth hormone either reduced the release or induced an uptake of peptide-associated amino acids. The results of the above studies on metabolic/physiological effects of in growth hormone in growing cattle are consistent with reported changes and in some studies growth, induced by treatment with body composition, exogenous growth hormone. Overall growth hormone promotes protein accretion and lipolysis and apparently effects growth promotion. ii) Effects in lambs Several studies have been conducted to evaluate the e f f e c t s o f growth hormone on growth and carcase characterist its i n growing lambs. Wagner and Veenhuizen (1978) reported increased growth increased protein (25%) and decreased fat (37%) in carcases as well (20%), as increased efficiency of feed utilisation (14%) in wether lambs treated twice d a i l y w i t h c 0.19 mg/kg liveweight of ovine growth hormone for approximately 100 days. More recently Muir et al. (1983) reported results of a study in which wether lambs were treated for 56 days with 7 mg (c 0.25 mg/kg/d) ovine growth hormone in a slow-release base (designed to maintain Y high circulating levels of hormone). In this study growth rates were not affected by treatment but carcase protein (8% increase) carcase fat '0 (91 decrease) contents and efficiency of food utilisation (7% increase) were affected by treatment. Table 4. studies The above results are contradicted by results of several Muir et al. (1983) found that injecconducted in the intervening period. tions of growth hormone resulting in sustained and marked increases in plasma concentrations of the hormone had no effect on wool growth in rapidly-growing lambs. In a series of studies in which purified ovine growth hormone (daily doses of c 10 mg) was administered to Merino sheep during over relatively short periods (4weeks) wool growth was suppressed administration of growth hormone but showed prolonged acceleration (beyond that measured before treatment with growth hormone) after cessation of treatment (Wheatley et al. 1966; Wallace 1979; Wynn 1982). The depression in wool growth observed during growth hormone treatment was associated with increased nitrogen retention in the studies of Wheatley et al. (1966) and Wynn (1982). The latter worker interpreted this observation as evidence that growth hormone promoted muscle protein accretion for wool thereby depriving the wool follicle of amino acids essential growth. It was further proposed that the accelerated wool growth occurring after cessation of hormone treatment resulted from increased availability of amino acids from muscle protein breakdown. In view of the contradictory results it will be necessary for further studies to clarify the influence of exogenous growth hormone on wool growth. in terms of It would be of interest to examine the time course of response, wool growth, by monitoring wool growth throughout a prolonged period of administration of growth hormone. Furthermore, effects of age, breed/strain to growth of sheep as well as nutritional status on wool growth responses hormone should be evaluated. (c) Effects of growth hormone on milk production Brumby and Hancock (1955) were amongst the first to report galactopoietic effects of growth hormone in the dairy cow. Although this galactopoietic effect has been studied most extensively in dairy cows (see below) there have been reports that exogenous bovine growth hormone is galactoMcDowell and Hart 1983; poietic in sheep (Jordan and Shaffhausen 1954; Hart et al. 1984b) and goats (Mepham et al. 1984). Similarly, 'geneticallyengineered' porcine growth hormone was shown to increase milk production in lactating sows (Harkins et al. 1985). In recent years there have been numerous studies on the galactopoietic effects of exogenous growth hormone in the dairy cow. The commercial relevance of increasing milk yield in the cow has no doubt prompted the resurgence of research effort. Broadly, two types of studies have been performed. O n one' hand short-term studies lasting a few days or weeks have been performed using pituitary-derived (Bines et al. 1980; Peel et al. 1981, Fronk et al. 1982a, 1983; 1983 ; McDowell et al. 1983) or 'geneticallyengineered' (Bauman et al. 1982) bovine growth hormone. On the other hand, there have been a limited number of studies where growth hormone has been administered for periods varying from lo-27 weeks (Brumby and Hancock 1955; Machlin 1973; Eppard and Bauman 1984; Peel et al. 1985). A summary of effects of growth hormone on milk yield and composition is given in Table 5. Table 5. Summary of effects of exogenous bovine growth hormone on milk yield, milk composition, body weight and feed intake of lactating dairy cows Limited supplies of growth hormone have restricted the number of longterm studies. In recent years the substantial interest in use of growth hormone has prompted several commercial companies to promote research into long-term effects of exogenous growth hormone in the dairy cow. A number of these studies