Hormonal growth promoters

There are a variety of ways of making animals grow faster using drugs; the two commonest classes of drugs used for this are hormonal growth promoters and antibiotics (fed continuously at a low level (euphemistically called "production enhancers")).

Hormonal growth promoters, also known as anabolic steroids, are only widely used in cattle, although several preparations are sold for horses and dogs. They are all derivatives or analogues of sex hormones, usually testosterone.

Politics

The use of growth promoting agents in food producing animals is a political hot potato. They were banned in Europe in the late 1980s after (illegally used) stilboestrol was found in veal flavoured baby food in Italy. (There is still an enormous black market for them in Europe, particularly Belgium and Italy.) Europe has refused to accept any imports of meat produced using anabolic steroids since then, although there is more complete toxicity data for this class of drugs than for any others used in food animals. Recently, the USA has taken Europe to the World Trade Organisation and won its case that Europe's restrictions on imports are a barrier to trade that is not justified on scientific grounds. Europe has appealed but is likely to lose. As far as NZ is concerned, any animals treated with anabolic steroids must be clearly marked, and records kept, so that there is no chance of them getting into a consignment of beef to Europe.

Advantages of anabolic steroids include increased growth rate, food conversion efficiency and carcase quality; disadvantages include potential animal welfare problems and the attention of the food scare industry.

Anabolic steroids are also occasionally used in small animals, particularly old animals recovering from surgery and those with chronic kidney failure, with or without bone marrow depression and anaemia. There are several preparations licensed for use in horses; they should not be administered to competition horses.

The anabolic steroids abused by human athletes are often veterinary preparations, and vets have been struck off for supplying the human black market.

Anabolic steroids are usually androgens. However, in cattle, the highest growth rates are achieved when there is a balance of androgens and oestrogens (including those produced by the animal).

In the USA, recombinant growth hormone (somatotropin, BST) is sometimes used as a growth promoter in cattle, usually in combination with anabolic steroids since their effects seem to be additive. BST also increases milk yield, which is its main use there. It is banned in NZ. Equine recombinant somatotropin has recently been approved. It will probably be abused in racing animals but may be useful to promote tendon repair. Porcine somatotropin has been under development in the USA for several years, but is unlikely to make it to NZ under current political constraints.

Clenbuterol, and occasionally other adrenergic β2 agonists, are sometimes used illegally as “partitioning agents”. They do not seem to promote growth but ensure that any growth is of muscle rather than fat.

Thyreostatics have been used as growth promoters but they make animals fat rather than promoting muscle growth. They are now illegal.

It is important to realise that animals will not grow without an adequate supply of good food. Anabolic steroids are not a substitute for good feeding.

Mechanism of action

Most of the hormonal growth promoters appear to increase nitrogen retention in muscle cells and reduce catabolism; muscle cells grow faster than fat cells. Exactly how the drugs do this is not clear.

Androgens have a direct effect on muscle cells, block corticosteroid catabolism and enhance thyroxin’s effects. Nandrolone, ethylestrenol, stanozolol and methandriol are used in dogs, horses (and man); testosterone and trenbolone are used in cattle.

Oestrogens cause increased growth hormone release from the pituitary, enhance the effects of insulin (or insulin like growth factor?) and thyroxin. Recently, oestrogen receptor subtypes have been found which may shed more light on the mechanism of action. Oestrogen is only used in cattle. Oestradiol (natural oestrogen precursor) and zeranol (not strictly a steroid but binds to oestrogen receptors) are used. Zeranol is derived (via zearalenone) from a fungus (various Fusarium spp) which grows on clover, residues are frequently found in cattle in NZ, presumably from eating mouldy clover. Caterillars can concentrate the zearalenone to an extent that can cause serious problems if they are eaten by grazing animals: this caused an epizootic of abortions in mares in Kentucky in 2001. Stilbenes such as stilboestrol are banned as they may cause cancer when given in high doses (as may the endogenous oestrogens).

Progestagens’ main effects are probably to increase appetite and reduce bulling behaviour leaving more time for eating. They may also bind to testosterone receptors and elevate oestrogen levels. Progesterone is the only progestagen used in NZ, melengestrol is used in America.

