Journal of Canine Development & Research 2018 Vol (14) 16-27 y Journal of Canine Development & Research ISSN : 0973-3272 REVIEW ARTICLE website : www,jedrindia.com DOGS - Th NON SURGICAL FERTILITY CONTROL IN MALE AND FEMALE e Current Status 4G Sasi! , Trilok Gocher’, G.N. Purohit’ and Rajendra Mehra Deparetment of Veterinary Gynaecology and Obstetrics College of Veterinary and Animal Science, Bikaner-334001, Rajasthan India "MVSc Scholar *professor & Head *Corresponding author e- mail id- gosasivet@gmail.com ‘Mobile -9944343297 ARTICLE HISTORY ABSTRACT Received Revised Accepted 2 17052019 02.06.2019 +: 20.062019 Key words : Contraception Dogs Estrus Fertility control GnRH hormone Testosterone ‘on surgical fertility control can resultin either sterilization or temporary contraception and could offera cheaper way to keep dog population under control. About 75% of dogs worldwide are free to roam and reproduce, thus creating locally over- abundant populations (Massei et al,, 2013). Problems caused by roaming dogs include diseases transmitted to livestock and humans, predation on livestock, attacks on humans, road traffic accidents, and nuisance behavior, Traditional neutering of companion animals has been accomplished through surgical methods of sterilization, namely ovariohysterectomy (spaying) and orchidectomy (castration), However, not all The present review article analyse the methods of non-surgical control of fertility in dogs like Hormone agonists and antagonists, immunocontraception , cytotoxin conjugates, chemical targeting, contraception devices and gene therapy. owners have their pets surgically sterilized. Reversible pubertal postponement is usually required for genetically valuable pure-bred dogs intended for working and/or breeding purposes. Inasurvey in Sao Paulo, Brazil, 56.5% of owners of adopted shelter dogs were against surgical Sterilization, citing compassion (58.1%); unnecessary procedure (11.4%), cost (9.5%), and behavior change (4.8%) as reasons against this oe of limiting pet reproduction (Soto etal., ). For the purposes of this discussion, For be ton willbe de®ned as areversible method forblocking fertility (and will notinclude pregnancy ermination). Pharmacologic methods of 16 Scanned with CamScannerJournal of Canine Development & Research 2018 contraception and sterilization can be safe, reliable and reversible. The aims of this review were to evaluate the available approaches for temporary and permanent fertility control in male and female dogs. Methods of the non-surgical control of fertility in dogs can be classified in to following sub groups : 1, Hormone agonists and antagonists (a) GnRH agonist (b) GnRH antagonist (©) Progestin (@ Androgens (©)Prolactin 2.Immunocontraception (@) Immunization against GnRH (b) Luteinizing hormone receptorimmunization (©) Zona pellucida immunization (@) Sperm antigen immunization 3. Cytotoxin conjugates (@) GnRH toxin conjugates 4, Chemical targeting (a)Embelin (Embelia ribes) (@)Alpha-chlorohydrin (b) Ketoconazole 5. Contraception devices (a) Barrier contraception devices in dogs 6.Gene therapy (a) Gene silenceing technology 1. Hormone agonists and antagonists (a) GnRH agonists GnRH agonists act by a two-step mechanism. First, their agonist properties on the pituitary will cause marked LH (luteinizing hormone) and FSH (follicle-stimulating hormone) secretion into the blood- stream, accompanied by an increase in the concentrations of sex steroid hormones (Fontaine and Fontbonne, 2011). Then, in case of constant administration, GnRH agonists will lead to pituitary desensitization and FSH and LH levels will collapse, That is called "flare up effect”. Inrecent years, effective low-dose, slow-release implants containing potent agonists (superagonists) have been commercialized for use in veterinary medicine in the European Union (EU), such as deslorelin and azagly- nafarelin (Herbert and Trigg 2005, Gobello, 2007). Deslorelin is a gonadotrophin- releasing hormone (GnRH) analogue that has a longer half-life and is up (0200 times more potent than natural GnRH (Herbert and Trigg 2005; Kutzler 2007). GnRH agonists use in male dogs ‘The first report of chemical sterilization in a dog was published in 1984 (Vickery et al., 1984). Deslorelin acetate (Suprelorin®, Virbac) is