currently are in progress. Effects on milk yield in both short- and longWithout exception, i> term studies exogenous growth hormone has increased milk yields of treated cows. Most studies have been performed in cattle after peak lactation has been attained. In these studies responses varying from c 10040% increases in yield have been recorded - the response being approximately linear between O-60 IU hormone/day (see Eppard et al. 1985). Reports of a limited number of studies in cows treated with exogenous growth hormone at or prior to peak lactation have shown a positive effect on milk yield but the increase, expressed as a proportion of milk yield for control observations, has been less (< 10%) than for cows treated after peak lactation (McDowell et al. 1983; Richard et al. 1985). ii) Effects on milk composition The effects of exogenous growth hormone have varied. McCutcheon and Bauman (1985) expressed the view that where cows are in positive energy and nitrogen balance, protein and fat contents o f milk are not influenced by treatment. On the other hand, when treated cows are in negative energy balance fat content increases and protein content decreases. The latter response most commonly has been observed in short-term studies where rapid and often marked increased in milk production occur, after initiation of treatment, without adjustment in feed intake (see In this connection, McDowell et al. (1985a) recorded that lactose below). content, decreased significantly, protein content tended to decrease and fat content tended to increase in milk of cows treated with growth hormone at peak lactation. These cows were in negative energy balance which was exaggerated by growth hormone treatment. There is evidence to show that plasma non-esterified fatty acids released in response to growth hormone are utilised for milk fat synthesis. In this connection Bitman et al. (1984) recorded decreased proportions of short (C6:0-10:0) and medium (C12:0-16:O) chain and increased proportions of long chain (C18:l) fatty acids in milk fat of cows treated with growth hormone. Similar changes have been observed in other studies with cows and sheep (J.M. Gooden and P. Niumsup, personal communication). ' In short-term studies increased milk produciii) Effects on feed intake tion, following treatment with growth hormone, has occurred in the absence of a measured or allowed increase in feed intake (McDowell et al. 1983, see also McCutcheon and Bauman 1985). Under these conditions treat1984; ment induces a loss of body weight and an accompanying alteration in the partition of nutrients (see below). Effects of treatment with growth hormone on feed intakes of cows treated for long periods with growth hormone have only been reported from (1985) reported that feed two studies. Both Bauman (1984) and Peel et al. intakes of cows treated for long periods gradually increased such that body in spite of weights of treated cows were similar to those of control cows, maintenance of high milk yields by treated cows. The latter is significant in view of concern over the e f f e c t s o f treatment with exogenous growth hormone on milk production in subsequent lactations. Although the data is extremely limited, McCutcheon and Bauman (1985) cited evidence which indicated no detrimental effects of long-term It can be expected treatment with growth hormone on subsequent lactation. that further information will become available on this aspect in the near future. Indeed such information must be obtained to satisfy concerns with regard to animal health aspects. Bauman and Currie (1980) iv) Metabolic actions of growth hormone proposed that hormones such as growth hormone act to regulate metabolic adaptat ions such as those required to support nutrient requirements during They considered that these metabolic for example pregnancy and lactation. adaptations were the result of the actions of homeorhetic hormones (such as growth hormone) which act to effect partition of nutrients without interferring with homeostatic balance. To date, evidence obtained from studies where exogenous growth hormone has been administered to farm animals generally and dairy cows specifically suggests that growth hormone acts as a metabolic regulator or homeorhetic hormone. Amongst the important actions of the hormone are the lipolytic and diabetogenic effects (see Hart 1983). Results of short-term studies have indicated that growth hormone does not alter digestibility of dry matter energy or nitrogen and there are data to show that growth hormone does not change maintenance requirements or Thus it appears that growth hormone part ial efficiency of milk synthesis. improves efficiency of milk production by diluting maintenance costs (see McCutcheon and Bauman 1985). E f f e c t s o f growth hormone on fat metabolism in the dairy cow were reported by Williams et al. (1963) who showed that treatment of cows increased plasma concentrations of non-esterified fatty acids. Similarly Kronfeld (1965) reported