Exogenous and endogenous effects of growth hormone in animals

Livestock Production Science, 27 ( 1991 ) 61-75 Elsevier Science Publishers B.V., Amsterdam

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Exogenous and endogenous effects of growth hormone in animals John J. Kopchick and Joseph A. Cioffi Department of Zoology, Molecular and Cellular Biology Program, and Edison Animal Biotechnology Center, Ohio University, Athens, OH 45701, USA

ABSTRACT Kopchick, J.J. and Cioffi, J.A., 1991. Exogenous and endogenous effects of growth hormone in animals. Livest. Prod Sci., 27: 61-75. Exogenous administration of growth hormone to animals has been shown to affect a variety of physiological processes including growth and lactation. Also, endogenous production of growth hormone in transgenic animals has been reported to alter animal growth and metabolism. In this report, we will review some of the physiological effects of endogenous and exogenous growth hormone in animals.

INTRODUCTION

Recent efforts to augment the production characteristics of domestic livestock using growth hormone (GH) have met with considerable success. This has been made possible, in part, by advances in biotechnology. For example, recombinant DNA technology has provided a means for production of large quantities of pure GH for administration to animals at a fraction of the cost of pituitary-derived GH. Furthermore, the physiological effect of foreign GH gene expression on growth and development of transgenic farm animals are currently under investigation. GH is a protein which is synthesized and secreted by somatotrophs in the anterior pituitary gland (Andrews, 1966; Miller et al., 1980). GH is synthesized as a precursor protein with an amino terminal signal peptide which is removed during secretion (Miller et al., 1980; Leung et al., 1986). The mature, secreted form of GH is composed of approximately 191 amino acids ( ~ 22 000 daltons molecular mass) and contains two intrachain disulfide bridges (Dellacha et al., 1966). The synthesis and secretion of GH by the pituitary is controlled by two hypothalamic peptides, somatostatin and growth hormone-releasingfactor, the former acting to inhibit secretion and the latter acting to stimulate synthesis and secretion. 0301-6226/91/$03.50

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On the basis of sequence identity, GH is thought to be a member of a family of homologous proteins that includes prolactin and placental lactogen. Although the growth-promoting properties of GH are well known, the precise manner in which GH coordinates the complex metabolic processes responsible for growth is not fully understood. However, it has been established that, following secretion, GH acts directly by binding to receptors on precursor bone, muscle and fat cells which results in their differentiation and proliferation (Boyd and Bauman, 1989). Also, GH acts indirectly by binding to hepatocytes and other cell types and stimulating secretion of insulin-like growth factor-I (IGF-I) which acts on peripheral tissues to promote growth (Froesch et al., 1985; Zapfand Froesch, 1986; Rechler, 1988). The administration of GH to GH-deficient animals leads to increased protein synthesis and fat mobilization, and decreased glucose utilization (Daughaday, 1981 ). As a consequence of its anti-insulin activity, GH inhibits the uptake of glucose by muscle. This "diabetogenic" effect of GH may result in hyperglycemia and is often associated with hyperinsulinemia. These same physiological effects have been observed in normal animals administered exogenous GH (see below). It has been proposed that, in the long term, GH plays a vital homeorhetic role in partitioning nutrients towards some specialized physiological target, such as growth or lactation (Bauman and Currie, 1980; Bauman et al., 1982; Boyd and Bauman, 1989). The following discussion is not intended to be an all-embracing review of GH biology. Excellent reviews of the molecular biology (Paladini et al., 1983 ) and biological actions (Peel and Bauman, 1987; Boyd and Bauman, 1989) of GH can be found in the literature. Rather, the physiological effects of exogenously administered GH and expression of GH transgenes in animals will be discussed. EXOGENOUS ADMINISTRATION OF GH

