THE MERCK VETERINARY MANUAL
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Steroid Hormones

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In general, the principle that dictates which type of hormone to be used is the need to supplement or replace the particular hormone type that is deficient in the animals to be treated. Females produce estrogens normally, so better results are obtained from the administration of male androgens, eg, trenbolone acetate (TBA). Estrogens should not be used in animals to be retained for breeding purposes.

Manufacturers' instructions must be followed to ensure proper implant placement and dose administration. Anabolic hormones should not be administered by IM injection for growth-promoting purposes. Additionally, steroid hormones must not be used for anabolic or other purposes unless the indication is specifically approved by the appropriate regulatory body. The EU has banned the use of hormonal growth promoters in meat production. Appropriate surveillance programs have been established to ensure compliance by producers.

Endogenous Steroids

The steroidal compounds used for anabolic purposes in food animals are estradiol, progesterone, and testosterone. Gender and maturity of an animal influence its growth rate and body composition. Bulls grow 8%–12% faster than steers, have better feed efficiencies, and produce leaner carcasses. Superior performance of bulls is due to the steroids produced in the testes (mainly testosterone but also estradiol, which in ruminants is also anabolic and is produced in relatively large quantities). Testosterone, or one of its physiologically active metabolites, binds to receptors in muscle and stimulates increased incorporation of amino acids into protein, thereby increasing muscle mass without a concomitant increase in adipose tissue. Estradiol, on the other hand, may act by stimulation of the somatotropic axis to increase growth hormone and thus IGF-1 production and availability by modulation of the IGF binding proteins. Naturally produced endogenous steroids are not orally active, require picogram concentrations of estradiol and nanogram concentrations of testosterone in blood for physiologic effects, and can transiently affect the behavior of treated animals (see Natural Steroid Hormones for Consideration as Growth PromotersTables).

Table 1

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A potent anabolic agent in ruminants at blood concentrations of 5–100 pg/mL, estradiol is administered as an ear implant, either as compressed tablets or silastic rubber implants. When estradiol is formulated as compressed tablets, a second steroid (usually testosterone or progesterone) is typically present when administered to feedlot cattle fed a high-energy diet, in a ratio of ~1 part estradiol to either 5 or 10 parts of the other, androgenic, steroid. The release of hormones from compressed pellets is biphasic, with a relatively rapid rate lasting 2–7 days after insertion (50–100 times higher than baseline), followed by a slower rate of release for the next 30–100 days (5–10 times higher than baseline). Hormone concentrations gradually decline up to day 80–100, when concentrations are no different from those in control animals.

Estradiol formulated in silastic rubber enhances the effective life span of the implant relative to pelleted formulations. The pattern of release includes a short-lived spike in plasma estrogen concentration for 2–5 days after insertion, followed by a stable but modest increase (5–10 times greater than baseline). Toward the end of the effective life span of the implant, there is a gradual decline to estradial concentrations found in control animals.

Estradiol, on its own, increases nitrogen retention, growth rate by 10%–20% in steers, lean meat content by 1%–3%, and feed efficiency by 5%–8%. It can be used in steers to best advantage, but it has some anabolic effects in heifers and veal calves. It works best in lambs in conjunction with androgens. It is not effective as an anabolic agent in pigs.

A potent anabolic agent at the relatively high concentrations of 1–5 ng/mL in peripheral circulation, testosterone is not used on its own as an anabolic agent in farm animals, because it is very difficult to achieve the effective physiologic concentrations for long periods (up to 100 days) with current delivery systems. It is generally used as a propionate formulation in conjunction with 20 mg estradiol benzoate (EB) in a compressed tablet implant; its major role in the compressed pellet may be to slow down the release rate of estradiol. In high concentrations in blood, testosterone induces male sexual behavior (eg, aggression and mounting), but this is not seen with the concentrations delivered by compressed pellets in the ear (1 ng/mL). Behavior resulting from use of 20 mg EB and 200 mg progesterone is not different from that seen after the use of 20 mg EB and 200 mg testosterone propionate.

Unambiguous data suggesting progesterone is anabolic in farm animals does not exist. Its major use is to slow the release of estradiol from compressed pellet implants.

Synthetic Steroids

Synthetic steroids are commercially available in some countries because of their efficacy, their relatively mild androgenicity, and because they cause few behavioral anomalies (see Synthetic Steroid Hormones for Consideration as Growth PromotersTables). Commercial synthetic steroids are androgenic (TBA) or progestogenic (melengestrol acetate, MGA).