increased plasma concentrations of non-esterified fatty acids in lactating cows treated with growth hormone. The latter worker also noted increased plasma ketone bodies and decreased incorporation of acetate into milk fat, similar to that observed in spontaneous ketosis, leading to the suggestion that growth hormone may play a role in the genesis of bovine ketosis. patho- There are several recent reports which indicate that treatment of lactating cows with exogenous growth hormone increases plasma concentrations McDowell et al. of non-esterified fatty acids (Peel et al. 1981, 1983 ; 1984) and the whole body irreversible loss of non-esterified fatty 1983, acids (Peel et al. 1982b; McDowell et al. Recently, 1983, 1985a). McCutcheon and Bauman (1985) discussed this lipolytic effect of growth hormone and considered that the lipolytic effects of the hormone are expressed when cows are in negative but not positive energy balance. It is of interest to note that plasma concentrations of and whole body irreversible losses of non-esterified fatty acids were not increased in cows treated with growth hormone at peak lactation (McDowell et al. 1983, 1985a). This observation is difficult to explain in the light of other data but may losing body been due to the fact that the cows in this study were weight at the time treatment commenced and were thus unable to respond to the lipolytic effects of the hormone. it appears that lactating cows treated with growth In general terms, hormone respond by reducing accretion of fat to preserve supplies of glucose (and probably amino acids) required to support increased milk synthesis. This suggestion is supported by the recent observation in studies with midlactating sheep that whole body oxidation of non-esterified fatty acids, but increased in response to exogenous growth hormone (McDowell et not glucose, al. 1985b). Results of studies by McDowell et al. (1983, 1985a) indicate that the metabolic actions of growth hormone differ depending on stage of lactation. Whole body irreversible losses of key metabolites were measured in cows at peak lactation and later during mid-lactation in cows treated with saline or growth hormone. At peak lactation exogenous growth hormone significantly increased irreversible loss of glucose, consistently but not significantly increased irreversible losses of urea and acetate and in most cases (4/5 > substantially reduced the irreversible loss of non-esterified fatty acids. Irreversible losses at mid-lactation were increased for non-esterified fatty acids and acetate, These decreased for urea and unchanged for glucose. differential reflected effects of exogenous growth hormone presumably changes in energy balance, and body tissue mobilisation/accretion at the different stages of lactation. In a recent study with lactating ewes Niumsup et al. showed (1985) that exogenous growth hormone had marked effects on arterial plasma triglyceride concentrations. Total plasma concentrations of triglyceride and concentrations of very low density lipoproteins were significantly reduced during treatment with growth hormone. This suggests that growth hormone exerts an effect on the synthesis and/or release of triglycerides from the liver. Although available evidence supports the concept that growth hormone alters the partition of nutrients/nutrient utilisation in the lactating cow, direct evidence was lacking until recently. McDowell et al. (1984) used mid-lactating cows surgically-prepared to allow simultaneous collection of arterial blood and venous blood draining leg muscle and mammary tissues to During treatment study effects of growth hormone on nutrient partition. hormone mammary arterio-venous concentration differences for with growth non-esterified fatty acids increased dramatically and there was a marked in arterio-venous difference of glucose across leg muscle tissue. decrease These data confirm the effects of growth hormone on nutrient partition/ utilisation in the body. In the above animals marked effects of growth hormone on exchanges of acids across muscle and mammary tissues were recorded by Jois et al. (1984, 1985b). Arterio-venous differences across both tissues for most There were plasma free amino acids were not affected by growth hormone. however large changes for exchanges of peptide-associated amino acids. Whereas most peptide-associated amino acids were released from muscle .and mammary tissues during control periods, growth hormone either reduced the amino acids. The output or resulted in an uptake of peptide-associated Even so it significance of this observation remains unclear at present. that growth hormone may influence the rate of protein breakdown in appears tissues thereby affecting availability of amino acids for tissue metabolism. amino v> Bauman (1984) discussed Effect of growth hormone on mammary growth the limited data on the effects of exogenous growth hormone on mammary commencing growth. In heifers treated with growth hormone for 14 weeks, there was a