Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/168—Steroids
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/184—Hormones
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K50/00—Feeding-stuffs specially adapted for particular animals
  • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines

Definitions

• This invention relates to a method of promoting the growth and increasing the food conversion efficiency of meat-producing animals in general and improving the quality of meat obtained therefrom and is concerned more particularly with the administration to a meat-producing animal, such as pigs, cattle, fish and the like of at least one female gonadal steroidal hormone prior to its sexual maturation, and preferably at an early state of its growth, so as to retard the sexual development of the animal while simultaneously promoting its growth to a surprising degree.
• a meat-producing animal such as pigs, cattle, fish and the like of at least one female gonadal steroidal hormone prior to its sexual maturation, and preferably at an early state of its growth, so as to retard the sexual development of the animal while simultaneously promoting its growth to a surprising degree.
• castration Another long-recognized approach adopted for male meat-producing mammals is castration of animals usually at an early stage in their development for the purpose of achieving a kind of feminization of the male animal while simultaneously eliminating its normal aggressive behavior and sexual activity. More recently, castration has been combined with hormone administration typically accomplished by a continuous release hormonal implant inserted, for instance, in the ear of the castrated animal at an age typically of 2-3 months.
• castration alone or combined with a hormone implant has some beneficial consequences on the ultimate meat production in terms of increased weight pro ⁇ duction and thus better feed efficiency, much of the improvement is in the form of increased fat, e.g., a higher ratio of fat to lean which, of course, offsets the overall improvement by reduced meat quality.
• an unexpected and surprisingly selective or differential response has been found, by which spermatogensis and secondary sexual development are temporarily suppressed or blocked while simul ⁇ taneously androgen and growth hormone-prolactin production, as manifested, for example, by the level of the male gonadal hormone testosterone is not only not suppressed but remains at least comparable to, if not higher than, that taking place in similar untreated animals.
• the animal can be brought to its normal slaughter weight at a time significantly earlier than is required for untreated or intact animals or castrated animals.
• the characteristics of the meat in other respects such as flavor, tenderness, texture and so on do not appear to be adversely affected by the practice of the present method and remain at least as acceptable as, if not better than, those of meat obtained from untreated animals, including castrates. Additional benefits have also been observed in some species notably the pig.
• Sexual maturation in the male pig occurs, on the average, at around five months and is mani- • fested by aggressive behavior and sexual activity such as fighting with other males and attempted mountings.
• the seminal system become-s operative resulting in the strong odor characteristic of boars and this strongly oderiferous seminal fluid permeates the tissue of the animal causing its meat to be tainted for most human consumption.
• Male pigs treated according to the present invention do not exhibit such aggressive behavior and are free from the obnoxious scent and meat flavor of untreated male pigs.
• the present method has been shown to lead to induction, proliferation and increased gene expression of growth and prolactin cells in the pituitary that secrete growth hormone, growth factors and prolactin hormone.
• Prolactin has both a growth stimulating effect and a gonad suppressing effect.
• Pituitary gonadotrophs that secrete folicle stimulating hormones (FHS) and luteinizing hormones (LH) appear to be suppressed in number and function.
• the pro-opioid- corticotropin cells appear to be increased.
• Incereased endor- phins (and other opioid compounds) from these cells may have a sedative-tranquilizing effect on the animals.
• Increased corticotropin (ACTH) enlarges the vascular and reticular zone of the adrenal cortex and increases glucocorticoid and androgen production..
• an effective amount of at least one female gonadal steroidal compound i.e., of the steroidal estrogen and progestagen types, is administered to meat producing animals, such as pigs, cattle, fish and other species, before the sexual maturation of the animal, and preferably at an early, and optimally very early, stage in its development, such administration in amount and duration being sufficient to repress the gonadal function of the animal during a significant portion of its growth period and being terminated so that the administered steroidal compounds are at least substantially eliminated by the natural metabolic action of the animal prior to its slaughter so that the resultant meat is essentially free of added hormones and within the acceptable limits for safe human consumption or as imposed by government regulation.
• meat producing animals such as pigs, cattle, fish and other species
• a mixture of a steroidal estrogen compound and a steroidal progestagen compound be administered in which the progestagen compound considerably predominates.