Pigs Numerous studies have shown that daily administration of porcine GH (pGH) to growing pigs significantly increases growth (Machlin, 1972; Chung et al., 1985; Etherton et al., 1986; Campbell et al., 1988; Bryan et al., 1989; Hanrahan, 1989; McLaughlin et al., 1989). In general, pGH increases average daily gain (ADG) 10 to 20%, decreases feed intake 10 to 15%, improves feed efficiency 15 to 35%, decreases lipid accretion by 30 to 40%, and increases protein deposition by 20 to 30%. Some variability in the growth response is likely due to variations in the biological potency of pituitary-derived pGH (ppGH) preparations. Recombinant DNA technology has provided a means of obtaining large quantities of highly purified pGH with uniform biological activity. Recently, Evock et al. ( 1988 ) have shown that the effects of ppGH on growth are mimicked by recombinant pGH (rpGH) although the

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latter was more efficient at reducing carcass adipose tissue. Other factors such as dose of GH, method of delivery, and diet may affect animal responsiveness. The optimum dose of GH for finishing pigs is dependent upon the growth variable to be maximized. For example, Boyd et al. (1986) showed that the optimal dose of highly purified ppGH for maximal rate of gain was lower than that required for maximal feed efficiency. It would be interesting to test whether a pulsatile method of delivery of exogenous GH similar to the pattern of endogenous release from the pituitary would effectively reduce the optimal dosage in pigs. In addition, the marked changes in carcass composition, growth rate and feed intake associated with GH administration suggest that modifications in the animals' diet may be required to adequately support the rate of protein deposition for a given dose of pGH. Treatment of pigs with pGH increases plasma glucose and insulin concentrations (Etherton et al., 1987; Evock et al., 1988). This effect is consistent with the diabetogenic activity of GH and is a manifestation of an insulinresistant state. High doses of either ppGH or rpGH have been shown to be associated with some systemic abnormalities such as liver and kidney degeneration, edema and an arthritis-like condition characterized by an impairment of mobility (Machlin, 1972; Bryan et al., 1987; Evock et al., 1988). In conclusion, the exogenous administration of GH to pigs results in marked improvements in growth rates and carcass quality. By manipulating the biological activity of the GH molecule, dose, method of delivery, duration of treatment and diet, it may be possible to enhance these desirable traits and completely eliminate the negative side effects of exogenous GH in pigs.

Sheep The available evidence on the effects of exogenous GH on growth, feed efficiency and carcass composition in ruminants is limited (see review by Enright, 1989 ). In growing lambs, the effects of exogenous pituitary-derived ovine GH (Wagner and Veenhuizen, 1978; Muir et al., 1983; Beerman et al., 1988; Heird et al., 1988; Wise et al., 1988), bovine GH (Johnsson et al., 1985; Wolfrom et al., 1985 ) or recombinant bovine GH (Pullar et al., 1986; Johnsson et al., 1987; Pell and Bates, 1987) are inconsistent. In most cases, there was an improvement in ADG as well as feed conversion efficiency, although these increases were not always significant. A decrease in carcass fat of approximately 10 to 20% was observed in some trials but further studies will be required to substantiate these effects. The effects of GH on wool growth are intriguing. Increased wool growth was usually observed in animals treated with bGH while in those treated with oGH, wool growth was depressed during treatment and increased post-treatment. If the differential effects o f b G H and oGH on wool production are real, then it may be possible through the use of recombinant DNA technology to engineer a chimeric GH molecule with potent wool growth-promoting activity.

