GnRH-immunocastration: an alternative method for male animal surgical castration

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TYPE Mini Review PUBLISHED 31 October 2023 DOI 10.3389/fvets.2023.1248879 GnRH-immunocastration: an OPEN ACCESS alternative method for male animal surgical castration EDITED BY Izhar Hyder Qazi, Shaheed Benazir Bhutto University of Veterinary and Animal Sciences, Pakistan REVIEWED BY Chun Wang 1, Cuiting Yang 1, Yutian Zeng 1 and Ming Zhang 1,2,3* Waseem Ali Vistro, 1 College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China, 2 Key Yangzhou University, China Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of *CORRESPONDENCE Animal Science and Technology, Sichuan Agricultural University, Chengdu, China, 3 Farm Animal Genetic Ming Zhang Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science zhangming@sicau.edu.cn and Technology, Sichuan Agricultural University, Chengdu, China RECEIVED 27 June 2023 ACCEPTED 10 October 2023 PUBLISHED 31 October 2023 Castration of male animals is intended to produce high-enhance quality of animal meat, prevent unpleasant taste, reduce aggressive behavior, and manage CITATION Wang C, Yang C, Zeng Y and Zhang M (2023) overbreeding. Over the years, Tranditional methods of mechanical and surgical GnRH-immunocastration: an alternative castration have been employed over the years, but they fall short of meeting method for male animal surgical castration. animal welfare requirements due to the associated risk of infection, pain, and Front. Vet. Sci. 10:1248879. doi: 10.3389/fvets.2023.1248879 stress. Immunocastration, specifically Gonadotropin-releasing hormone (GnRH)- COPYRIGHT immunocastration, targeting the hypothalamic–pituitary-testis (HPT) axis, has © 2023 Wang, Yang, Zeng and Zhang. This is emerged as an

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nRH)- COPYRIGHT immunocastration, targeting the hypothalamic–pituitary-testis (HPT) axis, has © 2023 Wang, Yang, Zeng and Zhang. This is emerged as an animal-friendly alternative to surgical castration, effectively an open-access article distributed under the addressing these issues. This review seeks to systematically summarize the terms of the Creative Commons Attribution License (CC BY). The use, distribution or principles, development, current applications and challenges of GnRH- reproduction in other forums is permitted, immunocastration, offering insights into its role in promoting animal welfare. provided the original author(s) and the copyright owner(s) are credited and that the KEYWORDS original publication in this journal is cited, in accordance with accepted academic practice. immunocastration, surgical castration, male animal, animal welfare, GnRH No use, distribution or reproduction is permitted which does not comply with these terms. 1. Introduction Capon production, an ancient practice dating back over 3,000 years, persists globally (1–3). While capon production constitutes a modest segment of the market, it holds significant growth potential due to its dustinctive sensory attributes cherished by consumers (4–7). Capon are male chickens that undergo surgicalcastration before reaching sexual maturity, a practice also applied to other male livestock like boars and rams. The objectives are to reduce unpleasant odors, increase intramuscular fat deposition, improve carcass composition and meat quality. Castration leads to androgen deficiency, hindering male secondary characteristics, such as the comb and flesh hair, reducing aggressive behaviors and eliminating fighting and snorting (8). The energy consumed by capon in territorial protection, fighting,

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flesh hair, reducing aggressive behaviors and eliminating fighting and snorting (8). The energy consumed by capon in territorial protection, fighting, and courtship behaviors is greatly reduced compared intact rooster, making their feed energy utilization more efficient for growth and fat deposition (9). Consequently, castration enhances fat deposits and intramuscular fat content, elevating meat sensory qualities such as tenderness, juiciness, and flavor (7, 9–11). However, surgical castration also has some limitations, including postoperative complications, increased susceptibility to infections, and animal welfare concerns. Additionally, the procedure needs to be performed at an appropriate age, and the high demands on surgical skills, and other cost- effective resources (12). In contrast, GnRH-immunocastration minimizes animal stress, reduces infection risk and complications associated with surgery, and substantially greatly improves animal welfare. Furthermore, it poses no risk of drug residue, making it easy to apply in production. Consequently, GnRH-immunocastration has the potential to be a safe alternative to surgical castration. Frontiers in Veterinary Science 01 frontiersin.org Wang et al. 10.3389/fvets.2023.1248879 2. The comparison of different within the HPT axis through immunological means to reduce the castration techniques for male concentration of target hormones and achieve castration (29, 40). animals GnRH is located at the upper end of the HPT axis, plays a pivotal roleinitiating and controlling the physiological functions of the entire Currently, various techniques for castrating male animals exist, reproductive axis (41). Therefore, GnRH-immunization is the most including chemical castration, Bloodless castration, surgical castration, widely

