In general, the need to supplement or replace a particular hormone type that is deficient dictates the type of hormone to be used. Females produce estrogens normally, so better results are obtained from administration of androgens (eg, trenbolone acetate) alone in heifers than in steers. Most implants, however, include estrogen alone or in combination with a progestin or an androgen. Estrogen increases frame size of animals by its action on growth hormone and influence on long bone growth. Estrogens should not be used in animals (female or male) to be retained for breeding purposes.
Manufacturer instructions must be followed to ensure proper implant placement and correct dose administration. Anabolic hormones should not be administered by IM injection for growth-promoting purposes. The EU has banned the use of hormonal growth promoters in meat production. Appropriate surveillance programs in the EU 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. Sex and maturity of an animal influence growth rate and body composition. Bulls grow 8%–12% faster than steers, have better feed efficiency, and produce a leaner carcass. 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-I production and availability by modulation of the IGF binding proteins. Naturally produced endogenous steroids are not orally active. Their biological effects are brought about by the hormone in circulation and are found in very low concentrations (on the order of picograms to nanograms of testosterone per milliliter in blood for physiologic effects), and they can transiently affect the behavior of treated or intact animals ( See table Natural Steroid Hormone Growth Promotantsa).
Natural Steroid Hormone Growth Promotantsa
Hormone | Formb | Dose | Duration of Effect (days) | Growth Response | Potential Adverse Effects |
|---|---|---|---|---|---|
Estradiol + progesterone | Pellet | 20 mg estradiol benzoate + 200 mg progesterone (steers) | 90–120 | 10%–15% | Transient increase in sexual behavior Udder development Vaginal and rectal prolapse Ventral edema |
10 mg estradiol benzoate + 100 mg progesterone (suckling calves ≤ 400 lb and > 45 days old)c | 100–120 | 3%–5% | Transient increase in sexual behavior Udder development Vaginal and rectal prolapse Ventral edema | ||
Estradiol + testosterone | Pellet | 20 mg estradiol benzoate + 200 mg testosterone propionate (heifers) | 90–120 | 5%–15% | Transient increase in sexual behavior Udder development Vaginal and rectal prolapse Ventral edema |
Estradiol | Silastic rubber | 44 mg estradiol (steers and heifers) | 400 | 10%–15% | Transient increase in sexual behavior Udder development Vaginal and rectal prolapse Ventral edema |
26 mg estradiol (steers and heifers) | 200 | 10%–15% | Transient increase in sexual behavior Udder development Vaginal and rectal prolapse Ventral edema | ||
Polylactic acid | 28 mg estradiol (steers) | 365 | 10%–15% | Transient increase in sexual behavior Udder development Vaginal and rectal prolapse Ventral edema | |
a Individual product labeling should be consulted for specific purposes and dosages in food-producing animals. b Implants must be placed subcutaneously between the ear cartilage and skin to comply with label instructions so that consumption of residues may be avoided. c The FDA recognizes two subsets of animals within the beef cattle calfhood (suckling) phase: (1) < 2 months old and (2) ≥ 2 months old. US Food and Drug Administration, Classes of Major Food-Producing Animals for New Animal Drug Applications. Accessed November 17, 2023. | |||||
Estradiol Use in Animals
Estradiol is administered as an ear implant, either as compressed tablets or silastic rubber implants, and is a potent anabolic agent in ruminants at blood concentrations of 5–100 pg/mL. When estradiol is formulated as compressed tablets, a second steroid (usually testosterone, trenbolone acetate, or progesterone) is typically present. When administered to feedlot cattle fed a high-energy diet, trenbolone acetate is present in a ratio of ~1 part estradiol to either 5 or 10 parts trenbolone acetate. Estrogen administered in pellet form can be blended with progesterone (for steers and heifers) or testosterone (for heifers only), and these implants are used in suckling, growing, and finishing cattle. The release of hormones from compressed pellets is biphasic, with a relatively rapid rate lasting 2–7 days after insertion (50–100 times as great as baseline), followed by a slower rate of release for the next 30–100 days (5–10 times as great as baseline). Hormone concentrations gradually decline up to day 60–120, when concentrations are no different from those in nonimplanted animals.
