One of the interesting biological technologies that have been introduced to the livestock production is the synthetic somatotropin (ST) or growth hormone (GH). Exogenous ST has been used to increase production in farm animals. In dairy animals, ST has been shown to increase lactation performance (Bauman and Vernon, 1993). This effect has been investigated extensively in dairy cattle after available of recombinant bovine ST (rbST). rbST has been shown to increase milk yield with minor change in milk composition. In addition, rbST has been demonstrated that it could increase milk yield effectively in dairy goat (Disenhaus et al., 1995, Polratana et al., 2004; Sallam et al., 2005). Although there are multiple factors that can determine the magnitude of rbST effect on milk yield which include the nutritional status and feed quality. Cows injected with rbST adjust their nutritional status partly by changing voluntary food intake related to feed quality and their milk production. For the dairy animals fed in Thailand, lactation performance is attenuated partly by the inadequacy of nutritional status. However, it has been shown that rbST could increase milk yield in both dairy cows and goat (Polratana et al., 2004; Chaiyabutr et al., 2005). Interestingly, these experiments revealed that feed intake was also increased after rbST treatment (Polratana et al., 2004; Boonsanit et al., 2010). The effect of rbST on milk production, feed intake and nutrient digestibility in lactating goat is an interesting view of this proposal.
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Food intake is a complex behavior that provides energy and necessary nutrients to the body. To ensure that body receives adequate energy and nutrient especially during lactation, this behavior is controlled or influenced by multiple organs. The internal control of feed intake includes the interplay between peripheral sensing and signaling systems (sensory organ, gastrointestinal tract and adipose tissue etc.) and central integration (the brain). Leptin (from adipose tissue) is an internal factor that produces anorectic effects on feed intake. The satiety effects of leptin are also observed in ruminants. Administration of human leptin in ewes for 3 days decreased the voluntary dry matter intake to approximately a third of the preinfusion intake (Henry et al. 1999). Moreover, Chanchai et al. (2010a) found that administration of rbST in dairy cows decreased leptin concentration in all stages of lactation.
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Endocrinology aspects on mammary gland development and milk production
The physiology of lactation consists of mammary gland development (mammogenesis), the start of milk production (lactogenesis) and maintenance of milk production (galactopoiesis). The mammary gland development is stimulated by oestrogen and progesterone, somtotropin and IGF-I, prolactin and inhibited by mammary derived growth inhibitor. The lactogenesis is stimulated by prolactin, oestrogen, glucocrticoids, insulin and inhibited by progesterone. The galactopoiesis is influenced by some hormones such as somatotropin, thyroid hormones, and prolactin for stimulation and glucocorticoids, oestrogen for inhibition.
Hormonal effects on mammary gland development
Oestrogen stimulates mammary duct growth, and oestrogen and progesterone act synergistically to stimulate lobule-alveolar development. Progesterone is elevated throughout gestation and oestrogen is particularly increased during the late pregnancy in the rodent (Mizoguchi et al., 1997). Thus, mainly duct and lobular growths occur during the first half of pregnancy, with lobule-alveolar growth occurring during the second half of pregnancy. In addition, oestrogen also stimulates the secretion of IGF-I hormone and thereby increases the epithelial cells. Prolactine and growth hormone (ST) are needed for the steroid hormones to be effective and levels of prolactin, ST and insulin decrease during gestation. Thus, no mammogenic activity happens in the absence of growth hormone and prolactin (Tucker, 2000).
Mammary-derived growth inhibitor (MDGI) is produced by mammary epithelial cells. It acts in an autocrine manner to inhibit cell growth and especially to induce differentiation in mammary epithelium. MDGI levels increase in mammary gland two weeks prior to parturition and are high in lactating cows.
ST stimulates the growth of ducts during mammary gland development near puberty and lobule-alveolar growth during pregnancy. Injection of ST increases growth of the parenchyma and total mammary cell numbers in cattle (Radcliff, 1997). This occurs via action of IGF-I. The negative effects of high feeding level on mammary growth near puberty may be due to increased local production of IGFBP-3, which binds IGF-I to inhibit it.
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Hormonal effects on lactogenesis
There is considerable species variability in the effects of hormones on lactogenesis. Oestrogen stimulates the release of prolactin from the anterior pituitary and increases the number of prolactin receptors in mammary cells. There is a surge of prolactin several hours before parturition. But prolactin is not important during ruminant lactation. In dairy goat, inhibition of prolactin secretion has only small influences on milk yield and administration with prolactin did not increase milk yield (Jacquemet and Prigge, 1991).
