Department of Animal Science,
University of Sydney,
Camden, NSW, Australia 2570.
Somatotropin is an anterior pituitary peptide hormone released under the influence of growth hormone-releasing factor. High-producing dairy cows have elevated circulating levels of somatotropin (5,43). Recombinant bovine somatotropin (rbST) has biologic activity similar to the pituitary-derived somatotropin (7).
Peptide hormones, like bST, are subject to digestive processes and hence are not active orally. There is not sufficient similarity between bovine and human growth hormone for bovine somatotropin to be active in humans if injected. The lack of oral activity of bST and the relatively low amounts of somatotropin and IGF-1 that are excreted in the milk of treated cows were important factors in allowing milk from rbST treated cows to be considered safe for human consumption (47). Recombinant bST is commercially produced through insertion of the gene for bovine somatotropin into the DNA of E. coli. The E. coli are fermented and a process of isolation and purification is used to obtain the recombinantly produced somatotropin. The product is commercially marketed as a weekly or 14 day injection.
Changes in metabolism. Table 1 (Click here to view Table 1). outlines the homeostatic and homeorhetic changes through which somatotropin responses are obtained and compares these to monensin. An important adaptive response to rbST treatment is a change in the partitioning of nutrients. In early lactation there is an increased loss of glucose from the body and an increase in plasma free fatty acids associated with increased concentrations of milk lactose and milk fat (49, 58, 68). The magnitude of changes in blood metabolites depends on the stage of lactation, dose of bST used, and energy balance of the cow when treatment with bST is commenced. It has been suggested that cows that are treated with somatotropin while they are in negative energy and protein balance respond with increased levels of plasma free fatty acids (68) whereas, in those that are in positive energy balance, blood nutrient composition does not appear to be altered unless high doses of bST are used (8, 49, 54, 59, 73). Reports of blood mineral levels indicate no significant changes between treatment groups (32); and Eppard et al. (33) found no statistically significant differences in levels of milk calcium, copper, phosphorus, iron, sodium, and manganese. Concentrations of blood metabolites generally return to normal ranges following increased feed intake.
Impact on feed intake. Initial treatment for approximately 10 days with somatotropin may cause a decrease in appetite (9, 63). However, long-term trials demonstrate an increase in voluntary feed intake for cows treated with somatotropin (20, 69). There are probably no changes in the efficiency of digestibility of feed. You don't get something for nothingincreased production will need to be met with increased feed intake.
Effect on mammary perfusion and efficiency. Somatotropin increases blood flow to the mammary gland as a result of increased cardiac output and an increased proportion of blood flow diverted to the mammary gland (22, 23, 46). A 10% increase in cardiac output was noted by Davis et al. (23) and this was accompanied by a 30% increase in udder perfusion. These authors concluded that this was a major homeorhetic change, which could explain much of the increase in milk production.
Somatotropin appears to have an indirect action on the gland through the insulin-like growth factors (IGF-1 and IGF-2; 12, 24). Davis et al. (25) noted a 35% increase in mammary uptake of glucose and increased mammary uptake of oxygen, acetate, and triglyceride. The administration of bST to cows 10 to 12 weeks into lactation markedly increases the uptake of amino acids by the mammary gland and muscle (58).
The ionophore antibiotic monensin is a naturally occurring, active compound produced by the bacteria Streptomyces cinnamonensis. The rumen is the primary site for the action of monensin in the cow. Monensin is available in various forms for use in cattle and has been available for use in beef cattle and heifers for about 20 years. It can be incorporated into feed as a powder or given as a ruminal bolus by the use of a variable geometry device, also called a controlled-release capsule. The capsule consists of a plastic cylinder with folding wings at one end, which allow the capsule to be retained in the rumen (29). These capsules, which contain 32 gm of monensin released over 100 days, have proved to be a useful means of conducting large randomized controlled trials. Typical inclusion rates for monensin in feed is 10 to 30 mg per kg of finished feed.