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ist, reproductive axis (41). Therefore, GnRH-immunization is the most including chemical castration, Bloodless castration, surgical castration, widely used in production compared other targeted hormone and immunocastration (Table 1). Unlike mammals, rooster’s testicles immunocastration involves Animals are inoculated with GnRH are located in the abdominal cavity, hanging ventral in the anterior part vaccine, which prompts the production of specific anti-GnRH of the kidney through the mesangium and with the posterior tibial vein antibodies in the body, anda lot of anti-GnRH antibodies bind with and aorta on both sides, which makes avian castration is more endogenous GnRH, continuously inactivating endogenous challenging than that of mammals. In the poultry industry, traditional GnRH. Consequently, GnRH-immunization leads to a decrease in surgical castration is performed without anesthesia or analgesic luteinizing hormone (LH) and follicle stimulating hormone (FSH) control, resulting in roosters’ suffering and violating animal welfare secretion. Eventually, this inhibition of animal gonadal functionresults principles (38). Although geldings are banned in the EU (European in the achievement of castration (42). Union) due to concerns about animal welfare, they are still used in traditional agricultural systems, representing a derogatory toward age-old practices (39). Surgical castration also incurs mortality rates 4. GnRH-immunocastration is a safe ranging from 5 to 20%, and sometime even up to 50% (39). castration method in line with animal welfare 3. Principles of Physiological doses of GnRH can significantly increases LH levels GnRH-immunocastration and slight increase FSH levels in plasma, reaching the gonads via the pituitary portal circulation, This stimulated

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es LH levels GnRH-immunocastration and slight increase FSH levels in plasma, reaching the gonads via the pituitary portal circulation, This stimulated the synthesis and Immunocastration primarily targets reproductive hormones secretion of gonadal steroid hormones, promoting gonadal within the HPT axis (Figure 1), disrupting reproductive hormone development, gamete production, and the occurrence and TABLE 1 Comparison of four castration techniques. Method Item Surgical castration Bloodless castration Chemical castration Immunocastration Principle Cutting, and removing the Rubber ring, pliers or Burdizzo Injection of chemical Using exogenous reproductive hormone gonads castration, blocking the scrotum drugs(Lactic acid, phenol, targets to produce antibodies in vivo, or spermatic cord, preventing benzyl alcohol, etc.), causing combined with endogenous hormones, blood flow and causing necrosis testicular parenchymal lesions, lowering testosterone levels and inhibiting testicular function suppressing testicular development and spermatogenesis Characteristics It demands someone skilled in Simple and economical to operate; Low stress, no drug residue, Suitable for both young and late castration techniques to operate suitable for young animals; inexpensive, less time production; strengthen immunity irreversible permanent castration consuming, easy to perform according to demand Castrated animals Pigs, Chickens, Cattle, Sheep, Cattle，Sheep Dog, Cat Pigs, Chickens, Sheep, Cattle, Mice, Foals Horses, Deer, Cat castration effect Irreversible, The castration is Irreversible, The castration is clean Irreversible; Insufficient Reversible, The castration effect is mild, clean and thorough and thorough injection or inaccurate injection and a small number of animal individuals site