Glucocorticoids bind to receptors in mammary tissue to increase the development of the rough endoplasmic reticulum and other ultrastructural changes to increase the secretion of Î±-lactalbumin and Î²-casein. Binding to the corticosteroid binding globulin (CBG) reduces the activity of glucocorticoids in serum. During the periparturient period, levels of the CBG decrease and free glucocorticoid levels increase. Glucocorticoids also suppress the immune system, which may contribute to the increased incidence of mastitis during early lactation (Kehrli, 1991).
Insulin is important in stimulating glucose uptake and the expression of milk protein genes required for lactogenesis. Insulin concentration was low during lactation in most species (Neville and Picciano, 1997). It would be important for shunting the nutrients away from body depots and had more available nutrients for milk synthesis.
Progesterone has been suggested to work by increasing the mammary threshold to prolactin, by altering the secretion of prolactin from the pituitary or acting as a glucocorticoid receptor antagonist. The level of progesterone is high during gestation and serves to inhibit lactogenesis until just before parturition and its concentration depends each species, around 6-130 ng/ml in the rat, 35 ng/ml in sheep (Mellor et al., 1987). The level decreases about 2 days before parturition to remove the inhibition of milk synthesis.
Hormonal effects on galactopoiesis
Thyroid hormones are required for maximal milk production. During lactation there is decreased conversion of thyroxine (T4) to the active hormone triiodothyronine (T3) in liver and kidney, but increased conversion to T3 in the mammary gland. This may be enhanced the priority of the mammary gland for metabolites compared to other body tissues. Administration of thyroid hormone causes a temporary increase in milk production for several weeks, but milk yield was unchanged when thyroid hormones administration to animal for more than seven weeks (Blaxter et al., 1949).
High levels of exogenous glucocorticoids and oestrogen decrease milk production. Prolactin is required for the maintenance of milk production in rats, with decreases in milk yield of 50% or more after bromocriptine administration and much less effective in ruminant. Moreover, prolactin and IGF-I levels increase with effects of long day photoperiod. These contribute for increasing milk yield in cattle (Dahl et al., 2000). These may be explained that prolactin has negative effects on the IGFBP-5 protein and IGFBP-5 is a factor which inhibits cell survival by inducing apoptosis (Flint et al., 2001).
Overview of somatotropin
ST is a protein hormone synthesized from somatotroph cell of anterior pituitary gland. The structure of ST (about 191 amino acids) is relative species specific in which bovine ST and porcine ST share up to 90% similar amino acid sequence (Table 1), while human ST shares only 35% similarity (Bauman and Vernon, 1993; Etherton and Bauman, 1998).
Control of the somatotropin release and mechanism of action
The secretion of ST, basal and episodic patterns, from anterior pituitary gland is regulated by the interplay of the two main hypothalamic peptides; growth hormone releasing factor (GHRF) and somatostatin (SS) (Fig.1). GHRF is a 44 amino acid peptide synthesized by cells in the arcurate nucleus of the hypothalamus (Fig. 1). It is secreted from neuron- secrectory nerve terminals and transported to the anterior pituitary gland by the hypophyseal portal system. GHRHF binds to a G-linked protein receptor in somatropes, stimulating in cAMP and activating GH release via the transcription factor. Somatostatin is produced in the periventricular nucleus of the hypothalamus. It is 14 amino acids that is found in many tissues outside the hypothalamus. This includes the CNS and delta cells of endocrine pancreas and gut. SS inhibits the release of GH from the anterior pituitary by reducing cAMP concentrations within the somatotropes. SS also inhibits several other hormones and metabolites such as PTH, calcitonin, gastric HCl, acetylcholine (Hossner et al., 2005).
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Table 1 Amino-acid sequence of somatotropins from various species.