• a proportionation conforms generally to the levels of these hormones occurring' naturally in mammals as well as those recognized safe for administra ⁇ tion to humans for other purposes, for example, birth , control
• An optimum ratio has been found to be approximately 5:1 but other ratios including equality and even an excess of the estrogen compound are possible within the broad scope of the invention.
• a factoral design useful in determining suitable dosage combinations for this mixture of female steroidal hormones appears below as Table 1:
• an estrogen type hormone or a progestagen type steroidal hormone can be administered exclusively, although a combination of the two is much preferred and has been found to give significantly ⁇ more useful beneficial effects in the treated animals.
• a single hormone of these types is selected, the levels of administration thereof should be substantially increased, say at least doubled, over the amounts of the corresponding compound in the preferred compound in the preferred combination.
• steroidal estrogen and steroidal progestagen each refer to groups of closely related compounds, there having now been developed a great variety of specific compounds or derivatives within both of these groups, as can be identified with any of the variously available pharmacological handbooks. Certain of these compounds are produced naturally in the animal and are available as extractants from natural sources. As natural compounds, they are usually accepted as safe for administra ⁇ tion to animals and humans, within reasonable limits, without the necessity for any special approval by governmental agencies, e.g., the Food and Drug Administration, and such natural compounds are somewhat preferred for this reason.
• a preferred estrogen steroidal hormone is estradiol, preferably in the form of one of its pharmacologically acceptable esters, such as the dipropionate, and hydroxy- progesterone, preferably in the form of one of its pharma ⁇ cologically acceptable esters, such as the caproate are among the most preferred compounds.
• estrogenic and progestagenic hormones are in principle applicable in the practice of this invention and broadly speaking, any one of these categories of hormones that have been established to have an estrogenic or proges- tagenic function so as to be useful, for example, in hormone therapy in humans or animals can be employed here from those which are already or subsequently become available in the pharmaceutical field.
• the present invention resides in the application of hormones known in themselves, for a specific and extraordinary function rather than in the development and perfection of new kinds of specific hormones.
• estradiol, estrone and estriol are identified in Merck's Index together with the various commonly known derivatives thereof, a particularly lengthy list of derivatives appearing in the 8th edition, 1968, of this text. Most of these derivatives are mono- or polyesters of various organic acids, of which the 3-benzoate and the dipropionate of estradiol are especially preferred. Other forms of these compounds such as their salts are also known and pharmaceutically acceptable salts where available and accepted for hormone therapy are useful in principle.
• An additional tabulation of estrogens and progestagens appears in the text Essentials of Medicinal
• steroidal hormones in general are readily metabolized by the animal's system so that any excess over the natural "level of the hormone in the animals (and both male and female each have significant measurable levels of both estrogen and progesterone type hormones as well as testosterone) is removed within 24-48 hours.
• the administration of the female gonadal hormone here must continue over a sufficient period of time during the develop ⁇ ment of the animal as to exhibit or retard its sexual matur ⁇ ation until after slaughter, 'say 30 days or so, although longer and somewhat shorter times could be utilized if desired.
• the application of multiple dosages of the steroid compound during this period is a workable approach but may not always be convenient.
• a preferred mode of administration to mammals is the hypodermic injection of the hormone in an acceptable carrier or other form which retards the release of the hormone into the animal's system.
• the preferred compounds designated above have little solubility in water but are sufficiently soluble or dispersable in oil vehicles as are conventional and typically used for pharmacological compositions designed for injection, of which vegetable oils, such as olive oil, are preferable, although other pharma ⁇ cologically useful oil vehicles should be acceptable in principle.
• the combination of the oil vehicle and the hormone combines to achieve a sufficiently slow release of the hormone into the animal's system for present purposes covering a period of considerable days and even up to about 30 days especially if the injection is accomplished sub- dermally to produce a pocket of the hormone in oily vehicle immediately below the skin of the animal which is gradually absorbed.
• Intramuscular injection is also possible but usually entails an increased " rate of absorption as is known.
• the amount of the mixture injected may vary but a few ml, say 2 ml, is ordinarily sufficient, depending of course on the concentration of the hormone.
• a single dosage at an effective level of the female gonadal hormone will suffice in the present practice? however, as mentioned, multiple dosages may be utilized especially for larger animals, or multiple dosages at reduced levels at intervals of several days, perhaps 2-3 days to 7 days, or longer in some cases, could be substituted if preferable.