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rsible, The castration effect is mild, clean and thorough and thorough injection or inaccurate injection and a small number of animal individuals site can lead to castration failure fail to respond effectively to antigens, resulting in immune failure Anesthesia Yes No No No Reaction Increase animal stress, produce Strong pain, long duration, stress No pain No pain pain, postoperative infection response and cause complications Side effect Prone to postoperative Improper operation leads to Inaccurate injection sites can Slight redness and inflammation at the bleeding, causing infection and cessation of blood supply to the lead to degeneration of other injection site complications bottom of the scrotum and tissues secondary tissue necrosis Animal welfare No No Yes Yes Cost Lower Lower High High Reference (7, 13–20) (21–24) (25, 26) (27–37) Frontiers in Veterinary Science 02 frontiersin.org Wang et al. 10.3389/fvets.2023.1248879 FIGURE 1 Effect of immunocastration on the hypothalamic–pituitary-testicular axis. The vaccines: 1–6, Immunocastration vaccine targeting Kisspeptin; 7–13, Immunocastration vaccine targeting GnRH; 14–15, Immunocastration vaccine targeting LH. maintenance of secondary sexual characteristics. GnRH 6. Current challenges for immunocastration induces a lot of GnRH-antibodies that neutralize GnRH-immunocastration in male endogenous GnRH, and the production of the antibody is a sustained animals biological effect. As a result, GnRH immunocastration consistently inhibit testicular or ovarian endocrine function, reducing hormone Immunocastration, often administered using the GnRH vaccine, has levels and reproductive activity, and associated odors, primarily undergone extensive investigation in male mammals and birds (Figure 2) skatole and

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s levels and reproductive activity, and associated odors, primarily undergone extensive investigation in male mammals and birds (Figure 2) skatole and androstenone (43–46). Immunization with GnRH leads (43, 57–61). Outcomes vary based on the animal species, animal age, to a substantial decrease in androstenedione and testosterone in male individual response, and immunization frequency (62). GnRH plays a animals (29, 32, 34, 47, 48). Consequently, European countries are crucial role in regulating gonadal development and function through the advocating for GnRH-immunocastration as a surgical castration pituitary gland. GnRH-immunocastration significantly decreases alternative, improving animal welfare. Immunocastration alleviates reproductive performance of male animals by inhibiting the development animal stress, reduces the risk of infection and complications testes. Studies have confirmed that immunizing male animals with associated with surgical castration, reduces pain and enhances animal GnRH can cause infertility, gonadal atrophy, and changes in meat quality welfare. GnRH-immunocastration is considered relatively safe by directly or indirectly acting of testosterone (63). alternative to surgical castration. 6.1. In male mammals 5. Current application of GnRH-immunocastration vaccine In mammals, the majority of research on GnRH- immunocastration has focused on male animals, and spermatogenesis Immunocastration is not limited to pork production but is also is inhibited after GnRH immunization. For example, immunizing employed in other livestock animals as an alternative to surgical male animals such as boars, bulls, stallions, rams, bucks, and rats with castration. Its key advantage lies in eliminating pain, wound infection GnRH vaccine leads to the suppression

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s, stallions, rams, bucks, and rats with castration. Its key advantage lies in eliminating pain, wound infection GnRH vaccine leads to the suppression of testicular, epididymal, and risks, and potential losses associated with castration (49). Now, several vas deferens development. This results in reduced sperm concentration commercial immunocastration products have been applied in animal in the testicles with low viability, constriction of the seminiferous production (Table 2). However, in Europe, Improvac is the sole tubules, and inhibition of spermatogonia and spermatoblast product approved for commercial use in pigs., yet its market share is production in the deep epithelium (29, 59, 60, 64–68). only 2.8% of all male pigs, despite EU approval almost a decade ago. At present, GnRH immunocastration is the most widely used in Belgium produces about 15% of the castration vaccine in Europe, boars. Androstenone is a male hormone that is formed in the cells of while globally, Brazil and Australia hold a market share of more than the Leydig and has a urine-like odor (69). Skatole is a metabolite of 50% (55, 56). the amino acid tryptophan with a fecal odor that is synthesized by Frontiers in Veterinary Science 03 frontiersin.org Wang et al. 10.3389/fvets.2023.1248879 TABLE 2 Several commercial immunocastration products on the market. Indication/Target Vaccine Supplier Formulation Doses Reference species Improvac/Valora Ceva Santé Animale, Immunocastration and Active substance: Gonadotropin Two subcutaneous (50) Libourne, France prevention boar taint/swine releasing factor (GnRF) analog- doses, at least 4 weeks protein conjugate +Adjuvant: apart. 300 mg Diethylaminoethyl (DEAE)-Dextran +2 mg Chlorocresol Bopriva Zoetis, Parsippany, NJ, Immunocastration, fertility 400 μg