Although the effect of GHRF and somatostatin is stimulation and inhibition of ST synthesis and secretion, however, the mechanism of pulsatile secretion of ST is still unclear (Mueller et al., 1999; McMahon et al., 2001). It is well known that ST produces broad range of physiological functions including: postnatal growth (bone & muscle), nutrients metabolism, modulation of cell cycle, control of immune system, heart and brain function, mammary gland and lactation. These functions of ST can be divided into somatogenic and metabolic effects. The first effects are the stimulation of cell proliferation while the latter effects change the whole body metabolism by partitioning of all nutrients to support the specific action of ST. (Bauman and Vernon, 1993; Etherton and Bauman, 1998). With the wide range of ST function, it suggests that the mechanism of ST action should be tightly regulated. Somatotropin mediates its function directly via growth hormone receptors (GHR) or indirectly via insulin like growth factor (IGF) system (Bauman and Vernon, 1993; Brooks and Waters, 2010). The direct effect of ST is transmembrane receptor belong to class I cytokine receptor super-family. The expression of GH receptor has been demonstrated in many organs or tissues, eg. liver, adipose tissue, heart, brain, kidney etc. This wide distribution of GHR indicates the pleotropic effect of ST (Kopchick et al., 2002). One of the most important mediators from the ST-IGF axis is IGF-I. IGF-1 belongs to a family of insulin-like growth factors (IGFs) that shares close structural homology to the precursor form of insulin (pro-insulin). Although circulating IGF-I which acts as endocrine fashion appear to come mainly from liver, the local production of IGF-I as paracrine or autocrine has been known as well (LeRoith et al., 2001).
Recombinant bovine growth hormone (rbGH) or rbST refers to bovine growth hormone that is manufactured in a laboratory using genetic technology. This synthetic hormone is approved by United State of American Food and Drug Administration (US FDA online) and marketed to dairy farmer to increase milk production.
Carbohydrate, lipid, protein and mineral metabolism
Figure 1. Regulation of growth hormone release
To make rbST, the plasmid of a bacterium is cut by enzymes, and then combined with a cow's DNA. It is reintroduced to the bacterium, placed in a fermentation tank and allowed to multiply, then separated and purified before delivery to the farmer (Roush, 1991). This modern technology permitted the development of rbST, which provided an unlimited source of ST for research and for commercial application. Recombinantly derived bST products differ slightly from bST derived pituitary gland which the manufacturing process can add a few extra amino acids to substitute for the terminal alanine residue (Table 2) (Hammond et al., 1990). The number of extra amino acids differs from 0 to 9, depending on the particular manufacturing process.
Table 2.The products of rbST on the market
Amino acid replace for alanine (191)
Treatment with rbST has been shown to increase milk yield with minor change in milk composition. Although the exact mechanism that rbST stimulates mammary gland activity is still unclear, several evidences supported that the pharmacological effect of rbST on lactation apparently mediate main via IGF dependent pathway. Firstly, IGF receptor was successfully demonstrated from mammary tissue, while GHR expression was very scarce at mRNA level and could not be detected at protein level. Secondly, the closed infusion of ST to the mammary artery failed to produce the effect on milk yield, whereas the same infusion by IGF-I significantly increased milk production. Supplement with rbST dramatically increased circulatory IGF-I (Etherton and Bauman, 1998). In Thailand, the effect of rbST on milk production has been extensively investigated in crossbred dairy cattle (Chaiyabutr et al., 2009; Boonsanit et al., 2010; Chanchai et al., 2010b; Chanchai et al., 2010c). In addition, milk yield from dairy goat also increased after rbST supplement (Polratana et al., 2004). It was concluded from above experiments that rbST improve the lactation performance in crossbred dairy cattle and dairy goat in hot and humid environment of Thailand.
Recombinant somatotropin and nutrient metabolism
Effect of recombinant bovine somatotropin on carbohydrate metabolism (glucose)
Effect of recombinant bovine somatotropin on nitrogen metabolism
Effect of recombinant bovine somatotropin on fat metabolism
Effect of recombinant bovine somatotropin on feed intake and nutrient digestibility
Supplemented with rbST has been shown to affect feed intake in dairy animal (Polratana et al., 2004; Boonsanit et al., 2010; Chanchai et al., 2010a). Some experiments have been demonstrated no effect of rbST on feed intake (Disenhaus et al., 1995; Chadio et al., 2000; Chaiyabutr et al., 2005; Chaiyabutr et al., 2007; Sallam et al., 2005). This discrepancy information suggested that these results probably came from the difference in experimental condition and reflected that this behavior was controlled by multiple factors. In crossbred dairy cattle fed in Thailand, there was no significant effect of rbST on feed intake (Chaiyabutr et al., 2007). However, the latter investigation from the same group reported that an increase feed intake in the crossbred dairy cattle treated with rbST compared with control at all stage of lactation (Boonsanit et al., 2010; Chanchai et al,. 2010a). In dairy goat and ewes, dry matter intake did not differ significantly between control and rbST treatment (Disenhaus et al., 1995; Chadio et al., 2000; Sallam et al., 2005). However, Polratana et al (2004) found that dry matter intake of concentrate in rbST injected goat was significantly higher than control group during late lactation. As mention above, the increase feed intake may depend on the increase in milk production, energy status, environmental condition and the nutrients of diet (particularly energy). Overall, dairy animals supplemented with rbST appear to adjust their voluntary feed intake in relation to the additional nutrient required for increased milk yield.