Table 2

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Synthetic steroidal androgens are not commonly used as anabolic agents except for TBA. TBA is currently the only synthetic androgen approved for use for growth promotion in cattle; it is used to a lesser extent in sheep and not in pigs or horses. It has weak androgenic activity but has greater anabolic activity than testosterone. When administered repeatedly during the feedlot phase when cattle are fed a high-energy diet, TBA can alter the physical appearance and behavior of steers, causing them to look and act like bulls. TBA has significant anabolic effects on its own in female cattle and sheep, but in castrated males it gives maximal response when used in conjunction with estrogens. It is administered as a pellet-type implant containing 140–200 mg TBA for heifers and cull cows, and it can be used with estradiol in doses ranging from 140–200 mg TBA as either combined or separate implants.

Melengestrol acetate (MGA) is an orally active synthetic progestagen. It is fed at dosages of 0.25–0.5 mg/day per heifer in the feed. It suppresses recurrent estrus in feedlot heifers and increases growth rate and feed efficiency (see Table 2: Synthetic Steroid Hormones for Consideration as Growth PromotersTables). It is not effective in pregnant or spayed heifers or in steers. Its mode of action is to suppress ovulation, presumably by suppressing luteinizing hormone (LH) pulse frequency; however, large follicles develop, which can increase concentrations of estradiol and growth hormone, and hence growth. MGA is permitted for use in the USA but not in the EU. When used in the absence of a growth-promoting implant, MGA increases growth rate through the increased estradiol released by the follicles; however, when used in conjunction with either estradiol or combination estradiol/TBA implants in the feedlot, the growth-promoting benefits of MGA are primarily derived from suppression of the excess, unproductive, and potentially harmful activities associated with recurrent estrus.

Synthetic Nonsteroidal Estrogens

Two major classes of synthetic nonsteroidal estrogens have been used as production enhancers in food animals. Stilbene estrogens (either diethylstilbestrol [ DES] or hexestrol) have been banned in most countries as anabolic agents because of residue and food safety concerns.

The discovery of a naturally occurring estrogen, zearalenone (produced by the fungi Fusarium spp), led to the development of the synthetic analog zeranol. Zeranol is estrogenic and has a weak affinity for the uterine estradiol receptor. It is used in animal production as a SC ear implant at a dose of 36 mg for cattle and 12 mg for sheep, with a duration of activity of 90–120 days. In steers, zeranol increases nitrogen retention, growth rate by 12%–15%, and feed conversion by 6%–10%. However, lower responses are seen in heifers. Its effects are additive to those of androgens (generally TBA).

Use in Cattle

Calves have a high conversion of feed into animal tissue compared with young growing swine or poultry. Therefore, their responses to anabolic agents are variable. Responses of 0–10% have been obtained when zeranol was given to 3-mo-old castrated male calves. Bull calves in an intensive bull beef system can be given an estrogen implant at 1–2 mo of age to suppress testicular development, which may lead to subsequent reduction in mounting and aggression. A growth response of ~5%–8% is also obtained from this implant. Reimplantation every 80–100 days is necessary if compressed pellet implants are used.

A major limitation to the use of anabolic agents in lightweight weaned calves is the low liveweight gain they may achieve because of poor nutritional status. Hence, anabolic agents should be considered only if the weanlings are expected to gain >0.25 kg/day. Zeranol, estradiol, and TBA can be used in male castrates. Dairy heifer replacements cannot be given steroid implants as weanlings.

Higher and more consistent responses are obtained in yearling and older cattle than in calves or weanlings, due primarily to greater intake and to the higher plane of nutrition. In the case of pellet-type implants with effectiveness of 90–120 days, consideration can be given to reimplanting cattle midway through the grazing season, provided gains >0.5 kg/day are maintained. Silastic implants of estradiol are effective for 200–400 days, depending on dose used. Daily gains in feedlot cattle fed a high-energy diet may be increased 20%–30% after implantation with an estrogen and an androgen; daily gain in pasture cattle is typically improved by 10%–15%.

Responses to growth promotion are good when animals are on a high plane of nutrition. Feed conversion efficiency is improved, and lean meat content of the carcass is generally increased. Although less clear, conformation of implanted cattle tends to improve. Negative impacts of implants on marbling content of the loin muscle can be minimized by finishing cattle to a fat-constant endpoint.

In steers and heifers in the feedlot and provided a high-energy diet, use of an androgen plus an estrogen hormone combination is common. Pellet-type implants are effective for as long as 150 days; reimplanting cattle after 70–100 days should be considered because of decreasing response from the pellet-type implants over time.

Results from large-pen studies (>25 animals/pen) show that heifers benefit from a combination of estradiol, TBA, and MGA. In small-pen research, however, when fed in combination with growth-promoting implants, MGA use results in reduced gain, feed efficiency, and ribeye area, as well as increased fatness. These contrary findings suggest that although progesterone may have an “anti-growth promoting” effect, the growth-promotion benefit realized from suppression of estrus overcomes the minor negative physiologic impact of progesterone in conventional large feedlot pens.