Estradiol formulated in silastic rubber enhances the effective life span of the implant relative to pelleted formulations by nearly 2-fold. 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 as great as baseline). Toward the end of the effective life span of the silastic rubber implant, there is a gradual decline to estradiol concentrations found in non-implanted animals.
Estradiol, on its own, increases nitrogen retention, growth rate by 5%–30% in steers, lean meat content by 1%–3%, and feed efficiency by 5%–10%. It can be used in steers to best advantage; however, it also has anabolic effects in heifers and veal calves. It works best in lambs in conjunction with androgens; however, due to the influence of estradiol on bone growth, estradiol is not commonly used due to increased incidence of spool joints, which is a major quality defect. Estradiol is not an effective anabolic agent in pigs.
Testosterone Use in Animals
Testosterone is not used on its own as an anabolic agent in farm animals because it is difficult to achieve the effective physiologic concentrations for long periods (up to 100 days) with current delivery systems, due to its half-life in circulation. Testosterone is a potent anabolic agent at relatively high concentrations of 1–5 ng/mL in peripheral circulation. It is generally used in a propionate formulation in conjunction with 20 mg of estradiol benzoate in a compressed tablet implant (for heifers only); 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) and can result in development of secondary sexual traits (eg, coarseness of neck and thickening on skin around the eyes); however, this does not occur with the concentrations delivered by compressed pellets in the ear (1 ng/mL). Behavior resulting from use of pellets containing 20 mg of estradiol benzoate and 200 mg of progesterone is not different from that which occurs after the use of pellets containing 20 mg of estradiol benzoate and 200 mg of testosterone propionate.
Progesterone Use in Animals
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 that in turn allows for a greater duration of effective anabolic stimulation post-implantation.
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 table Synthetic Steroidal and Nonsteroidal Estrogen Hormone Growth Promotants in Cattle and Sheepa). Commercial synthetic steroids are androgenic (trenbolone acetate) or progestogenic (orally active melengestrol acetate).
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 analogue zeranol. Zeranol is estrogenic and has a weak affinity for the uterine estradiol receptor. It is used in animal production as an 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 occur in heifers. Its effects are additive to those of androgens (generally trenbolone acetate).
Synthetic Steroidal and Nonsteroidal Estrogen Hormone Growth Promotants in Cattle and Sheepa
Hormoneb | Doseb.c | Duration of Effect (days) | Growth Response | Potential Adverse Effects |
|---|---|---|---|---|
TBA | 200 mg (heifers) | 60–90 | 5%–12% | |
TBA + EB | 200 mg TBA + 28 mg EB (steers and heifers) | 150–200 | 10%–20% | Transient increase in sexual behavior Udder development Vaginal and rectal prolapse Ventral edema |
100 mg TBA + 14 mg EB (steers and heifers) | 100–140 | 10%–20% | Transient increase in sexual behavior Udder development Vaginal and rectal prolapse Ventral edema | |
150 mg TBA + 21 mg EB (coated implant, steers and heifers grazing pasture) | 180–200 | 10%–20% | ||
200 mg TBA + 28 mg EB (coated implant, steers and heifers) | 200 | |||
TBA + E | 200 mg TBA + 20 mg E (steers and heifers) | 80–120 | ||
200 mg TBA + 20 mg E (coated implant, heifers) | Initial and delayed release implant that provides hormonal payout for up to 200 days after implantation | |||
200 mg TBA + 20 mg E (coated implant, steers) | Delayed release implant that does not begin hormonal payout until ~70 days after implantation | |||
200 mg TBA + 40 mg E (coated implant, steers) | Initial and delayed release implant that provides hormonal payout for up to 200 days after implantation | |||
120 mg TBA + 24 mg E (steers) | 100–140 | |||
140 mg TBA + 14 mg E (heifers) | 100–140 | |||
80 mg TBA + 16 mg E (steers) | 100–140 | |||
80 mg TBA + 8 mg E (heifers) | 100–140 | |||
40 mg TBA + 8 mg E (steers and heifers grazing pasture) | 100–140 | |||
Zeranol | 36 mg | 70–100 | 10%–15% | |
)12 mg | 90–120 | 10%–15% | ||
Melengestrol acetate | 0.25–0.50 mg/day (heifers) | For the intended duration | 3%–10% | Increased mammary development after long-term administration |