In addition, rbST administration in dairy cows had no effect on nutrient digestibility when compare to control in entire lactation cycle and also no significant difference between cooled cow and non-cooled cow (Chanchai et al., 2010b) in agreement with other studies that carried out in lactating buffaloes (Khattab et al., 2008). Most of previous studies have been done nutrients digestibility on dairy cattles or buffaloes when administrated with rbST. Thus, it remains to investigate the effect of bST on nutrient diegestibility of dairy goat during early period in this proposal.
Role of leptin on feed intake and energy balance
Leptin is protein hormone secreted from the adipose tissue into the circulation. This hormone meets the criteria of adiposity signals which play an important role for the control of feed intake and body weight. Firstly, the concentration of plasma leptin has positive relationship with body fat mass. Secondly, exogenous leptin decreases food intake and body weight, and increases energy expenditure. Thirdly, leptin signals to the brain after release by the adipocyte and gives information about the status of the body energy stores. Leptin receptors are located in several hypothalamic nuclei. Leptin not only influenced on feed intake and body weight, but also affected on other physiological functions such as: reproduction, the immune and inflammatory response, angiogenesis by various biological mechanisms (Schwartz et al., 2000; Wood and Seeley, 2000; Kershaw and Flier, 2004). In addition to the extensive investigation of leptin effect was found in rat and mouse, the effect of leptin on feed intake has also been studied in dairy animal (Henry et al., 1999; Blache et al., 2000; Morrison et al., 2001; Leury et al., 2003; Liefers et al., 2003; Whitley et al., 2005). Voluntary feed intake decreased approximately one third after 3 days leptin administration in ewes (Henry et al., 1999). However, the anorectic effect of leptin was lost when growing and adult sheep were underfed (Morrison et al., 2001). In crossbred dairy cattle, plasma leptin was lower in rbST treatment compared with control. The lower of plasma leptin in rbST treated cows was associated with an increase of feed intake (Chanchai et al., 2010a). These results suggested that the effect of rbST on feed intake appeared to be mediated partly by influence of plasma leptin.
From above information, it is important to carry out this experiment in dairy goat during early lactating period and to understand the relationship between plasma leptin and rbST induced feed intake in consistent with increase of milk production.
Effects of recombinant bovine somatotropin on lactation performance
Milk yield gradually increased in both dairy cattle and goat after treated with rbST. rbST consistently results in a greater peak milk yield and an increased persistency in yield over the lactation cycle in both temperate and tropical zone (Bauman and Vernon, 1993; Etherton and Bauman, 1998). In dairy cattle, an increased milk yield after rbST administration is found of all parities. However, the magnitude of the increase in milk production differs to be due to the stage of lactation. In general, small response is found when lactating animals are injected rbST in early lactation prior to peak yield. In addition, rbST increases milk yield by 10% when administered in early to mid-lactation, and by 40% in late lactation (Bauman and Vernon, 1993). In Thailand, rbST increased lactation performance by 22% during early lactation (Chaiyabutr et al., 2009). Chanchai et al. (2010a) and Boonsanit et al. (2010) who studied the influence of cooling system in crossbred dairy cattle treated with rbST (500 mg rbST/dairy cattle/two weeks) during hot & humid conditions reported that the milk yield of cooled cows (ambient temperature from 29 - 32 0C and relative humidity from 70 - 78%) treated with rbST was slightly higher than non-cooled cows (ambient temperature about 34 0C and relative humidity from 50 - 64%).
Similarly, milk yield rose significantly over the entire experimental time when lactating goats supplemented with rbST (Disenhaus et al., 1995; Gallo et al., 1997; Chadio et al., 2000; Sallam et al., 2005). In Thailand, supplement with 250 mg rbST every 2 weeks in dairy goat doubled milk yield during late lactation (Polratana et al., 2004). It remains to be investigated whether milk yield during early period of lactation in dairy goat still response at this dose of rbST. The relationship of milk production responses to dose and stage of lactation in lactating animals are shown in Table 3.
Table 3 The relationship of milk production responses to dose and stage of lactation.
Milk yield (kg/d)