Useful effects

Most commercial drugs will increase the rate at which cattle gain weight by 10 - 15% and the cattle are bigger at slaughter. Under some circumstances, some drugs (especially androgens) will increase food conversion efficiency. The effects on carcase quality are more controversial. While the muscles are usually bigger, they contain less fat (which may or may not be a good thing, depending on the market) and they are usually tougher.

Horses and small animals are usually given anabolic steroids in an attempt to speed recovery from debilitating diseases, or in chronic renal failure. The aim is to reduce protein breakdown, which means that protein is converted to muscle and the kidney has less work to do excreting urea. Since they stimulate erythropoiesis, they are sometimes used in anaemia (see cardiovascular pharmacology notes).

Side effects

Inappropriate administration of sex hormones will interfere with breeding. Since none of the drugs promote growth in bulls, they should not be used. Bull calves given anabolic steroids are unlikely to be of any use for breeding. In heifers destined for breeding, anabolic steroids will increase their size (and possibly pelvic size) at the first oestrus, but reduce the chances of pregnancy. Oestrus cycles will be irregular. If given to pregnant heifers, everything from abortion to reduced milk yield is possible. In all animals behavioural changes will be seen, especially an increase in mounting behaviour, this often leads to injury. Other effects are rectal and vaginal prolapses, ventral oedema, teat and udder development (oestrogens).

Practical use

Cattle seem to grow best with the testosterone levels of a bull and the oestrogen levels of a young cow, however, none of the drugs have much effect on growth rates of bulls. Bulls generally grow about 10% faster than steers, this is about the same increase as anabolic steroids produce.

There is only consistent evidence of a beneficial effect in steers and prepubertal calves, but nearly all the published work relates to cattle fed on grain; there is very little information on the usefulness of these drugs in a New Zealand situation. The drugs are most effective when the animals are growing quickly.

Current use in NZ

Most animals are implanted at a young age to take advantage of the longer growth period, then re-implanted with the same or a shorter acting product for finishing. Re-implanting with trenbolone is not recommended as carcase quality suffers.

Remember that growth promoters are not a substitute for good husbandry and feeding.

Administration

Most anabolic steroids come in the form of a silicone rubber implant (to provide a depot with very slow release). Some preparations are in the form of pellets; care is needed not to crush these which could result in a faster than expected release of drug. These implants are deposited between skin and cartilage on the outside of the middle third of the ear using specially designed applicators like large syringes. The ear is used as it will be discarded when the animal is slaughtered and there is no danger of anyone eating a depot of drug.

A good implanting technique is important. The animal must be restrained in a head bail. The ear must be pulled straight, and with the bevel of the applicator needle a nick is made in the skin cranial to the dorsal ridge of the ear. This entry point should be quite close to the tip of the ear. With a fast action, the entire length of the needle is pushed forward under the skin towards the base of the ear, making sure to stay clear of the dorsal ridge (in this area, the skin is firmly attached to the cartilage and there is an artery). It is important not to penetrate the cartilage of the ear. When properly inserted, the implant can be clearly seen or felt just before the area of loose skin at the base of the ear. The implant is then secured in place by the thumb and the needle withdrawn. Check that only one implant is delivered. The animal must receive a specially designed ear tag at the same time. After administration, the hormone is released from the implant in a controlled manner over a certain number of days, which varies depending on the product used.

To reduce the possibility of infection, and thus the potential loss of the implant, hygienic and antiseptic procedures must be followed during implantation. The ear must be clean and dry When ears are wet or contaminated with soil, urine or faeces, the skin must be cleaned with an antiseptic soap and dried prior to implanting.

The needle of the applicator must be kept sharp and clean. To reduce possible transmission of disease or local infection, the needle must be disinfected before each implantation (between animals).

Controls on the use of anabolic steroids

Controls on the sale and use of these drugs are mandatory for access to European markets (at the moment, anyway). Basically, Brussels wants to know that we have a system to clearly separate the animals which have been implanted so that they do not get to Europe.