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Cattle In the studies cited by Beerman (1989) and Enright (1989), bovine GH (bGH) administration to steers or heifers usually resulted in a 10 to 20% increase in ADG and a 10 to 20% improvement in feed efficiency. These effects were found to be more pronounced in long-term studies in which animals were administered either pituitary-derived bGH or recombinant bGH for periods up to 250 days. In the majority of studies, GH had little or no effect on carcass weight. However, a significant increase (9%) in carcass weight was observed by Sandles and Peel ( 1987 ) who administered relatively large doses o f b G H to young heifers over a period of 147 days. Improvements in percent lean carcass were either insignificant or small while carcass fat was significantly decreased by 32% in one short-term study (Peters, 1986). Nitrogen retention was shown to be significantly increased by GH although the magnitude of response was highly variable. The stimulating effect of GH on milk yield in dairy cattle has been well documented (see reviews by Peel and Bauman, 1987; Chilliard, 1988; Chalupa and Galligan, 1989; Prosser and Mepham, 1989). Although the precise mechanisms remain to be defined, it is evident that in mammary and nonmammary tissues a complex interplay of several key regulators of metabolism functions in concert with GH to elicit this galactopoietic effect. The orchestrated changes in nutrient partitioning necessary to support the increased demands of the mammary gland during lactation, a process referred to as homeorhesis (Bauman and Currie, 1980), may be directly coordinated by GH. Evidence for the role of GH as a homeorhetic signal comes from the observation that when lactating cows are treated with GH, milk yield is increased immediately while feed intake does not increase until the 5th to 7th week of treatment. Therefore, nutrients must be mobilized from body stores to meet the requirements for lactation. The anti-insulin effects of GH could be responsible for decreasing glucose utilization by peripheral tissues, thereby increasing the availability of glucose for lactose synthesis in the mammary gland. One of the most potent metabolic effects of GH is its ability to decrease fat synthesis and stimulate lipolysis in adipose tissue (Vernon, 1989; Vernon and Flint, 1989). A decrease in body fat is usually observed as a result of GH administration to most domestic farm animals. In dairy cattle, increases in plasma non-esterified fatty acids as a result of GH administration typically occur when the animals are in negative energy balance. The adaptations in whole body metabolism due to GH administration to dairy cattle might be expected to alter milk composition. However, the concentrations of major nutrients in milk are largely unaltered (see Prosser and Mepham, 1989 and references therein). Small changes in milk protein or fat content that have been observed probably reflect the stage of lactation, energy balance status and diet. Therefore, GH treatment of dairy cattle may provide

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animal scientists with a unique opportunity to deliberately alter the composition of milk by adjusting the diet in early and mid-lactation. GH treatment has been observed to increase the rate of blood flow to the mammary gland (Mepham et al., 1984; Davis et al., 1988). It is not clear whether the increase in mammary blood flow is a cause or consequence of the increase in mammary activity although an increase in metabolic activity in other tissues such as skeletal muscle can cause localized vasodilatation (Milnor, 1980). Although changes in whole body metabolism probably reflect a complex interplay between GH and other metabolic hormones, it is unlikely that GH exerts a direct effect on mammary tissue function. This is strongly supported by the observations that mammary epithelial cells lack functional receptors for GH (Akers, 1985 ) and direct infusion of GH into the arterial blood supplying the mammary gland does not stimulate milk secretion (McDowell et al., 1987 ). Insulin-like growth factor I (IGF-I) may mediate some effects of GH on milk secretion. Prosser et al. (1989) have demonstrated a 30% increase in milk production by infusion of IGF-I into the pudendal artery of lactating goats. In contrast, Davis et al. ( 1989 ) have shown that IGF-I has no effect on milk production when infused into the jugular vein of lactating goats. However, the effects of dilution into the general circulation and possible sequestration of IGF-I by IGF-I-binding proteins in the serum may be responsible for the lack of effect observed in this latter study. Therefore, the role of IGF-I in GH-stimulated galactopoiesis is unclear. T R A N S G E N I C ANIMALS W H I C H EXPRESS G R O W T H H O R M O N E GENES

The ability to stably introduce new or mutated DNA into the germ line of animals and to subsequently produce families of offspring which carry the acquired trait loosely defines the term "transgenic" animals. GH genes have been introduced into the germ lines of mice (Palmiter et al., 1982, 1983), rabbits, sheep and pigs (Hammer et al., 1985a).

