bovine somatotropin bovine somatotropin bovine somatotropin or bovine somatotrophin (abbreviated bst and bst), or bovine growth hormone (bgh), is a peptide hormone produced by cows' pituitary glands. rbst is a product allowed only in certain jurisdictions and primarily given to dairy cattle by injection to increase milk production. like other hormones, it is produced in small quantities and is used in regulating metabolic processes. recombinant bovine somatotropin (usually "rbst"), is a synthetic version of the bovine growth hormone given to dairy cattle by injection to increase milk production. synthesis after the biotech company genentech discovered and patented the gene for bst in the 1970s, it became possible to synthesize the hormone using recombinant dna technology to create recombinant bovine somatotropin (rbst), recombinant bovine growth hormone (rbgh), or artificial growth hormone. industrial production four large pharmaceutical companies, monsanto, american cyanamid, eli lilly, and upjohn, developed commercial rbst products and submitted them to the us food and drug administration (fda) for approval. monsanto was the first firm to receive approval. other countries (mexico, brazil, india, russia, and at least ten others) also approved rbst for commercial use. monsanto licensed genentech's patent, and marketed their product as "posilac". in october 2008, monsanto sold this business, in full, to eli lilly and company for $300 million plus additional consideration. banning rbst has not been allowed since at least 2000 on the market in canada, or since 1990 in the european union (eu). australia, new zealand, japan, israel, and argentina have also banned the use of rbst. the fda, world health organization, and national institutes of health have independently stated that dairy products and meat from rbst-treated cows are safe for human consumption. an eu report on the animal welfare effects of rbst states that its use often results in "severe and unnecessary pain, suffering and distress" for cows, and is "associated with serious mastitis, foot disorders and some reproductive problems". history image of peptide somatotropine. in 1937, the administration of bst was shown to increase the milk yield in lactating cows by preventing mammary cell death in dairy cattle. until the 1980s, use of the compound was very limited in agriculture as the sole source of the hormone was from bovine carcasses. during this time, the knowledge of the structure and function of the hormone increased. with the advent of biotechnology, one of the pioneering biotech companies, genentech, in 1981 succeeded in cloning and patenting the gene for bst. monsanto had been working along the same lines and struck a deal with genentech in 1979 to license genentech's patents and collaborate on development of a recombinant version of bst – a process on which monsanto would invest $300 million. the two companies used genetic engineering to clone the bst gene into e. coli. the bacteria are grown in bioreactors, then broken up and separated from the rbst, which is purified to produce the injectable hormone. they published their first field trial results in 1981. lilly, american cyanamid, upjohn, and monsanto all submitted applications to market rbst to the fda, and the fda completed its review of the human safety component of these applications in 1986 and found food from rbst-treated cows to be safe; however, strong public concern led to calls for more studies, investigations, and public discussions, which included an unprecedented conference on the safety of rbst in 1990 organized by the national institutes of health at the request of senator patrick leahy. fda approved monsanto's application in 1993. monsanto launched rbst, brand-named "posilac", in 1994. mechanism of action an average dairy cow begins her lactation with a moderate daily level of milk production. this daily output increases until, at about 70 days into the lactation, production peaks. from that time until the cow is dry, production slowly decreases. this increase and decrease in production is partially caused by the count of milk-producing cells in the udder. cell counts begin at a moderate number, increase during the first part of the lactation, then decrease as the lactation proceeds. once lost, these cells generally do not regrow until the next lactation. administration of rbst or bst prior to peak production, in cows that are well-fed, slows the rate at which the number of mammary cells decreases, and increases the amount of nutrients directed away from fat and toward the mammary cells, leading to an extension of peak milk production. the effects are mediated by the insulin-like growth factor (igf) system, which is upregulated in response to bst or rbst administration in well-fed cows. use on farms from 2000 to 2005, the us department of agriculture national agricultural statistics service survey of dairy producers found that about 17% of producers used rbst. the 2010 usda national agricultural statistics service survey of wisconsin farms found that about 18% of dairy farms used rbst. role in synchronized fertilization on dairy farms by using cows that produce offspring within a one to two-week period, synchronized breeding allows dairy farmers to artificially inseminate cows for maximum pregnancy rates with minimal effort. bst is a placental lactogen (pl) hormone and falls under the class of growth hormone, or somatotropin. it is relevant to the practice of artificially expediting placental development in farm mammals, specifically dairy cattle. the mechanism through which the hormones of this somatotropin exert their effects can be observed at the cellular and molecular level in placental tissue. for mammals exposed to the hormone, bovine somatotropin associates with n-glycosylated proteins that are heavily involved in placental gestation. knowledge of this and how bst works in conjunction with growth hormones allows for agricultural researchers to experiment on the effects of synchronization in farm animals. synchronization involves treating cattle with a dose of bst before artificially inseminating them, according to a fixed interval schedule. synchronization and bst treatment may be used to increase first-service pregnancy rates while following this timed artificial insemination protocol. this would therefore allow agricultural researchers to observe the effects of hormones in relation to natural estrous cycles. dairy cattle experienced increased