• the site of the injection can be varied to suit an individual preference but the inguinal region or groin has been found entirely satisfactory in the case of pigs.
• the hormone can- be incorporated in the feed of the animal species at a very low level, say a fraction of a percent, e.g. 0.5, up to 1-2% by weight, as to be consistent with thorough mixing and safe application by avoiding pockets or localized areas of excessively concentrated material.
• a very low level say a fraction of a percent, e.g. 0.5, up to 1-2% by weight
• food pellets containing the hormone or pelletized hormones mixed with a greatly predominant amount of granular feed could be used, being made available to the animal during the administration period for a period of some days, dependent upon the particular species being treated.
• feed supplements containing enhanced levels of protein, minerals, vitamins and the like and small levels of the active hormone could be incorporated into such supplements, being made available to the animals separately from their • standard feed. In this fashion somewhat better control over the uptake of the hormone by individual animals can be exercised than if the active hormone is applied via the general feed mixture.
• the estrogen function or the progestagen function of a combined compound were less or greater as the case may be, than the desired relative proportions as determined for the separate compounds, then such a composite compound could be supple ⁇ mented with the amount of additional estrogen or progestagen compound as needed to achieve the desired relationship of the two hormone functions.
• sexual maturation is a gradual lengthy process, its culmination in the sense of the capacity to produce young either as a male- or female is for a given animal, as in humans, a fairly well defined event in time, although the point in time of that event will vary consider- ably between individual animals of the same species.
• Full sexual maturation can be identified scientifically by histological examination under, for example, an electron microscope of the brain cells and neurons of the animal to ascertain whether or not fully mature cell differentiation in critical areas of the brain, notably the pituitary, has already occurred.
• administration is strongly preferred to be initiated quite early and in any case long prior to full brain cell differ ⁇ entiation and sexual maturation.
• brain cell differentiation in the critical areas of sexual development and growth are at a minimum and thus the remarkable effects of the present concept on brain cell development are maximized.
• the optimal timing for mammals is during their so-called neonatal period, that is during the few days following their birth. In the pig, the neonatal period corresponds to days 1-7 after birth and administration during this period appears to be ideal for purposes of this invention. Indeed, administration at day 1.
• a single injection on day 1-3 of the administered hormone e.g., a mixture of a natural estradiol hormone and a progesterone compound in the proportions described above, say 50 and 250 mg, respectively, in a vegetable oil vehicle, has been itself to give eminently satisfactory results in achieving the objects of the present invention.
• a second dose at equal or reduced levels could be added at about day 7 particularly if the initial dose were reduced accordingly.
• the levels of administration of the female steroidal hormone do not appear critical and can vary considerably. While the hormones in question presumably have toxic limits like virtually all other medicinal compounds, such limits if they are known are far greater than even the maximum levels that need be applied in this invention, and toxicity thus is not a matter of concern here.
• the levels in the blood of the administered hormones When the hormone mixture is administered in an oily vehicle, the levels in the blood of the administered hormones, starting from an elevated level upon injection, drop gradually until at the 28-30 day age, where injection takes place on the first or second day, the levels have decreased to the normal blood levels for the hormones in question in the animal, Inasmuch as the animal is normally slaughered well after this time, slaugher in the case of pigs occurring when the pig reaches a.weight of about 100-110 kg (or about 220-240 pounds) which is reached when the pig is about 5 6 months old, this natural clearing effect of the hormone from the animal's system means that ' the hormone is completely eliminated well before slaughter.
• Elimination of the administered hormone, i.e., the excess above normal blood levels, not later than 60 days prior to slaughter is considered entirely safe, although it is believed that elimination not later than 30 days prior to slaughter will prove equally safe and acceptable. Given these acceptable time limitations, the administration can obviously continue past the one month period in pigs, for example, up to the point where clearance occurs at the appointed time prior to slaughter.
• the usual pharmacological inert carriers are entirely suitable, specialized measures could be adopted for achieving a sustained release of the active hormone if preferred.
• Inert polymeric matrices, such as that sold under the trade- name "Silastic" by Dow Chemical have been developed for this kind of release and could be utilized here along with similar developments.
