Immunocastration

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The immunocastration , also immunocastration called, is an immunological method for preventing the formation of the sex hormones , thereby for a limited time period, the same effect as in a surgical removal of the sex glands ( castration is achieved). The method is used in veterinary medicine primarily for horses and pigs and to control the population density of wild animals. It works like a vaccine in that it stimulates the immune system to produce antibodies against the body's own hormones.

Principle of action of immunocastration

The active ingredient used for immunocastration is a synthetic analogue of the hormone gonadoliberin (GnRH). In mammalian and human bodies, gonadoliberin is produced in the hypothalamus of the brain. The body's own gonadoliberin stimulates the formation and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the pituitary gland . In females, follicle stimulating hormone causes the growth and maturation of ovarian follicles ( follicles ) in the ovarian up to ovulation . In male individuals, it stimulates the formation of sperm ( spermatogenesis ) in the testes . The luteinizing hormone promotes ovulation and the subsequent luteal body formation in female individuals . In male individuals, it stimulates the production of the male sex hormone testosterone in the Leydig cells of the testicle. Among other things, testosterone promotes the development of secondary sexual characteristics, libido and sexual potency.

The synthetically produced GnRH analog used in immunocastration is modified in such a way that, on the one hand, it cannot develop any hormonal effects in the body itself after the injection and, on the other hand, is recognized by the immune system of the treated animal as foreign, so that B-lymphocytes begin to produce antibodies against the GnRH analogue. These antibodies also bind the body's own GnRH, which can no longer develop its stimulating effect on the pituitary gland. Since this no longer releases FSH and LH, there is no hormonal stimulation of the sex glands. Hormonally, a state is established that corresponds to the hormone status after surgical removal of the sex glands (castration).

Since GnRH is a very small molecule with a length of 10 amino acids , it has to be bound to a carrier molecule in order to be able to trigger the formation of antibodies as an antigen . In addition, the resulting active ingredient is combined with an adjuvant which, as an auxiliary, increases the immunological response. Since GnRH is very similar in mammals, the active substances developed are not species-specific in their effects and can be used in different animal species. However, there are differences between different animal species in terms of the duration of action achieved.

Immunocastration is reversible, as the formation of antibodies by the B lymphocytes only lasts for a certain time. When the antibody production decreases, the body's own GnRH is increasingly no longer bound, so that it can again develop its stimulating effect on the pituitary gland. The sex glands are stimulated again by FSH and LH, so that the hormonal status of an uncastrated animal is restored.

Compared to surgical castration, in which the sex glands are removed, immunocastration has the advantage that it is a non-invasive procedure, i.e. no surgery is necessary. Depending on the indication, the time limitation of the elimination of fertility and libido is an advantage over surgical castration, which cannot be reversed.

The meat of immunologically castrated animals is safe for human consumption and does not develop any hormonal effects in the human body. Due to the high homology of the GnRH molecules in the various mammals, including humans, inadvertent injection of the active ingredient can cause the same symptoms in humans as in the animals to be treated. Especially with a second or even further accidental injection, the active ingredient suppresses the GnRH effect in humans as well. In pig production, the active ingredient is therefore usually applied with a safety applicator, which prevents accidental self-injection. Since the hormonal effects of accidental self-injection are particularly serious in an existing pregnancy, pregnant women should not use the active ingredient. When used to control wild animal populations in the USA, the active ingredient may only be used by specially trained people.

Immunocastration in horses

indication

When mares and stallions are used as sport horses, unwanted behaviors caused by the sexual instinct can negatively affect training and performance. During the steeds , many mares show poor concentration and poor performance. Stallions are easily distracted by the presence of mares and stallions and often show defiant and aggressive behavior. When dealing with horses, pronounced sexually motivated behavior can therefore be dangerous for people and other horses, which is why some horse owners and riders wish to suppress the reproductive endocrine system of the horse.