Transgenic mice The first transgenic animals produced were mice which contained the human (Palmiter et al., 1982) or rat (Palmiter et al., 1983) GH genes. Expression of these genes was under control of the mouse metallothionein-I transcriptional (mMT-I) regulatory sequence. This transcriptional regulatory sequence directed gene expression in nearly all tissues in the mouse, with high levels of GH messenger RNA accumulating in the liver, intestine and kidney, and was inducible by heavy metals such as zinc. The ectopic production of GH in these mice would be expected to escape the normal physiological control mechanisms regulating GH production. Mice containing and expressing either hGH, bGH, rGH or oGH genes grew

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to approximately twice the size of control littermates (Palmiter et al, 1982, 1983; Hammer et al., 1985b; Orian et al., 1989; Shanahan et al., 1989 ). Maximum growth rates of these animals were found to occur between 5 and 11 weeks of age and were approximately 2 to 4 times that of control animals at that time. Also, growth rate was not related to the number of copies of the transgene inserted into the animal's genome or serum GH concentrations (Palmiter et al., 1982, 1983 ). Transgenic mice chronically expressing high serum concentrations of GH have been examined for a variety of morphological and physiological abnormalities (Quaife et al., 1989 ). The mass of the liver, kidney, spleen and pancreas in these animals was found to be 2 to 3 times that of control animals. Histological examination of kidneys from transgenic mice revealed that the tissue contained enlarged glomeruli with sclerosis. These lesions are similar to those found in mice with diabetic glomerular sclerosis. Lesions within hepatocytes were found to increase with age, resulting in dysplasia and sclerosis. Grossly enlarged hepatocytes were found around the central vein and became further enlarged with age. Cells of the spleen were morphologically normal but congested with a mild red cell hematopoiesis. Serum chemical profiles of these transgenic mice were also determined (Quaife et al., 1989). In general, the sera from bGH mice were opalescent. Albumin, globulin and total protein concentrations were similar in transgenic and control animals. Serum alkaline phosphatase concentrations were 2- to 3-fold lower in transgenic animals. Mice with high concentrations o f G H ( > 1 /tg/ml) were found to be hypercholesterolemic but triglyceride levels were normal. Serum insulin concentrations in bGH transgenic mice were 3- to 8fold higher than those in control animals, and serum glucose concentrations were normal. As expected, serum IGF-I concentrations in these mice were elevated approximately 2-fold.

Transgenic pigs Transgenic pigs have been produced by several groups (Vize et al., 1988; Pursel et al., 1989; Wieghart et al., 1990). However, one major concern is the low efficiency of production. In mice, 10 to 15% of the injected eggs result in pups, of which approximately 25% are transgenic. This equates to an overall efficiency ranging from 2.5 to 6% (Brinster et al., 1985 ). In comparison, the overall efficiency oftransgenic pig production ranges from 0.5 to 1% (Vize et al., 1988; Pursel et al., 1989; Wieghart et al., 1990). DNA molecules in which the mMT-I promoter was fused to either the hGH or bGH gene were obvious choices for insertion into pigs. A summary of data concerning the production of transgenic pigs which express the hGH or bGH genes has been presented by Pursel et al. ( 1989 ). Eight transgenic pigs were generated containing between 1 and 500 copies of the mMT-I-hGH gene and with serum hGH concentrations in the range of 3 to 1000 ng/ml. No direct