• the treated animals are found to be bigger and longer in size, the proportion of lean meat to fat has been significantly increased, slaughter weight is achieved within a significantly shortened period of time, e.g., about 15-20 days in the case of pigs, and the efficiency of the animal's conversion of the feed as expressed in terms of unit weight of meat product per unit weight of feed consumed is significantly increased.
• the pig Due to the significant acceleration of the feeding cycle, whereby the pig, for example, reaches a market weight of about 100 kg in about 165-170 days, compared to about 185 days for both intact and castrated pigs, the overall production cycle at a mass production facility can be definitely greater.
• spermatogenesis is inhibited as is the development of secondary sexual character ⁇ istics beyond the normal slaughter time, if the male animals should not be slaughtered, they eventually exhibit normal sexual development and activity although at a somewhat later time than untreated animals.
• the method of the invention does not cause any ultimate deformity or diminution in the sexual function of the animal, testicular development being normal with only spermatogenesis being temporarily delayed.
• the effects of the present treatment on castrated animals differs from those obtained with hormone implants on castrated animals.
• the latter is employed with cattle which are normally castrated at three months or so and the continuous release has a strong feminizing effect distinct from the growth stimulation of the invention.
• the neonatal period extends from day 1 through about day 21 and administration preferably takes place during this period and ideally quite early in this period, say day 1 or day 2 as with pigs, although delays beyond this date are readily possible.
• the level of adminis ⁇ tration for larger animals does not increase proportionately with increasing body weight of the animal at the time of administration, although some increase in the absolute amount of the administered hormone is indicated for larger animals.
• the level of the administered hormone should perhaps be twice that employed for new born piglets weighing about 1.1-1.2 kg, and the duration of administration for cattle should be around about two months or so but can continue longer in view of the con ⁇ siderably greater age of cattle for slaughter.
• beef cattle are normally slaughtered at an age greater than one year, say about 14 months, and the maximum conceivable dura ⁇ tion of administration is such as to be cleared from the animal's system about 30-60 days prior to slaughter.
• the latest time for administration to cattle would be at around four months of date but earlier times are much better.
• Multiple dosages might be more convenient with cattle, say three dosages, one at the preferred level of the mixture on day 1 or 2 and the next at a total of say 300 mg approximately two weeks later, and a third at 1-2 months of age at the 300 mg level.
• veal and so-called "baby beef” can likewise be treated.
• the principle of the invention is applicable to fish and shellfish, and the results of the practice of the inven ⁇ tion are in some respects even more extraordinary for fish than for mammals.
• Fish at birth or hatching are not sexually differentiated in contrast to mammals where the sex of a given animal can be readily discerned at birth (sexual differ ⁇ entiation of mammals generally occurring during gestation) .
• fish have a considerably less highly developed brain and endocrine system than do mammals at the time of birth so that the entirety of the hatch of young- fish can respond to the present method without the male/female differ ⁇ ences noted above in mammals.
• treatment of the fish by the present invention causes a substantial shift toward the development of females to give a male to female ratio of about 20-30:80-70.
• the disproportionate increase in the ratio of female fish is advantageous since female fish have better growth characteristics than males.
• the invention results in an increased number of herma ⁇ phrodite and sterile fish which is advantageous from the standpoint of meat production since it avoids the energy consumed by the sexual cycle, i.e., for egg production, which is considered wasted for purposes of meat production.
• the sexual maturation of the fish is likewise delayed so that they reach marketable weight earlier and can be harvested before breeding takes place.
• Newly hatched fingerlings are born with an attached yolk sac which is consumed by the fingerlings during about the first 3-4 months of their existence dependent upon such factors as water temperature and amount of available light so that the fingerlings do not actually begin feeding in the sense of consuming externally supplied food until 3-4 months of age.
• the hormone of the invention cannot be administered to fish until after they have begun to feed and preferably the administration is begun at their first feeding.
• the hormone is supplied to the fish via their food, being incorporated into the usual food pellets or granules at a level of about 0.5-2.0% by weight.
• the feeding can be extended for about 5-7 days and longer if desired, but 5-7 days has been found entirely sufficient and further adminis ⁇ tration of the hormone seems to produce no corresponding increase.
• the rate of growth for fish is affected by external conditions such as water temperature and the amount of available light
• fish such as rainbow trout are ready to be harvested and marketed at about one and one-half years age counting an initial three months period for assimilation of the yolk sac, or say about one to one and one-quarter years after the first feeding. By this time the administered hormone is fully cleared from the fish's system.