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jugate +Adjuvant: apart. 300 mg Diethylaminoethyl (DEAE)-Dextran +2 mg Chlorocresol Bopriva Zoetis, Parsippany, NJ, Immunocastration, fertility 400 μg GnRH–protein conjugate Two doses at an (51) United States control/cattle interval of 3 weeks with 1 mL Bopriva Equity Zoetis Inc., Control of estrus in horses 300 μg Iscomatrix Two doses, at least (52) Parsipanny, New and deer (dipalmitoylphosphatidyl choline 4 weeks apart. Jersey, United States + Saponin Quil A + Cholesterol) + 200 μg GnRH– DT GonaCon USDA, Pacarello, ID, Fertility control/white-tailed GnRH–protein conjugate Single dose (53, 54) United States deer, wild boar, horses, feral concentration:1,000 μg/mL cattle, and bison, prairie and Concholepas concholepas feral dogs, feral cat both haemocyanin +AdjuVac™ sexes (mineral oil-based) +166 μg/mL Mycobacterium avium concentration FIGURE 2 GnRH-immunocastration effects across diverse animals. PUFA, polyunsaturated fatty acids; WHC, water holding capacity; BW, body weight; PH, Pondus Hydrogenii. microbial degradation in the colon (44, 70). Immunocastration has (45). However, due to the short duration of the castration effect, the been shown to effectively prevent the accumulation of boar taint in control of boars taint requires multiple doses of GnRH vaccine, and adipose tissue by reducing steroid hormone synthesis in the testes the second vaccination is often carried out 4–6 weeks before slaughter Frontiers in Veterinary Science 04 frontiersin.org Wang et al. 10.3389/fvets.2023.1248879 in production, and even the third dose of vaccine is required for behavior. Multiple vaccinations are necessary to counter this effect, slaughter pigs with higher age and weight to control boars odor, which which in turn escalates costs. Moreover, there are associated

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nter this effect, slaughter pigs with higher age and weight to control boars odor, which which in turn escalates costs. Moreover, there are associated increases the cost. disadvantages for farmers, including increased expenses for Meat quality is increasingly valued by consumers, so male purchasing produce and labor management, the risk of accidental self- livestock are castrated in production to improve meat quality. injection by farm workers, and uncertainty regarding consumer Currently, a large number of studies have focused on the improvement attitudes toward meat from pharmacologically castrated animals. of meat quality through immunocastration. GnRH immunocastration However, it’s important to note that immunocastration offers several reduces the accumulation of taint compounds in adipose tissue and advantages, such as reducing animal stress, lowering the risk of improves meat quality and carcass characteristics in male mammals infections and complications associated with surgical castration, (71). However, the latest study found that the slaughter rate of significantly improving animal welfare, and being relatively immunocastrated boars is lower than that of surgical castrated boars straightforward to implement in production settings. Therefore, and intact boars, as immunocastrated boars have heavier liver and immunocastration may remain a safe alternative to surgical castration kidneys (72). The abdomen of immune castrated pigs is fatter than in the future. that of entire boars, and the lean meat rate is similar to that of surgical In the future development of commercial castration vaccines, castrated pigs, both of which are lower than that of entire boars. particularly GnRH immunocastration vaccines for male animals, Therefore, to some extent, it will affect