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correlation was observed between foreign gene copy number and serum hGH concentrations. In addition, eight transgenic animals containing the m M T bGH fusion gene were produced containing between 1 and 28 copies of the bGH gene. Serum bGH concentrations in these animals ranged from 5 to 1000 ng/ml. Again, no correlation was observed between foreign gene copy number and serum bGH concentrations. As in mice, bGH concentrations can be increased in pigs by supplementing the diet with 1000 to 3000 ppm of zinc (Pursel et al., 1989). IGF-I concentrations were found to be elevated in all but one bGH transgenic pig. Progeny from transgenic pigs have been generated which contain the MTI-bGH fusion gene (Pursel et al., 1989 ). Serum bGH concentrations in these offspring were similar to those in the parent animals. Two lines have been established in which bGH concentrations are approximately 1300 and 85 ng/ ml. In contrast to GH transgenic mice which grew to approximately 2 times the mass of control animals, bGH and hGH transgenic pigs did not display the enhanced growth phenotype (Pursel et al., 1989; Wieghart et al., 1990 ). However, bGH transgenic pigs were found to be approximately 15% more efficient at converting food into body mass (Etherton et al., 1987; Pursel et al., 1989), an effect similar to that observed in pigs which have been injected with exogenous pGH (Etherton et al., 1987 ). The most striking phenotype of bGH transgenic pigs was the decrease in mean backfat thickness which was approximately one-third that of control pigs (Pursel et al., 1989; Wieghart et al., 1990). GH transgenic pigs and pigs injected with pGH have been shown to have suppressed appetites. Pursel et al. (1989) have suggested that appetite suppression may limit essential nutrients required for growth. Indeed, when bGH transgenic pigs were placed on a diet containing elevated crude protein and supplemented with lysine, the animals grew approximately 10 to 15% faster than controls (Pursel et al., 1989 ). Many negative side effects were found associated with hGH expression in transgenic pigs including pericarditis, peptic ulcers and impaired fertility (Pursel et al., 1989). Fertility problems have also been described in hGH transgenic mice (Chandrashekar et al., 1988 ). Internal organs of GH transgenic pigs were enlarged in a manner similar to transgenic mice. In particular, m M T - b G H animals had enlarged hearts, kidneys, livers, thyroid glands and adrenal glands, as well as an increase in long bone circumference and weight (Pursel et al., 1989). GH transgenic pigs exhibited glucose levels that were slightly elevated and plasma insulin concentrations that were 20-fold higher than controls. This diabetic condition was also observed in pigs injected with pGH (Etherton et al., 1987; Evock et al., 1988). Analogous experiments in which a human metallothionein IIa transcriptional regulatory sequence was fused to the pGH gene (a cDNA with pGH

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genomic 3' flanking sequences) have been reported (Vize et al., 1988). Although only one animal was produced which expressed elevated concentrations of pGH, data for it were dramatic. This animal contained pGH concentrations approximately 2 times those of control pigs and grew to 90 kg in 17 weeks versus 22 to 25 weeks for control animals. The authors propose that the reason for enhanced growth was due to the use of a fusion gene which directs expression of the authentic pGH gene rather than heterologous GH genes used by others. Also, this animal had no health problems such as those exhibited by pigs expressing the hGH or bGH genes (Vize et al., 1988 ). A third approach to the production oftransgenic pigs has been one in which a phosphoenolpyruvate carboxykinase (PEPCK) gene transcriptional regulatory sequence was fused to the bGH gene (Wieghart et al., 1990). The PEPCK gene normally encodes an enzyme which catalyzes a key gluconeogenesis regulatory step in liver and kidney tissue. Expression of this fusion gene in mice can be regulated by dietary manipulation of carbohydrates and protein (McGrane et al., 1988). Transgenic pigs which possessed the PEPCKbGH fusion gene were found to express elevated concentrations of bGH primarily in the liver and to a lesser extent in the kidney (Wieghart et al., 1990). Of seven P E P C K - b G H transgenic pigs produced, all but one were found to express the gene in the liver. All transgenic pigs had serum bGH concentrations greater than 100 ng/ml on normal dietary rations. One of the transgenic male pigs was able to transmit the fusion gene to progeny. Progeny from this animal displayed enhanced production traits which included decreased backfat (41% that of controls) and increased feed efficiency, similar to m M T bGH transgenic pigs. Unfortunately, deleterious side effects were observed including abnormal joint pathology, stress susceptibility and respiratory distress, although these disorders occurred later in life relative to M T - b G H transgenic pigs (Wieghart et al., 1990). The authors suggest that the delayed development of these deleterious effects may be due to utilization of the PEPCK transcriptional regulatory sequences. This promoter is activated postnatally rather than prenatally as is the case for the mMT-I regulatory sequence (Wieghart et al., 1990). Tra nsgen ic sheep Various fusion genes have been introduced into sheep and the results of these experiments have been reviewed recently (Rexroad et al., 1990). The genes include hGH, bGH, oGH and hGH-releasing factor, attached to either the mMT-I, oMT, mouse transferrin or mouse albumin transcriptional regulatory sequences (Murray et al., 1989; Rexroad et al., 1990). The efficiencies of transgenic sheep production ranged from 0.1 to 4.45% (Rexroad et al., 1990). Two animals have been produced which express the mMT-I-bGH fusion gene. The concentrations of bGH in the sera were 36 and 718 ng/ml (Rexroad et al., 1989 ). Also, two animals have been produced which contain