• the period of administration can, therefore, certainly be extended safely but availability of the hormone at'the usual feeding intervals during the first week to two weeks after first feeding of the fish has been found entirely sufficient to produce significantly desirable results. Excess or over-feeding of the hormone-containing feed should be avoided during this period.
• an estrogen compound and a progestagen compound as preferred for mammals can likewise be utilized in the case of fish, it is preferred for the latter to administer an estrogen compound alone, selected from those available to the art.
• an estrogen compound alone selected from those available to the art.
• the inclusion of any pro ⁇ gestagen compound does not appear to significantly influence the response of fish to the present method. Both cold and warm water fish respond to the invention, including salmon, rainbow trout, carp and others currently being cultivated.
• the invention is also deemed to be applicable to various shellfish including shrimp, lobster, crayfish, oysters, mussels and the like, and in general, the treatment would follow the same pattern for these species as for fish, the hormone being administered early in the feeding cycle of the species via the feed that is supplied- thereto following principles that are now well developed for the forming of such species.
• chicks are differentiated sexually at birth and-have a higher level of brain and endocrine development than do fish, but nevertheless, the present method will have beneficial effects on both male and female chickens.
• the hatch time for chicken eggs is approxi ⁇ mately 30 days, and while it is technically possible to inject the chicken embryo with the hormone within the egg, this practice is contraindi ⁇ ated here due to the potential for causing increased abnormalities in the chicks after hatching.
• the hormone is applied to chickens via their feed being incorporated into the feed at a level of say about 0.5-2% by weight. Inasmuch as chickens are already bred to maximize feed efficiency, the effect of the-invention on chickens is not anticipated to be as high as for mammals, fish and the like.
• 150 male piglets of a strain of Swedish Landrace were divided into groups of 50 and were either castrated, left intact or given a single injection with the compound mixture under the skin in the s ⁇ rotal area during the neonatal period, specifically on day 1 or 2 after birth.
• the injected composition was a mixture of 50 mg of estradiol dipropionate and 250 mg of progesterone caproate, i.e., 17 -hydroxy- progesterone caproate, dissolved or dispersed in olive oil as a vehicle or carrier.
• animals Prior to weaning, animals were given a pre-weaning feed, and after weaning a post-weaning feed, followed by a growth and finally a finishing feed, all feed mixtures being regular formations of generally known types.
• the pigs were kept in semi-confinement, ten pigs in an open cage until an average weight of 50 kg was achieved, and then 20-22 pigs in a much larger open cage until market weight of approximately 100 kg had been reached. Animals were sheltered and had free access to water and feed. Every fourteen days the animals in all groups were weighed, the daily food consumption, and the food consumed per kg of body weight gain were calculated. Animals were sacrificed at intervals and meat quality observed.
• Table 2 the average food consumption per day is given.
• Table 3 shows the average food uptake or conversion per kg of weight gain, which is a measure of feed efficiency. The feed efficiency of the treated animals was considerably better than the castrated or intact animals at almost every test interval.
• Table 5 shows the average body weight at the stated interval plotted against age in days for -the intact, castrated and treated male pigs.
• the treated pigs were considerably heavier than the other two groups throughout the test period.
• the treated animals reached their market weight of 100 kg in 166 days, which was 20 days sooner than the other two groups.
• Table 5 Average Body Weight of Male Landrace-Yorkshire Pigs (Kg)
• Table 6 shows the average food consumption in kg for the three groups at various time intervals throughout the growth cycle.
• the treated hybrid pigs consumed slightly more feed per day than the other two groups, but with a considerably greater weight increase. In addition, they reached market weight much earlier. This means a considerable saving in feed, since the final growth phase before slaughter is the one with the poorest feed efficiency.
• the average food uptake or conversion per kilogram of weight fain (feed efficiency) is shown in Table 7.
• the first phase represents the post-weaning growth phase of pigs on a high protein diet.
• the treated animals have an actual feed efficiency of 2.86, compared with 3.00 for the intact, and 3.39 for the castrated animals.
• the treated animals have a 15.64% higher feed ef iciency compared with the castrated and about 4% higher than the intact animals.