substantial increase in the proport ion shortly before puberty, of mammary parenchyma by comparison with untreated (control) heifers. Similar observations were made in a study performed with growing lambs (Johnsson 1984). The above very encouraging results require extension to test effects of subsequent lactational performance of growth hormone treatment during the period around puberty. Several studies currently are in progress but results are pending. it has been suggested that growth hormone exerts local Although effects on the mammary glands of lactating animals (Eppard and Bauman 1984) available data do not support this suggestion - at least in situations where In this connection, the hormone is administered over short periods. McDowell and Hart (1984) reported results of studies where continuous infufailed sions of growth hormone into the mammary arteries of sheep and goats The results of this in vivo study are to increase milk production. consistent with the failure of growth hormone to stimulac synthesis of milk 1982; constituents by cultured mammary tissue of ruminants (Skarda et al. . Gertler et al. 1983). it is possible that long-term Notwithstanding the above results, treatment of lactating ruminants with growth hormone increases numbers of mammary cells and/or the activity of cells. vi) Implications of use of growth hormone in dairy cows Kalter (1984) discussed the commercial viability of using 'genetically-engineered' growth hormone to improve milk yield in dairy herds in North America. It was concluded that, at current market prices for milk, growth hormone is a viable commercial proposition - even allowing for increased costs of rations and costs of purchase of the hormone. use More recently Mix (1985) prese nted an appraisal of the impact o f the of growth hormone to increase mi lk production in North American herds. Amongst the predictions made were that the hormone would be available for use by 1988, rate of adoption would increase slowly at first then rapidly, improved production stemming from use of growth hormone would be slightly higher than that due to improved breeding/management (52:48) and numbers of farms and cows would decline steadily. Projected changes are shown in Table 6. Table 6. Some projected effects of using growth hormone in North American dairy herds (adapted from Mix 1985) (d) Delivery systems for growth hormone To date responses to exogenous growth hormone have been monitored in animals given the hormone on a daily basis by injection or infusion. Results of studies in lactating cows have shown that responses to subcutaneous intrainjections are essentially the same as those to intermittent venous infusions and continuous subcutaneous infusion (Fronk et al. 1983). Similar observations have been made in lactating sheep given continuous infusions or daily subcutaneous injections of growth hormone intravenous (G.H. McDowell and I.C. Hart, unpublished data). In growing cattle, Moseley et al. (1982) recorded similar effects on nitrogen retention of steers given continuous or pulsatile intravenous infusions of growth hormone. To date no details have been published of simple delivery systems capable of obviating the need for daily administration of growth hormone. It is understood that several groups are working to develop such a device. III. GROWTH HORMONE FRAGMENTS Lewis et al. 1984) showed that human growth hormone is not a (1980, molecular species but appears to comprise a heterogeneous group of peptides exerting different biological activities. This observation led Hart et al. (1984a) to fractionate bovine pituitary growth hormone on anion exchange resin. Four fractions obtained were examined for biological activities and the results of analyses are shown in Table 7. single Table 7. Biological and immunological activities of fractions of- bovine pituitary growth hormone obtained by separation on anion-exchange resin (adapted from Hart et al. 1984) These observations raise the possibility that modified forms or fract ions of bovine pituitary growth hormone might be exploited commercially. Use of the recent recombinant DNA techniques may allow production of forms of growth hormone capable of for example promoting growth without exerting To date lipolytic or diabetogenic activity (see Hart and Johnsson 1985). there is no published data on use of modified forms or fractions of growth hormone to alter productivity of farm animals. IV. It is controlling the releasing factor factor (SRIF) CONTROL OF GROWTH HORMONE RELEASE factors now apparent that the principal neuro-endocrine release of growth hormone are somatocrinin or growth hormone (GRF) and somatostatin or somatotrophin-release inhibiting see Fig. 1. (a) Growth hormone releasing factor The presence of a specific releasing factor for growth hormone had been suspected for many years but it was only recently that such a factor was isolated from human tissue (Guillemin et al. 1982; Rivier et al. 1982). Subsequently GRF has been isolated from hy