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and express the mouse transferrin promoter-bGH gene with serum bGH concentrations of 42 and 289 ng/ml (Rexroad et al., 1990). Transgenic sheep which expressed either oGH or bGH grew at rates equal to or slightly lower than control animals (Rexroad et al., 1990). However, transgenic lambs had one-half to one-fifth the levels of body fat of control animals (Ward et al., 1989) and no backfat or depot fat at necropsy (Rexroad et al., 1990). GH expression did not affect the feed/gain ratio in transgenic lambs (Rexroad et al., 1990). Increased GH in the sera of transgenic lambs resulted in increased IGF-I concentrations. Also, before 100 days of age, plasma glucose and insulin concentrations were elevated (Rexroad et al., 1990 ). After 100 days of age, plasma glucose and insulin concentrations were below those of control animals. Rexroad and co-workers have suggested that excess GH secretion in lambs may produce diabetes which results in death of the animals by one year of age. Unfortunately, GH-expressing progeny from transgenic sheep have not been produced. DISCUSSION

Agriculturally important animal traits are a result of the normal physiological processes of growth, reproduction and lactation. Animal products account for approximately 10% of the energy and 25% of the protein consumed worldwide (W. Hansel, personal communication, 1990). According to USDA figures, the total U.S. market for livestock products is approximately U.S.$79 billion, with beef and dairy products representing approximately U.S.$ 54 billion. Although tremendous progress has been made in the last decade regarding these physiological processes, the underlying genetic elements which control them remain largely unknown. Modern advances in biotechnology have contributed to a better understanding of the physiological effects of one gene product, i.e. GH, on animal growth and lactation. Two general modes of increasing GH concentrations in animals are exogenous administration via injection and generation of animals which possess and express foreign GH genes. Chronic administration of GH to swine increases growth performance and lean body mass. However, pigs injected with high doses of GH exhibit both hyperinsulinemia and hyperglycemia consistent with the diabetogenic effects of GH. It may be possible to alleviate this condition by modifying the diet during the period of GH administration. In the few studies in which GH was administered to sheep or cattle, data suggests that there is a clear potential for improvement of growth performance. More experiments need to be performed in order to determine the efficacy of GH treatment.

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Administration of bGH to lactating cows results in dose-dependent increases in milk yield. Improvements have been shown to be as high as 40% which is roughly equivalent to 12 kg milk per cow per day. The diabetogenic effect observed in pigs is not observed in dairy cattle. This may be due, in part, to the efficient removal of glucose from the bloodstream by the mammary gland for lactose synthesis. The inability to efficiently and economically deliver peptide hormones to animals is a major obstacle. Suitable means for GH delivery must be developed since daily injection in a large swine or dairy operation is very labour intensive and impractical. Systems are currently in development which will result in the slow release of peptide hormones to the animal; however, none has been approved for use. Transgenic biotechnology represents one possible alternative to exogenous administration of GH via injection. Transgenic animals which ectopically express GH genes have been generated. In transgenic pigs and sheep, GH gene expression results in a reduction in backfat. In pigs, a substantial increase in feed efficiency has been observed. Since feed consumption by animals represents the largest single production expense, a genetic improvement of this type would significantly reduce pig production costs. Unlike transgenic GH mice which grow to approximately twice the mass of control animals, GH transgenic livestock generally have not shown this phenotype. However, when the diet of GH transgenic pigs was supplemented with crude protein and additional amino acids, a significant improvement in average daily gain was observed (Pursel et al., 1989 ). Therefore, the nutritional requirement of GH transgenic animals is an issue that must be addressed in future experiments. Problems have been reported in transgenic animals which express elevated concentrations of GH, including sterility, diabetes, arthritis and loss of appetite, as well as serious effects on the liver and kidney. It has been suggested that expression of heterologous GH genes in transgenic animals may be responsible for these pathologies. In this regard, Vize et al. ( 1988 ) have generated a GH transgenic pig which does not possess any apparent abnormalities. The authors suggest that the lack of problems may be attributed to the fact that a homologous GH gene, i.e. pGH, was used in these experiments. A general problem encountered in the production of transgenic animals is the risk of disruption or alteration of "normal" host gene (s) expression due to integration of the foreign DNA into the host's genome. To date, only a few instances of this phenomenon have been documented. Production of transgenic animals using embryonic stem cells which contain foreign genes located at precise locations will alleviate this problem. The use of recombinant DNA technology will enable researchers to engineer potent analogs of GH with distinct biological activities, as well as GH agonists and antagonists (Chen et al., 1990). In addition to GH, other growthrelated genes such as IGF- l, GH receptor, GH-releasing factor and GH-bind-