Effects on bacteria. Monensin acts to selectively decrease populations of certain rumen bacteria. It does this by modifying the movement of ions across cell membranes (79, 81). Gram positive bacteria from the rumen produce hydrogen, ammonia, lactate, acetate, and methane and are more sensitive to monensin, while the gram negative bacteria which produce propionate and succinate are less susceptible (79). Differences in cellular membrane structure between gram-positive and gram-negative bacteria are chiefly responsible for the different sensitivities of bacteria to monensin. Some species of gram-positive bacteria, however, adapt over time to the presence of monensin and some gram-negative species are sensitive to high concentrations of monensin (26). Gram positive bacteria produce less methane when monensin is added to the diet.
Effects on metabolism independent of the rumen. Monensin can influence metabolism independent of the effects on rumen function. While monensin can be absorbed from the gastrointestinal tract, extensive hepatic metabolism and relatively low therapeutic levels result in trace amounts in the circulation. Intravenous administration of monensin to heifers, however, caused a significant decrease in plasma K, Mg, and P concentrations and increased glucose and FFA concentrations (4). The direct impact of orally administered monensin on metabolism is likely to be limited.
Changes in metabolism. Through the impacts on ruminal microbial populations monensin modifies metabolism to:
Energy metabolism. Monensin increases the efficiency of energy metabolism in the rumen. While the total volatile fatty acid (VFA) concentration in the rumen does not change, molar proportions of propionate increase, and molar proportions of acetate and butyrate decrease with treatment (14,70,77). Treatment may reduce ruminal production of methane by as much as 31% (82, 91, 93). Changes in VFA ratios and reduced methanogenesis, however, do not explain all of the increase in energy efficiency (93) and changes in ruminal pH, changes in digesta flow rates or altered cellulolytic activity may in part explain improved efficiencies of action. It appears that monensin alters the site of digestion, with a recent study finding a marked reduction in ruminal digestion of feed and a marked increase in intestinal rates of digestion (40).
The net effect of these changes is to increase glucose availability as reflected in increased plasma glucose concentrations (1, 39), to decrease mobilization of free fatty acids (1, 81, 89), and to markedly lower ketone concentrations (1, 81, 89).
The lower plasma glucose, ketone, and FFA concentrations may result from several actions of monensin:
The increase in propionate production is a favourable adaptation which results in a reduced dependence on FFA and ketone metabolism in the cow.
Monensin feeding increases the amount of dietary protein reaching the lower gut (27, 40, 97) and there is a decrease in ammonia production in the rumen and bacterial protein reaching the lower gut (74). Much of the protein sparing effect appears to be mediated through the impacts of monensin on Peptostreptococcus, important in deamination and sensitive to monensin (80). Recent studies have found that ruminal ammonia levels are markedly reduced by monensin treatment and there was a significant increase in the percentage of lysine and methionine apparently absorbed in the small intestine. There was a significant increase in flow of amino acids to the duodenum for 11 of 17 amino acids measured and approximately 13% more amino acids digested than controls (40). These changes have not been reflected in significant changes in plasma urea nitrogen in studies with dairy cattle (1, 89).
Monensin and mineral metabolism. Studies in pigs (45) and sheep with low blood selenium concentrations (2) noted an increase in glutathione peroxidase activity with monensin feeding. Costa et al. (21) found that selenium absorption measured by radioactive dosing of 75SeO3 in cattle was increased by 75% when monensin was fed. Stephenson et al. (89) found no significant increase in glutathione peroxidase activity when dry cows were treated with monensin, however, glutathione peroxidase activity is not a very sensitive indicator of change in selenium status in relatively short term studies. There is evidence suggesting increased copper absorption in lactating dairy cattle (89) and in sheep following monensin treatment (98). The changes in copper and selenium uptake are very favourable as these metals are important in antioxidant enzymes used in immune responses.
Monensin has been shown to increase the availability of magnesium, potassium, calcium, iron, and zinc in steers (86, 88). Unpublished New Zealand data indicates that plasma magnesium concentrations are greater in monensin treated dairy cattle (101). We found no significant difference between groups in plasma calcium concentrations (89) and risk of milk fever in monensin treated and untreated cows in a 1200 cow randomized controlled trial (13).