a Individual product labeling should be consulted for specific purposes and dosages in food-producing animals. b E, estradiol 17-beta; EB, estradiol benzoate; TBA, trenbolone acetate. c All administered as pellet implants except melengestrol acetate, which is administered in feed. | ||||
Synthetic steroidal androgens are not commonly used as anabolic agents except for trenbolone acetate. Trenbolone acetate is currently the only synthetic androgen approved for use for growth promotion in cattle in the US; it is used to a lesser extent in sheep and not in pigs or horses. It has weak androgenic activity; however, it has greater anabolic activity than testosterone. When administered repeatedly during the feedlot phase when cattle are fed a high-concentrate diet, trenbolone acetate can alter the physical appearance and behavior of steers, causing them to look and act like bulls. Trenbolone acetate has important anabolic effects on its own in female cattle and sheep; however, in castrated males, it gives maximal response when used in conjunction with estrogens. It is administered as a pellet-type implant containing 80–200 mg for heifers and steers, and it can be used with estradiol in doses ranging from 120 to 200 mg as either combined or separate implants. For dosing, product labeling for individual species and indications should be consulted.
Melengestrol acetate is an orally active synthetic progestin. It is fed at dosages of 0.25–0.50 mg/day per heifer in the feed. It suppresses recurrent estrus in feedlot heifers and increases growth rate and feed efficiency ( see Table: Synthetic Steroidal and Nonsteroidal Estrogen Hormone Growth Promotants in Cattle and Sheepa). 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 have an indirect impact on growth. Melengestrol acetate is permitted for use in the US but not in the EU. When used in the absence of a growth-promoting implant, melengestrol acetate increases growth rate through the increased estradiol released by the sexually intact heifer's follicles; however, when used in conjunction with implants of either estradiol or combination estradiol and trenbolone acetate in the feedlot, the growth-promoting effects of melengestrol acetate are primarily derived from suppression of the excess, unproductive, and potentially harmful activities associated with recurrent estrus.
Use in Cattle
Calves have a poorer conversion of feed into animal tissue compared with young growing swine or poultry. Therefore, responses to anabolic agents in swine and poultry are variable. Responses of 0%–10% have been obtained when zeranol was administered to 3-month-old castrated male calves, and this range in responses is likely due to milk production of the dam and forage availability to both the dam and calf. Bull calves in an intensive bull beef system can be administered an estrogen implant at 1–2 months 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 may be necessary if compressed pellet implants are used.; manufacturer instructions must be followed.
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 trenbolone acetate can be used in castrated males. Dairy heifer replacements cannot be administered steroid implants as weanlings. In the US, use is prohibited in calves intended for veal.
Greater 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 60–120 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 (25.7 or 43.9 mg of estradiol). 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%; however, responses are dependent on forage availability and intake above maintenance level.
Responses to growth promotants 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, and delaying implantation of finishing cattle until 14–28 days after arrival and intake are at ≥ 2% of body weight (dry-matter basis).
In steers and heifers in the feedlot that are provided a high-energy diet, use of an androgen plus an estrogen hormone combination is common. Pellet-type implants are effective for up to 150 days; reimplanting cattle after 70–100 days should be considered because of decreasing response from the pellet-type implants over time and due to the steroidal implants decreasing the fat content in liveweight gain, which is beneficial to cattle that are fatter.
Results from large-pen studies (> 25 animals/pen) show that heifers benefit from a combination of estradiol, trenbolone acetate, and melengestrol acetate. In small-pen research; however, when fed in combination with growth-promoting implants, melengestrol acetate use results in decreased gain, feed efficiency, and ribeye area, as well as increased fat. 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, and behavioral issues are less likely to arise in small pen facilities.