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ing proteins are possible candidates for gene insertion studies. Also, the use of genetic elements that strictly regulate developmental and tissue-specific expression of these genes is desirable. Since genes have only recently been introduced into the germ line of agriculturally important mammals, a considerable amount of basic research will be required before selecting genes for insertion into livestock. Additionally, the relationship between gene selection and husbandry practices must be considered when producing transgenic animals. The future role of GH in the regulation of animal growth and production is promising and will continue to require and benefit from the collaborative efforts of scientists from many disciplines. In this way, the complex mechanisms involved in the regulation of the physiological processes of growth and production and the role of GH as a homeorhetic signal in these processes will be better understood. ACKNOWLEDGEMENTS

We would like to thank Drs. T. Etherton, W. Hansel, C. Rexroad, Jr., C.A. Pinkert and H. Chen for valuable discussions and for providing information used in this review. We also thank Dr. W. Hansel for reviewing this manuscript. J.J.K. is supported, in part, by the State of Ohio Eminent Scholar's Program which includes a grant from Milton and Lawrence Goll. J.A.C. is a Post-Doctoral Fellow supported by the State of Ohio Eminent Scholar's Program. REFERENCES Akers, R.M., 1985. Lactogenic hormones: binding sites, mammary growth, secretory cell differentiation, and milk biosynthesis in ruminants. J. Dairy Sci., 68:501-519. Andrews, P., 1966. Molecular weights of prolactin and pituitary growth hormones estimated by gel filtration. Nature, 209:155-157. Bauman, D.E. and Currie, W.B., 1980. Partitioning of nutrients during pregnancy and lactation: a review of mechanisms involving homeostasis and homeorhesis. J. Dairy Sci., 63:15151529. Bauman, D.E., Eisemann, J.H. and Currie, W.B., 1982. Hormonal effects on partitioning of nutrients for tissue growth: role of growth hormone and prolactin. Fed. Proc., 41: 2538. Beerman, D.H., 1989. Status of current strategies for growth regulation. In: D.R. Campion, G.J. Hausman and R.J. Martin (Editors), Animal Growth Regulation. Plenum, New York, NY, pp. 377-400. Beerman, D.H., Hogue, D.E., Fishell, V.K., Dickson, H.W., Aronica, S., Dwyer, D. and Schricker, B.R., 1988. Effects of exogenous ovine growth hormone (oGH) and human growth hormone releasing factor (hGRF) on plasma oGH concentration and composition of gain in lambs. J. Anim. Sci., 66 (Suppl. 1 ): 282-283 (abstr.). Boyd, R.D. and Bauman, D.E., 1989. Mechanisms of action for somatotropin in growth. In: D.R. Campion, G.J. Hausman and R.J. Martin (Editors), Animal Growth Regulation. Plenum, New York, NY, pp. 257-293.

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