Impacts on feed intake. The impact of monensin on feed intake of feedlot cattle is well recognized. Feeding monensin decreases feed intake by about five to six percent on high grain rations, and three percent on high forage diets. This effect may be mediated through the effect of monensin in increasing rumen fill. There is limited feed intake data for dairy cattle fed monensin, but Sauer et al. (81) found lower feed intake in monensin treated cattle and Abe et al. (1) suggested that there may have been a depression of feed intake for dairy cattle given a monensin bolus within seven days after calving.
There are a large number of trials reporting both the short- and long-term effects of bST on milk yields. Difficulties arise in evaluating the results because of differing doses and products used and the differing environments under which studies were conducted. Early short-term trials on cows under research conditions (9, 11, 31) reported increases in milk production of 10 to 32 % and demonstrated that an increased dose led to increased yield, with a levelling off of response at higher dosages. Responses to bST can be characterized generally as curvilinear with an increased response to increasing dose, but decreasing response (to no further response) at high dose rates.
Responses to long-term treatment of cows with bST have been detailed (10, 30, 57, 69, 85, 92). Responses depended on trial site, bST formulation and dosage, and ranged from 11.8 to 41.2% increase in milk yield. There are now a considerable number of trials conducted in many countries under differing feed conditions (3, 19, 20, 34, 37, 41, 42, 44, 62, 66, 72, 95). Pasture-based dairy herds treated with rbST give similar milk responses to stall-fed or lot-fed cows (10, 44, 62, 95). An analysis of the 29 trials on bST (Posilac) use detailed by the Monsanto company (42) indicates that the mean percentage increase (ñ standard deviation) in milk production was 16.8 ñ 4.5% and that response was significantly (P = 0.08) lower with increasing level of milk production prior to treatment. It should not be assumed, however, that the results of these 12 week farm trials can be too readily extrapolated. There has been a considerable range of milk responses to bST, which indicates that environmental factors, especially nutritional management, will be substantial modifiers of responses to somatotropin. This is supported by the lower responses to rbST observed in herds in hot climate conditions and by nutritional modulation of the IGF factor system (60). McGuire et al. (60) found that by restricting feed intake to lactating cows plasma concentrations of IGF-1 were markedly decreased, indicating that many of the stimulatory effects of bST on lactation would not be observed in underfed cows. Underfeeding of cows resulted in a marked decrease in milk production despite bST treatment.
There are an increasing number of trials reporting milk production responses to multilactation trials with bST (3, 34, 37, 41, 72). In most, but not all, studies there has been evidence of a continued stimulus to production. Lean et al. (49) reported that milk production of cows treated for a second lactation did not significantly increase above untreated controls over the first 30 days of treatment, an observation supported by a failure of cows, primiparous in a first lactation of treatment, to respond in the second lactation (41) and a lower response of cows treated in a second lactation (3, 18, 37, 41, 49, 52). Hansen et al. (41) suggest that there is a need for further studies in this area. Dairy farmers, nutritionists, and veterinarians will need to observe herds using bST carefully to evaluate this area of concern.
There are a limited number of studies examining the effects of monensin on milk production and very few conducted under North-American conditions. Sauer et al. (81) found that monensin feeding decreased milk fat concentration and did not significantly increase milk production or milk protein concentration. However, very few cows were used in this study and the statistical power was low. Studies in Australian herds have shown a marked variability in response with monensin. Lowe et al. (55) found an overall increase in milk production of 1.1 litres of milk per day for treated cows. When the data from Lean et al. (51) were pooled, there was no significant milk production increase, but we observed a significant increase in milk production in our most recent large trial (13). Some herds in these studies were lot fed and produced at levels similar to North-American herds. In general a 0.5 to 1.5 litre per day production response can be anticipated with monensin use, however, the sources of variability in response have not been identified. Van Beukelen et al. (96), Lowe et al. (55) and Abe et al. (1) found that milk fat depression may result after monensin feeding. Paradoxically, however, herds with low milk fat content could potentially benefit from the potential for monensin to reduce acidosis, because of the capacity of monensin to reduce the numbers of S bovis.