In some studies in which bulls were treated with estrogens, growth rate increased by 2%–10%, and testicular growth was suppressed with a subsequent decrease 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 via 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 concentrations, with a concomitant reduction in aggressive behavior. However, there appears to be sufficient testosterone secreted to maintain an anabolic effect that can result in greater gains than in castrated cattle. Therefore, the repeated use of estrogens in bulls beginning at 1–3 months of age may lead to a hormonal castration effect coupled 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 analogue decreases testicular size in stallions. Decreased hormonal concentrations, especially LH, testosterone, and inhibin, adversely affect testicular microanatomy and spermatogenesis and transiently decrease sperm output and quality. One of the most commonly used compounds is 19-nortestosterone for treatment in debilitated and anemic horses. However, use of these compounds is contraindicated, and long-term treatment or large doses have serious adverse effects on reproductive tract function. Thus, use of steroidal hormones for growth promoting purposes is not commonplace.
Use in Other Species
In pigs, the growth responses from the use of estradiol, progesterone, and zeranol are variable but generally low. Trenbolone acetate seems to increase lean meat content of pig carcasses. Pigs are known to have better feed conversion than beef cattle, so steroidal hormones for growth promoting purposes are not as widely sought.
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, which is very similar to improvements in cattle gain when intake is adequate to support additional growth. Anabolic steroids should not be used in lambs to be retained for breeding. Also, implantation with zeranol decreases testicular development in ram lambs and delays the onset of puberty and decreases 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. Also, use of estrogen based implants increases the likelihood of growth plate closure resulting in a greater abundance of implanted sheep classified as mutton due to incidence of spool-joints, which is a major quality defect in finished lambs intended for the domestic market in the US.
In poultry, responses to estrogens include increased fat deposition. Androgens, however, have produced conflicting responses. Hence, their use is of no practical importance at this time.
In fish, methyl testosterone can induce sex reversal in rainbow trout, in turn promoting growth and improving feed conversion efficiency.
Possible Complications
Any hormonal implant has a negative feedback effect on pituitary gonadotropins, thereby reducing LH and FSH secretion. Therefore, hormonal implants can affect the onset of puberty and the regulation of estrous cycles as well as decrease 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 used for show purposes. If administered to pregnant heifers, trenbolone acetate results in increased incidence of severe dystocia, masculinization of female genitalia of the fetus, increased calf mortality, and decreased milk production in the subsequent lactation period.
The major problem associated with estrogenic implant use in feedlots has been a transient increase in mounting behavior and aggression in both steers and heifers. This mounting behavior is commonly referred to as buller syndrome (where one or more pen-mates repeatedly attempt to mount the buller throughout the day and over the course of several days). 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 feedlot population; however, this rate can double or triple during the late summer and early fall, especially when there is an abundance of dust in the air. An increase in yearling steers off native grass pasture (which are usually administered 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 in feedlot cattle. Feedlot pens with a greater number of animals in each pen experience a greater incidence of buller activity; incidence increases linearly with number of animals in pens with > 80 or 100 animals per pen. This suggests the agonistic behavior is a population phenomenon, requiring a critical mass of both the dominant, mounting animals and the submissive animals they are attempting to mount. Bullers have been shown to have greater circulating concentrations of monoamine oxidase and decreased circulating concentrations of progesterone than nonbuller pen-mates.
These effects generally last for 1–10 days after implantation and then generally subside. However, there have been a few reports of undesirable behavior in steers that lasted for 4–10 weeks. 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 immediately; 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 as a treatment option. Sometimes a small set of panels can be set up, allowing the animal that is being ridden to get away from riding pen-mates. This might be an option if buller pens are not readily available.
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. However, even animals with superior growth genetics can benefit from application of a steroidal implant and thus have a greater rate of gain than their nonimplanted counterparts.
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, that have been treated for parasites, and are under good husbandry conditions. Implants are an aid to, but not a substitute for, good husbandry. Consequently, there is little economic incentive in implanting cattle destined for a 3- to 4-month store period, during which time animals are fed to gain little or no weight. Responses are decreased in calves (based on health condition and diet), and responses are good in yearlings primarily due to caloric intake.
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 non-implanted 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.