A drug for immunological castration is available for use in horses. In stallions, immunocastration causes reduced sperm production and a reduction in testosterone, which reduces libido and sexually motivated aggressive behavior. In mares, the development of follicles is suppressed, which means that the sexual cycle is interrupted and the steeds fail to appear.

Another application of the immunocastration in the horse is the treatment of stallions with the pathogen of Equine arteritis are infected, the equine arteritis virus (EAV). In stallions, the virus can persist permanently in the testicles. It is excreted from these animals with the sperm during mating, which can lead to an infection of the mare that is covered, which is why affected stallions are excluded from breeding. The persistence of the pathogen in the testes is androgen-dependent. By suppressing testosterone secretion, immunocastration can prevent the virus from shedding. Since the effect on the formation of testosterone and thus the formation of sperm is reversible, but the virus excretion remains permanently prevented, the stallions treated by immunocastration can be used for covering again after the antibody formation has subsided.

application

For immunocastration to be successful, the active ingredient must be administered twice by intramuscular injection at an interval of four weeks. The duration of action is very different from horse to horse. In mares, the horses are suppressed for at least three months. In some mares, however, the lack of progesterone release can lead to the development of a permanent horse. In addition, it cannot be guaranteed that mares that have been repeatedly treated with the drug will develop a normal sexual cycle again after it has been discontinued and can therefore be used in breeding. As older stallions react with a lower immune response, three injections are often necessary for an effective suppression of testosterone production.

Immunocastration in pig fattening

background

Pigs are slaughtered in modern pig fattening with a slaughter weight of 110 to 125 kg, which they usually reach at an age of 6½ to 7 months. Most boars reach sexual maturity at this age, at which point they produce sexual attractants that are stored in adipose tissue and excreted with the boar's saliva in order to stimulate the sows' willingness to mate. When heating boar meat - such as cooking, frying or grilling - can boar taint occur, which is perceived by many consumers as unpleasant and urine-like or sweat. In addition, with the onset of puberty, the boar's aggressive biting behavior increases. These changes are caused by the sex hormone testosterone , which is produced in the testes and the substance largely responsible for the boar odor is androstenone , a metabolite of testosterone.

In Germany around 18 million male piglets are castrated in their first week of life every year in order to prevent the boar odor, which means a reduction in the quality of the meat. The testicles are removed with a scalpel so that testosterone formation is eliminated. Castration also makes it easier to keep the animals in groups, since castrated male animals do not show any hormonally controlled aggressive behavior. Piglet castration is allowed up to the seventh day of life according to EU directives 2001/88 / EG and 2001/93 / EG without pain elimination and is considered the safest method to avoid the occurrence of odorous boar meat. Since this procedure is usually carried out without anesthesia and there is increased public interest in animal welfare and animal welfare treatment, castration with pain elimination was required. As a result of the amendment to the Animal Welfare Act (TSchG) in 2015, the castration of piglets without anesthesia should have been banned in Germany within the first 7 days of life from January 1, 2019. On November 29, 2018, the Bundestag decided to allow castration without anesthesia for a further two years.

In addition to surgical early castration under anesthesia and pain elimination and boar fattening (fattening of uncastrated boars with slaughter before sexual maturity), immunological castration of boars is an alternative to the current practice of castration of young pigs without anesthesia.

application

In the active ingredient used in pig production, the synthetic GnRH analogue used is bound to a carrier protein from the bacterium Corynebacterium diphtheriae (diphtheria toxoid). The active ingredient has been available for over 15 years (as of 2016) and is approved in 64 countries for the treatment of boars in pig fattening.