In some studies in which bulls were treated with estrogens, growth rate increased by 2%–10%, and testicular growth was suppressed with a subsequent reduction in mounting and aggression. This should make the bulls easier to manage on the farm and less subject to “dark cutting” after slaughter. The mechanism involved appears to be the reduction of the gonadotropic hormones LH and follicle-stimulating hormone (FSH) from the pituitary gland by estrogen, which has a strong negative feedback effect on LH and FSH secretion. This reduction in LH and FSH results in decreased testicular size and lower testosterone levels, with a consequent reduction in aggressive behavior. However, there appears to be sufficient testosterone secreted to maintain an anabolic effect. Therefore, the repeated use of estrogens in bulls beginning at 1–3 mo of age may lead to a hormonal castration effect with increased growth rate.

Use in Horses

The use of anabolic agents in horses is not recommended because of adverse effects on the reproductive system. Administration of a steroid hormonal androgen analog decreases testicular size in stallions. Decreased hormonal concentrations, especially LH, testosterone, and inhibin, adversely affect testicular histology and spermatogenesis and transiently decrease sperm output and quality. One of the most commonly used compounds is 19-nortestosterone for therapy in debilitated and anemic horses. However, use of these compounds is contraindicated, and longterm treatment or large doses have serious adverse effects on reproductive tract function.

Use in Other Species

In pigs, the growth responses from the use of estradiol, progesterone, and zeranol are variable but generally low. TBA seems to increase lean meat content of pig carcasses.

In sheep, the responses to anabolic agents parallel those obtained in cattle. The most consistent responses have been obtained in lambs finished on high-concentrate diets; a 10%–15% increase in daily gain can be expected. Anabolic steroids should not be used in lambs to be retained for breeding. Also, implantation with zeranol reduces testicular development in ram lambs and delays the onset of puberty and reduces the ovulation rate in female sheep. Moreover, the short finishing period and the extensive nature of some production systems militate against widespread practical use of growth promotants in sheep on economic grounds.

In poultry, responses to estrogens include increased fat deposition. Androgens, however, have given conflicting responses. Hence, their use is of no practical significance at this time.

In fish, methyl testosterone can induce sex reversal in rainbow trout, thereby promoting growth and improved feed conversion efficiency.

Possible Complications

Any hormonal implant has a negative feedback effect on pituitary gonadotropins, thereby reducing LH and FSH secretion. Therefore, they can affect the onset of puberty and the regularity of estrous cycles, as well as reduce conception rate in females and testicular development (and thus sperm output) in males. Hormonal growth promotants should never be used in animals that are or may be used for breeding purposes; nor should they be used before puberty to increase growth in yearling thoroughbreds or young pedigree bulls for show purposes. If given to pregnant heifers, TBA results in increased incidence of severe dystocia, masculinization of female genitalia of the fetus, increased calf mortality, and reduced milk yield in the subsequent lactation.

The major problem thought to be associated with estrogenic implant use in the feedyard has been a transient increase in mounting behavior and aggression, commonly referred to as buller syndrome (see Buller Steer). However, it is also believed that the estrogen in the implant alone is not sufficient to cause bullers. Buller syndrome generally affects 2%–3% of the feedyard steer population, but this rate can double or triple during the late summer and early fall months. An increase in yearling steers off native grass pasture (which are usually given a high-dose implant immediately on arrival), diurnal temperature fluctuations (hot days and cool nights that shift social activity to early evening hours), dusty pen conditions (exacerbated by evening social activity), feeding corn or hay that may be moldy, and incomplete fermentation on freshly harvested silage can also contribute to increases in buller syndrome. These effects generally last for 1–10 days after implantation and then subside. However, there have been a few reports of undesirable behavior in steers that lasted for 4–10 wk. The cause of this unpredictable adverse behavior is not clear; it may be a function of rearing and socialization climate. It is generally more severe in dairy cattle used for beef production. If the problem is severe, the buller steers should be identified and removed; if very severe, removal of the implants or administration of 50–100 mg of progesterone in oil for a number of days to suppress behavior should be considered.

In addition to buller syndrome, estrogenic implants may increase the size of rudimentary teats.

Factors Affecting Response

A number of factors affect the response to growth-promoting implants, including genetic makeup, plane of nutrition, and the sex and age of the animal.

Animals should be gaining a minimum of 0.25 kg/day before an economic response is obtained. Implants are best used in animals on a high plane of nutrition and under good husbandry conditions. They are an aid to, but not a substitute for, good husbandry. Consequently, there is no point in implanting cattle destined for a 3- to 4-mo “store period.” Responses are reduced in calves (based on health condition and diet), and responses are good in yearlings.

Prior implantation does not affect the response to the next implantation. Also, once the implant effect has ceased, the rate of gain reverts to the rate that would be expected in nonimplanted animals, assuming the level of feeding is the same. Also, extra weight induced by implants in early life is transferred through to extra carcass weight at slaughter.

Last full review/revision December 2013 by Christopher D. Reinhardt, BS, MS, PhD

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