• the actual feed efficiency of the treated animals is 3.27 compared with 3.62 for the intact and 3.73 for the castrated. Probably the most important comparison is the overal feed efficiency from weaning to market weight, i.e., over the full range of 20-100 kg.
• the treated animals show an overall actual average feed efficiency of 3.08 compared with 3.32 c for intact, and 3.57 for castrated pigs.
• the treated reach market weight of 100 kg in a considerably shorter time. This not only means an additional feed saving but a saving in labor costs, heating and other expenses in producing the animals. More animals can thus be brought to market since it becomes possible to have more production cycles from weaning to slaughter per year for a given size facility.
• Table 8 Comparison of Feed Efficiency per Growth Phase —
• Fig. 1 is a comparative group of plots of the level of estradiol in the blood serum of the animal versus the age of the animals during the experiment for each of intact animals, castrated animals and animals treated in accordance with the invention, the regression or trend line of each of the graphs being shown in broken lines;
• Fig. 2 is a similar group of graphs for serum concentration of progesterone.
• Fig. 3 is a similar group of plots for the serum concentration of testosterone in the various groups of animals
• the blood serum for groups of each of these animals was analyzed for the content therein of the hormones in question by means of known radioimmunoassay techniques at intervals following the administration by injection into the treated animals and the results of these analyses are set forth graphically in Figs. 1-3.
• the injection composition consisted of the preferred combination of 50 mg estradiol and 250 mg of progesterone dissolved or dispersed within olive oil as a carrier, the administration being applied at day 1.
• the variation in the analyzed values of the respective hormones at each time of measurement is indicated in the graphs by solid vertical bars.
• Fig. 1 the subcutaneous dose of estradiol in oil is cleared by 28 days, reaching by that time a basal level compared with the castrate and intact animals.
• Fig. 2 demonstrates that the progesterone levels in the treated animals likewise come to the same levels as the intact animals by day 28.
• the intact animals exhibit a secondary increase that represents an endogenous secretion of progesterone from the tests, and to a lesser extent from the adrenals,, from day 28 to day 84 with a peak at day 56.
• Both the treated and the castrated animals in this time period have a much smaller rise in endogenous progesterone, coming entirely from the adrenal cortex in the case of castrated, and mostly from the adrenal cortex in the case of the treated animals.
• Fig. 1 the subcutaneous dose of estradiol in oil is cleared by 28 days, reaching by that time a basal level compared with the castrate and intact animals.
• Fig. 2 demonstrates that the progesterone levels in the treated animals likewise come to the same levels as
• Example IV shows the endogenous levels of androgen expressed as testosterone, in the three groups of animals. This is testosterone from the testis and, as would be expected, in the castrated animals is almost zero. The treated animals show a first peak rise in testosterone beginning at day 7 similar to the intact animals but to a lower level. Interestingly enough, the secondary phase which shows an increase in testosterone after day 28, as measured by blood levels, is greatest in the treated animals. The dotted linear regression or trend line in the treated animals shows this increase quite clearly. This represents the induced—anabolic effect of the inventive treatment and is part of the improved growth effect thereof.
• Example IV shows the endogenous levels of androgen expressed as testosterone, in the three groups of animals. This is testosterone from the testis and, as would be expected, in the castrated animals is almost zero. The treated animals show a first peak rise in testosterone beginning at day 7 similar to the intact animals but to a lower level. Interestingly enough, the secondary phase which shows an increase in testosterone after day 28, as measured by blood levels, is greatest in the treated animals. The dotted linear regression or
• This example illustrates the application of the invention to fish, specifically rainbow trout (Salmo gairdneri) as well as the influence of different growing conditions, especially temperature and light, on the response of the fish to the instant treatment.
• the fish in the experiment at each location were separated into two groups, the first group being fed with the usual pellet- ized feed or "bricket" and the other were fed the same feed on which estradiol benzoate was incorporated at a concentra ⁇ tion of 0.5% by weight and given to the fish for four consecutive days, beginning with the first feeding of the fish at an age of four months, after which the treated and untreated fish were supplied with the same feed on the same basis.
• These experiments were terminted when the fish reached their consumption or marketing weight which occurred at the age of 17 months for the fish at the warmer location and at the age of 20 months for the fish in the colder location.

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• 1985
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