Use in male pigs requires two injections, both of which are carried out during the fattening phase. After the first injection, which can be done from the age of 8 weeks, the B-lymphocytes still produce relatively few antibodies, so that no effects on the physical appearance or behavior of the animals can yet be determined. The second injection is given at least four weeks after the first injection and four to six weeks before the planned slaughter date. The B-lymphocytes now produce large amounts of antibodies (booster effect), which effectively prevent the formation of androstenone and thus the boar odor . After the second vaccination, the animals become significantly calmer and their sleeping behavior is similar to that of neutered animals. Due to the lack of stimulation of the testicles, they decrease significantly in size, testosterone production does not occur, so that no more androstenone is produced. This also significantly reduces the production of Skatole.

The effect of the immunization is temporary: if slaughter is intended later than 10 weeks after the second dose, a third dose should be given four to six weeks before the planned time of slaughter. If this point in time were exceeded, insufficient antibodies would no longer be formed and the testes would begin to develop again to their full function and size, so that boar odor would develop again.

Acceptance of the procedure

Consumers and marketers

In a consumer survey carried out in 2010, consumers had little knowledge about piglet castration. Only around a quarter of those questioned knew the meaning of the terms “boar taint” and “castration”. After being informed by the interviewers about the methods of surgical castration and immunocastration, 41 percent considered immunocastration and 19 percent surgical castration to be the best method in a final survey. 40 percent of those questioned did not prefer either method.

In Switzerland, where immunocastration has been permitted since 2007 and castration without anesthesia has been banned since 2010, according to consumer surveys, the meat of immunocastrated animals is so poorly accepted that the two largest supermarket chains Migros and Coop refuse to sell such products. In Germany, too, the meat produced in this way has so far been rejected by consumers and marketers, which is why many slaughterhouses do not accept immunocastrated boars for slaughter. So far, REWE is the only retail company ready to market meat from immunocastrated animals.

Although the treatment is approved in Japan, the country, like Singapore, does not import meat from immunocastrated boars, as consumers there are skeptical of any interference with the natural hormonal balance of the animals and the resulting effects on consumer safety.

Agriculture

In Australia around 60% and in Brazil around 50% of the boars are immunologically castrated. In the European countries, however, the process has not yet been able to gain acceptance among agricultural pig producers. It has been approved in Belgium since 2010. Here immunocastration has been used by around 15% of farmers so far. In the Belgian internal market, 30% of boars are vaccinated. In the other European countries, immunocastration is only used by individual farmers. The reasons for this are the poor acceptance by consumers described above and the associated lack of sales opportunities for the correspondingly treated animals for slaughter at meat producers. The second vaccination in particular is associated with dangers for the user due to injuries caused by the animals, which are already very heavy at this point, and also makes keeping in separate-sex fattening groups necessary, which can only be implemented in very large fattening farms.

In Germany, the cost of two injections is currently € 3.40 to € 5.45 per animal. The active ingredient is currently only offered by a single manufacturer worldwide; However, since the main patent expires in 2018, it is to be expected that other manufacturers will then also offer similar preparations, which is expected to reduce the costs per vaccine dose. While the treated boars show a feed intake and growth behavior similar to that of the uncastrated boars up to the second injection, the metabolism of the animals changes after the second injection, as a result of which they tend to accumulate a lot of fat. After the second injection, the animals eat significantly faster and, at up to 4 kg per day, consume around 20% more food than surgically castrated boars. In order to counteract excessive obesity, which is undesirable in modern pig production, adapted feeding concepts are therefore necessary. In the carcass evaluation, the immunocastrated animals perform worse in all parts of their bodies than the carcasses of uncastrated boars, which cannot be compensated for by the higher growth performance in the last fattening phase. As a result, the immunocastrated animals, taking into account the vaccination costs, achieve a contribution margin of around € 7 to € 15 less than uncastrated young boars.

Some agricultural associations such as the interest group of pig farmers in Germany certainly see the possibilities of boar fattening with or without immunocastration, but demand clarity from the retail trade regarding the purchase of meat from uncastrated animals. The QS system, a joint initiative of meat producers and marketers, puts immunocastration on an equal footing with boar fattening and castration with anesthesia / pain elimination, but sees a particular need for international coordination of the withdrawal from anesthesia-free castration in order to avoid any disadvantages for German agriculture to create international competition.