Of potential importance to health and production of cows in future lactations is the effect of bST treatment on body condition and body composition. Carcasses from cows treated for eight weeks with bST were leaner, wetter, and contained less fat than control cows (15). Long term (36 week) treatment with bST resulted in greatly reduced fat content of cows (85). These changes in body composition are reflected in decreased serum free fatty acid concentrations in bST treated cows calving after one lactation of treatment (52). While some studies have found that body condition can be regained during treatment and the dry period prior to calving, others have not. Close monitoring of body condition is an essential role for the veterinarian or nutritionist working in herds using bST.
There is very little information on the effects of monensin on bodyweight changes in lactating dairy cattle.The role of monensin in increasing weight gains in heifers and beef cattle has been long established and weight gain increases of up to 10%, and usually 5 to 8%, over controls are anticipated.Abe et al. (1) found that monensin treated cows did not significantly lose more weight than untreated controls, while Sauer et al. (81) found the treated cows did not gain significantly more weight. Larger studies are needed to consider the effects of monensin on weight change in lactating cows.
There is fairly conclusive evidence from a number of trials that bovine somatotropin, when used at doses consistent with increased milk production, increases the incidence of twinning (42, 71) and has a negative influence on reproductive performance (19, 41, 42, 57, 67, 92). The latter function mimics the now well recognized antagonism between increased milk production and reproductive performance. The mechanism through which somatotropin acts, however, is not clearly defined and may not be limited only to the effects of increased production. A role for IGF-1 in stimulating follicular growth has been determined and bST has increased luteinizing hormone (LH) response to GnRH challenge (35) and blood progesterone concentrations (36). It has been observed that small doses of bST may be beneficial for fertility (87), but this observation has been challenged (41). The effect of bST on increasing follicular recruitment and development has been used in attempts to increase the success of multiple-ovulation, embryo-transfer, programs (38). The primary negative effects on reproduction appear to be increased days open for treated cows and increased removal of cows for reproductive failure. We recommend that treatment with bST be withheld until pregnancy is established in cows from which progeny are desired.
Studies demonstrated that beef (64) and Holstein heifers (61) fed diets containing sodium monensin displayed estrus earlier than controls. A mechanism for the reduction in time to estrus was not determined. However, the effect did not appear to be related to increased bodyweight gain (61, 64) as heifers fed monensin were younger and lighter at puberty than those fed control diets. There is some evidence that monensin feeding influences ovarian and pituitary function of heifers (75, 76). Randel et al. (75) found that LH concentration peak and surge was greater in monensin treated heifers than controls following treatment with gonadotropin releasing hormone. Bushmich et al. (18) found that prepubertal heifers fed with monensin had greater ovarian size, ovarian weight, and follicular stroma than controls after stimulation with exogenous follicle stimulating hormone and human chorionic gonadotrophin.
These apparently favorable physiologic responses to monensin in heifers have not been reflected in reproductive performance in adult, lactating dairy cattle. In two large randomized controlled trials each involving more than 1000 cows, both grazing and in lots (13, 51), we have not found a consistent, significant impact of treatment on conception rates or days open. There is, however, some evidence of variability in results with some herds reporting significantly improved conception rates. Given the remarkable effects of monensin on plasma metabolite concentrations, particularly glucose and -hydroxy butyrate, these findings provide some degree of challenge to postulated interactions between blood metabolites and fertility. The role of plasma glucose and plasma ketone concentrations in modulating pulsatile production of luteinising releasing hormone as postulated by Schillo (83) may be questioned, as monensin treated dairy cows had higher plasma glucose and lower plasma -hydroxy butyrate concentrations, but longer intervals to first ovulation and estrus (1).