The use of “hormonally active substances for the purpose of promoting growth” is restricted to veterinary surgeons. They can only be administered by a vet or a trained technician under veterinary supervision after a consultation. It is illegal for vets to sell hormonal growth promoters to farmers. They are for use in cattle only. Every implanted animal must be identified with a special ear tag, as well as two other identifying ear tags (MAF do not seem to realise that cattle only have two ears). Auditable records on special forms must be kept in triplicate of all cattle implanted and of supplies of drugs kept. One copy of these forms has to be sent to MAF within 10 days after implantation. Records must be retained for at least five years. There are huge fines for failure to comply with these regulations. Before implanting any cattle, check the latest regulations at http://www.maf.govt.nz/animalproducts

MAF routinely audit the compliance of veterinarians and their clients with the above conditions of use of HGPS. Identified "flagrant" non-compliances, abuses, or missuses will result in consideration of either a formal complaint being laid before the veterinary council or prosecution as appropriate. Veterinary delegations from the EU also make random checks on HGP product licensees, wholesalers and retailers, as well as random on-farm inspections of treated cattle to see that those using HGPs have indeed complied with the requirements for the use of HGPs in cattle.

Animal welfare

There are several potential welfare problems with these drugs:

Human safety

Residues in the meat.

Anabolic steroid implants are designed to release very small amounts of drug slowly. For instance, “Compudose 200” contains 24mg oestradiol designed to be released over 100 - 200 days; a cow in late pregnancy produces several hundred mg oestradiol per day! The concentrations reached in meat are much lower than those of endogenous hormones. This, combined with the depot of drug being in an inedible part of the animal, mean that there is no witholding time for these drugs. There were initial concerns about persistence of the synthetic compounds zeranol and trenbolone, but these have been shown to be groundless. This assumes that the drugs have been used correctly; implantation into muscle could result in serious residues (common practice in the European black market - no detectable pellet in ear). The risk to people eating meat is further reduced as most steroids are rapidly broken down in the stomach or on first pass through the liver.

Carcinogenic potential.

Oestrogen can both start and maintain tumours. However, most women in developed countries eat oestrogen containing contraceptive tablets every day without obvious problems. The EU has argued that oestrogen has not been shown to be safe in prepubertal girls, but it has not been shown to cause problems either. Many plants contain phytoestrogens, to which we are all exposed anyway. Sex hormones in laboratory animals can turn on a number of oncogenic viruses which can go on to cause various cancers. It is theoretically possible that anabolic steroids could turn on such viruses in farm animals and that these viruses could be transmitted to people. Another potential food scare? Alterations in sex hormone concentrations in people have been statistically correlated with altered incidence of a variety of tumours - in most cases the alteration in incidence after therapeutic (large) doses is small. Prostate cancer in men has been associated with increases in IGF 1.

Contamination of pasture and soil over the long-term.

Administration of exogenous substances to animals may result in their passage into the environment via faeces and urine. In theory, this could lead to accumulation of these substances or their metabolites in plants or drinking water subsequently consumed by humans. Oestrogens are excreted by the animal in faeces and urine, but are degraded by soil bacteria into biologically inactive compounds and are then lost into the ground. Contamination from implants is infinitesimally smaller than from industrial pollution with oestrogenic compounds such as polychlorinated biphenols; or endogenous phytoestrogens common in clovers and beans. Most of our rivers receive sewage high in oestrogens from the urine of women on the pill.

Human abuse.

There is a black market for anabolic steroids for use in people. Only androgens work in people, it is usually the drugs marketed for horses such as nandrolone, stanozolol and ethylestrenol which are abused. Keep them somewhere secure.

The future?

Very heavily muscled cattle, such as Belgian Blues, have a defect in the gene responsible for making the protein myostatin. It appears that myostatin normally regulates (stops) muscle growth; if an antagonist for myostatin could be found it would be a potential winner as a growth promoter. Anabolic steroids tend to increase the size of muscle fibres, which usually makes the meat tougher, Belgian Blues have bigger muscles because they have a bigger number of muscle fibres, so the meat is more tender. Work on myostatin genes is going on at Ruakura, ERMA permitting.

Further reading

MacColl D. (1994) Growth promotion for beef cattle - HGPs and rumen modifiers. Proceedings of the Sheep and Beef Cattle Society of the New Zealand Veterinary Association Veterinary Continuing Education Publication No. 159, 132-156.

Reynolds I.P. (1980) Correct use of anabolic agents in ruminants. Veterinary Record, 107, 367-369.