The veterinary profession sees boar fattening, slaughter before sexual maturity and immunocastration as the only practical alternatives to castration without anesthesia, which is still common today. Breeding on pigs without boar odor, as well as sperm sexing and fattening exclusively female pigs would be alternatives, but they are not yet ready for practical use.

Animal welfare organizations

The German Animal Welfare Association recognizes immunocastration as one of three alternatives to castration without anesthesia. ProVieh, on the other hand, favors boar fattening and sees immunocastration only as an interim solution due to the considerable concerns with regard to consumer acceptance. The Veterinary Association for Animal Welfare (DVT) sees the fattening of immunocastrated young boars as the first choice among the currently available alternatives to anesthetized piglet castration.

Use for population control in wild animals and feral pets

In the USA, immunocastration is used to make white-tailed deer ( Odocoileus virginianus ) sterile. The method was developed by the National Wildlife Research Center (NWRC) and is used in areas where the deer population is increasing because they cannot be decimated by hunting in cities or suburbs, for example. The animals pose dangers and nuisances here, for example through increased accidents with wildlife, aggressive behavior of male animals towards humans during the rutting season or damage from browsing and stepping on cultivated and ornamental plants. If the population is too dense, the animals are also threatened with malnutrition and the increased transmission of diseases, including between different species of deer.

When used in wild animals, the need for two injections is a problem as it is difficult to ensure that animals treated once will receive the second injection within a certain period of time. For this reason, a special combination of active ingredients has been developed for use in wild animals, which suppresses hormone production with a single injection without a second injection for boosting over several years. This is based on the one hand on the use of a special adjuvant that contains an extract from Mycobacterium avium and triggers a prolonged immune response. For the synthesis of the GnRH analog, the epitope was also coupled to the carrier protein Keyhole Limpet Hemocyanin (KLH), which is often used in the production of animal vaccines to increase their immunogenicity .

Since the treatment induces a significantly longer duration of action in female animals than in male animals, the female individuals of the population are treated. The active ingredient is administered intramuscularly to female animals. A single injection three months before the rutting season leads to infertility for at least a year. If a second injection is given 30 to 60 days after the first injection, the infertility will last for several years.

The preparation was approved by the US Environmental Protection Agency (EPA) as a restricted indication pesticide in 2010 . This is currently limited to use on female white-tailed deer. The agent may also only be used by employees of the USDA Wildlife Service and the state authorities for wildlife management, as well as by persons appointed by them. Users must be certified for the use of pesticides. In 2015, the same combination of active ingredients was approved in the USA for population control in wild horses and donkeys.

Although studies have already shown that the active ingredient combination approved for white-tailed deer also works well in other animal species such as the California ground squirrel , domestic and wild pigs, bison and black- tailed deer ( Odocoileus hemionus ), it has not yet been approved for use in other animal species.

Feral dogs and cats are a problem in many countries, which is why there is an intensive search for population control options for these animal species. Feral dog populations in some countries represent a reservoir for the rabies that can be transmitted from these animals to pets and humans. Immunocastration to reduce the dog population in combination with widespread rabies vaccination is viewed by veterinarians as an effective method of combating rabies. Studies with the combination of active ingredients approved for white-tailed deer have shown, however, that dogs and cats react increasingly with local reactions to the adjuvant used, so that a different formulation would first have to be developed for these animal species, so that no approved drug is available.

A disadvantage of population control through immunocastration is that the reduction in population size occurs relatively slowly, as this only changes gradually due to the death of individual individuals and the lack of offspring. Immunocastration is therefore often used to keep the population size constant following a short-term reduction through hunting. Compared to hunting, immunocastration is more widely accepted as a method of population control because the animals are not killed, which often meets with resistance.

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