There is now a significant body of data published on the role of bST in increasing the risk of mastitis. A number of workers have pooled data to evaluate responses, but a formal meta-analysis of the bST mastitis data has not been performed. If the effect of bST in increasing mastitis is considered without controlling for increased milk yield, it has been demonstrated that there is an increase in risk (53, 100, 102). However, increased milk production is associated with increased mastitis incidence and costs (28, 84) and it appears, therefore, reasonable to assess risk in terms of increased milk production and, possibly, increased time milking. White et al. (100) evaluated the risk of mastitis in bST trials conducted for the Monsanto company and found that the increased risk of mastitis was consistent with that expected from similar milk production achieved through genetic gain. This conclusion should be evaluated cautiously, as it pertained to cows which did not have mastitis prior to treatment. Cows which may be more susceptible to mastitis, that is cows that have mastitis prior to treatment, are an important consideration in the field. Treatment with bST does, however, increase the recovery rate in cows with experimentally induced mastitis and appears to favorably modify the immune response (16, 53). We conclude that there needs to be further, critical evaluation of the impact of bST on mastitis and that veterinarians must attempt to ensure that milking and mastitis management is rigorous on farms when bST is used.
Reports of health disorders, apart from mastitis, generally suggest that somatotropin has little effect on health. However, there are substantial difficulties in interpreting the data, because of different treatment programs, formulations, and doses used and because many disorders are of a low incidence, which means that many hundreds to several thousand cows will usually be needed to determine differences in risk of disease with confidence. There is some evidence that the incidence of lameness may be slightly increased by treatment (41), despite recent findings of no significant effect (99), and that the incidence of cystic ovaries may increase (41, 42), but the incidence of ketosis can be significantly lower after calving in cows treated in the previous lactation than controls (50). There has been little or no evidence to suggest that bST will increase the incidence of clinical ketosis during treatment periods. Recent unpublished work at the University of Sydney strongly supports these findings.Further, bST treatment appears to have some potential benefits for treating cows with hepatic lipidosis after calving (56). There is a need for more critical evaluation of bST health data in order to determine which, if any, disorders of cattle are increased or decreased with bST use and to allow effective preventive management programs to be developed, if needed.
Monensin appears to have several substantial beneficial actions on health and it has been used in Australia and Canada in bloat prevention.Lowe et al. (55) found that bloat was significantly reduced in pasture-fed dairy cattle that were treated with a controlled release intra-ruminal device, containing 32g of monensin, released over approximately 100 days. These findings support previous studies in cattle exposed to alfalfa (48) and in beef cattle on feedlot rations (6). The greatly reduced rates of methane and CO2 production may be substantially responsible for this effect. Other beneficial actions of monensin, which can reduce the risk of bloat, include a decreased rumen fill rate and the removal of bacteria responsible for bacterial slime formation and mucin destruction.
By removing S bovis, monensin treatment will reduce the production of (D and L) lactic acid and increase the clearance of lactate from the rumen.This has the effect of maintaining a more stable rumen pH and reducing the risk of lactic acidosis (17, 65). These actions are potentially of benefit in dairy cattle and may influence milk production responses and the sequelae of lactic acidosis including rumenitis, hepatic abcessation, and lameness.Recent University of Sydney studies of the incidence of disease in monensin treated cattle provide support of these postulated benefits.
While there is little published evidence to support the effect of monensin on clinical ketosis, the evidence to show that monensin has a profound effect on ketogenesis is strong. Published reports (78) indicate that monensin is also highly effective in reducing the risk of clinical ketosis. Lean et al. (50) found that an important factor influencing the risk of clinical ketosis was the ability to maintain appetite. Given the marked anti-ketogenic effect of monensin and the capacity to reduce the risk of lactic acidosis and consequent inappetence during the period of rapid adaptation to high grain diets, it seems probable that monensin treatment will be effective in the prevention of clinical ketosis.
Other beneficial effects of monensin treatment include effective control of coccidiosis and a reduction in the risk of atypical interstitial pneumonia. The inclusion of monensin in heifer rations to prevent coccidiosis and increase weight gains is strongly recommended. It is also possible that horn fly infestation may be reduced with monensin feeding. As with any agent that increases milk production, the impact of monensin treatment on the risk of mastitis needs to be thoroughly evaluated. There is evidence (90), however, that neutrophils from monensin treated cattle have a greater capacity to respond to a chemotactic stimulus. Given the effects of monensin on uptake of metals involved in anti-oxidant defence mechanisms, it may be anticipated that the health of treated cattle may be improved under some dietary regimes.