rates of pregnancy during synchronization when exposed to bst. the effects of bst on this treatment are dependent on the step in the estrous cycle, seeing how bst has a stimulatory effect of progesterone on the corpus luteum. controversy though approved by the fda in 1993, rbst has been immersed in controversy since the early 1980s. part of the controversy concerns potential effects on animal health and human health. animal health one meta-analysis published in 2003 suggested a negative impact of rbst's effects on bovine health. findings suggested an average increase in milk output ranging from 11–16%, an approximate 24% increase in the risk of clinical mastitis, a 40% reduction in fertility, and 55% increased risk of developing clinical signs of lameness. the same study reported a decrease in body condition score for cows treated with rbst, though an increase in their dry matter intake occurred. another meta-analysis (2003) reported on body condition scores (bcs) but could not reach a conclusion due to lack of homogeneity in study design and reporting. they found a trend towards decreased bcs in treated cows but state "depending on the level of body condition in these cows, this effect may have been beneficial or detrimental." this analysis did not report on clinical mastitis. a more recent meta-analysis (2014) published by the journal of the american veterinary medical association showed no significant increase in risk of clinical mastitis nor other adverse effects on cow health and well-being. this review included 26 peer-reviewed studies that involved the use of the rbst-zn formulation available to us producers in accordance with the label instructions for treatment initiation (57 to 70 days after birth), dose (500 mg, every 14 days), and route (subcutaneous). mastitis has cost american dairy industries an estimated $1.5 to 2 billion per year in treating dairy cows. in 1994, an eu scientific commission was asked to report on the incidence of mastitis and other disorders in dairy cows and on other aspects of their welfare. the commission's statement, subsequently adopted by the eu, stated that the use of rbst substantially increased health problems with cows, including foot problems, mastitis, and injection site reactions, impinged on the welfare of the animals, and caused reproductive disorders. the report concluded, on the basis of the health and welfare of the animals, rbst should not be used. health canada prohibited the sale of rbst in 1999; the external committees found that there was health risk to humans, and the drug present a threat to animal health, and, for this reason, cannot be sold in canada. monsanto-sponsored trials reviewed by the fda asked whether the use of rbst makes cows more susceptible to mastitis. according to the fda, which used data from eight monsanto-sponsored trials in its decision in 1993 to approve monsanto's rbst product, the answer is yes. the data from these eight trials, which involved 487 cows, showed that during the period of rbst treatment, mastitis incidence increased by 76% in primiparous cows and by 50% for multiparous cows. overall, the increase was 53%. conversely, however, a study from the university of georgia on the monitoring post-approval of rbst, showed that there was no statistically significant (p > 0.05) derivation in cases of clinical mastitis in dairy cows treated with rbst. macronutrient composition the overall composition of the milk including the fat, protein, and lactose content is not altered substantially by the use of rbst in dairy cows. the milk may have a slight change in fat content within the first few weeks of rbst treatment as the cow is allowed to adjust her metabolism and feed intake. the changes in the fat content have been shown to be temporary. the composition of the milk has been examined in more than 200 different experiments. natural variation within milk is normal with or without rbst treatment in cows due to genetics, location, feed, age, and other environmental factors. protein in milk content has also been studied and was shown to have no apparent change in rbst treated cows. the vitamins and minerals that are normally in milk were also unaltered in milk from rbst treated cows. freezing point, ph, thermal properties, and other manufacturing characteristics of milk were shown to be the same regardless of whether it came from rbst treated cows or not. hormones bst is destroyed in the digestive system and even if directly injected, has not been found to have any direct effect on humans. researchers have found that "igf-1 in milk is not denatured by pasteurization and the extent to which intact, active igf-1 is absorbed through the human digestive tract remains still however uncertain" implicating that an extensive study on the nature of igf-1 in relation to rbst milk is required. fda rbst labeling guidelines state, "fda is concerned that the term 'rbst free' may imply a compositional difference between milk from treated and untreated cows rather than a difference in the way the milk is produced. without proper context, such statements could be misleading. such unqualified statements may imply that milk from untreated cows is safer or of higher quality than milk from treated cows. such an implication would be false and misleading". the fda has determined that no significant difference has been shown between milk derived from rbst treated and non-rbst treated cows. the fda, world health organization, and national institutes of health have independently stated that dairy products and meat from rbst-treated cows are safe for human consumption. the american cancer society issued a report declaring, "the evidence for potential harm to humans is inconclusive. it is not clear that drinking milk produced using rbgh significantly increases igf-1 levels in humans or adds to the risk of developing cancer. more research is needed to help better address these concerns." human health the effect of rbgh on human health is an ongoing debate, in part due to the lack of conclusive evidence. a few of the most debated issues include: insulin-like growth factor 1 (igf-1) is a hormone found in humans that is responsible for growth promotion, protein synthesis, and insulin actions over the lifecycle. the hormone has been shown to influence the growth of tumors in some studies and may be linked to the development of prostate, colorectal, breast, and other cancers. igf-1 is also found in milk. previous research has proposed an increase