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of which are lower than that of entire boars. particularly GnRH immunocastration vaccines for male animals, Therefore, to some extent, it will affect consumers’ choices. Bellies there should be an exploration of the construction of immunogens, from immunocastrated pigs are fatter and firmer than those from immune dosages, immune strategies, and timing. Attention should boars. In addition, although immunocastration increases be directed toward enhancing the effectiveness and prolonging the intramuscular fat content and reduces polyunsaturated fatty acids, the duration of immune response for these vaccines. Currently, research effect of improving intramuscular fat is still not as effective as surgical on GnRH vaccines primarily focuses on chemical synthesis of castration, and boars that undergo surgical castration have lower polypeptides, dual conjugate vaccines, DNA vaccines, tandem polyunsaturated fatty acids (73). Similarly, studies have shown that conjugate vaccines, among others. However, these approaches have compared to surgical castration, GnRH immunocastration improves their limitations. Considering the existing challenges with GnRH gene cattle weight, but there are no differences in beef pH, color, fat vaccines, it’s worth considering research and development of GnRH coverage, cooking loss, or tenderness (74). gene engineering vaccines and GnRH recombinant adenovirus vaccines in the future. In summary, the future focus of immunocastration vaccine development will revolve around creating 6.2. In male birds products with sustained immunogenicity, easy production, and stable effects. These advancements could hold the key to the future of The utilization and assessment of immunocastration vaccines in immunocastration vaccines. pigs has been extensively reported

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the key to the future of The utilization and assessment of immunocastration vaccines in immunocastration vaccines. pigs has been extensively reported (34, 48, 75). However, there is currently no commercially available vaccine for chickens. Recently, only three studies have investigated the use of the GnRH vaccine for Author contributions immunizing roosters. Quaresma and colleagues evaluated the effects of Improvac on the body and bone development, meat color, and CW: drafting the manuscript. YZ and CY: provision of study composition of roosters, and found that the color parameters of materials. MZ: conceptualization and supervision. All authors Improvac birds, such as brightness, red, and hue angle, were between contributed to the article and approved the submitted version. roosters and capons (5). In addition, i.c. Antunes et al. found that immunocastration had little effect on the fatty acid profile of broilers, but improved overall lipid markers in breast and leg meat to some Funding extent, which could partially enable GnRH immunization (6). Previous studies have shown that both caponization and ovariectomy This research was supported by National Key Research and likely improve the meat quality of the breast muscle based on the Development Projects of China (2021YFD1600200). objective indices of IMF, appearance (color), texture, and minor change of the fatty acid profile; ovariectomy improves flavor-related indices (76). In our study, we found that roosters inoculated with Conflict of interest Improvac had some effect on muscle development, but the effect was not completely satisfactory (77, 78). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of

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declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 7. Conclusions and perspective Immunocastration currently faces challenges related to Publisher’s note immunization failure. These challenges include significant variations in individual responses among immunized animals, insensitivity to All claims expressed in this article are solely those of the authors antigens in some individuals, failure to elicit an immune response, or and do not necessarily represent those of their affiliated organizations, a shorter duration of immune effect. This shorter duration leads to an or those of the publisher, the editors and the reviewers. Any product increase in testosterone concentration during the recovery period that may be evaluated in this article, or claim that may be made by its compared to the previous phase, resulting in a gradual return of sexual manufacturer, is not guaranteed or endorsed by the publisher. Frontiers in Veterinary Science 05 frontiersin.org Wang et al. 10.3389/fvets.2023.1248879 References 1. Calik J. Capon production–breeding stock, rooster castration and rearing methods, 25. Spruijt A, Kooistra H, Oei C, Vinke C, Schaefers-Okkens A, De Gier J. The and meat quality–a review. Ann Anim Sci. (2014) 14:769–77. doi: 10.2478/aoas-2014-0050 function of the pituitary-testicular axis in dogs prior to and following surgical or chemical castration with the GnRH-agonist deslorelin. Reprod Domes Anim. (2023) 2. Sokołowicz Z, Krawczyk J, Świątkiewicz S. 4. Quality of poultry meat from native 58:97–108. doi: 10.1111/rda.14266 chicken breeds–a review. Ann Anim Sci. (2016) 16:347–68. doi: 10.1515/aoas-2016-0004 26. Hami M, Veshkini A, Jahandideh

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