a GnRH agonist developed as an implant, whose ‘main indicationis transitory contraception in adult ‘male dogs. Although the original stimulating effect causes serum FSH and LH concentrations to rise from 20 min after treatment , with a peak after 40 min (Junaidi er al, 2007), these values return to normal inthe nextS hours then collapse an average 2-9 days later (Vickery et al,, 1984; Hoffmann, 2005; Junaidi er al, 2007). However, with a 4.7- mg implant, the blood testosterone concentration remains low for an average of 400 days in dogs weighing <10 kg, whereas in dogs weighing more than 25 kg, ithas proven impossible to suppress testosterone for more than 400 days (Trigg eral, 2006). Implants with 9.4-mg deslorelin were effective in reducing testosterone to-11 months (Saxena et al., 2002) with a return to a normal, physiologic reproductive state after antibody titers declined. (b) Zona pellucida immunization receptor Immunocontraception is the process using the 2 Scanned with CamScannerJournal of Canine Development & Research 2018 body's own immune system to block fertility. In the dog secretion of the ZP originates from the oocyte, as demonstrated by transmission electron microscopy and immune gold staining (Barber et al, 2001). The ZP proteins mediate species specific spermatozoa binding, leading toacrosome reaction and in consequence allowing the fusion of the sperm with the oocyte membrane. Itis also involved in the polyspermy block (Aitken et al., 1996; Gupta er al., 2009). Three glycoproteins produce the canine ZP matrix (ZP2, ZP3 and ZP4). The principle of ZP vaccine is that antibodies against ZP proteins would block the binding of the sperm preventing all the foreseen events and maybe it will also affect folliculogenesis (Gupta et al, 2011). Infertility caused by porcine ZP3 seems to be through ovulation failure rather than impairment of sperm-binding sites, as progesterone concentration did not increase during oestrus in vaccinated bitches (Mahi-Brown et al., 1982). Immunization against ZP2 failed to prevent pregnancy in mated bitches; therefore, canine ZP2 is not a good candidate for developing contraceptive vaccine (Gupta et al., 2011). Porcine zona pellucida (pZP)- based product (SpayVVac, North Saanich, BC, Canada; SpayVac- for-Wildlife, Canada) was only available in the United States in the early 2000s. pZP has not been a consistently successful contraceptive when applied to dogs (Kutzler and Wood, 2006). The primary problem seems to have been identifying an adjuvant that renders the vaccine effective without generating unacceptable side effects, such asinjection site reactions (Munks, 2012). (©) Sperm antigen immunization Spermatozoa are very antigenic and could be effective for males and females. Sperm antigens are an excellent target for contraceptive vaccines because these proteins are viewed as "foreign’ to the immune system of both male and the female (Talwar and Naz, 1981). Anti-sperm antibodies affect both fertilization and fertility. However, the entire spermatozoon cannot be used for vaccine development because it shares several antigens ‘with other somatic cells (Naz ef al., 2005). Therefore, research has focused on delineating appropriate sperm: fic epitopes that would increase immunogenicity (specifically within the reproductive tract) and efficacy. Lactate dehydrogenase (LDH-C4) and acrosin have been jsolated as two of the main sperm-specific antigens (Talwar and Naz, 1981). To date, sperm antigen immunization has not resulted in a satisfactory control of fertility (Naz et al., 2005). 3. Cytotoxin conjugates (a) GnRH toxin conjugates In addition to targeting GnRH using immunocontraception, toxins conjugated to GnRH can be used to disrupt the hypothalamic-pituitary- gonadal axis, Toxins must be carefully selected as, tobe safe in other tissues without GnRH receptors. Arrecent study has attempted to inhibit reproductive function in male dogs with the use of GnRH conjugated to pokeweed antiviral protein (PAP) (100 mg/kg) (Sabeur et al., 2003). GnRH-PAP caused a reduction in basal LH and testosterone concentrations and testes size. By week 20 post treatment basal LH and_ testosterone concentrations showed evidence of recovery (Sabeur et al., 2003). 4. Chemical targeting (a) Embelin (Embelia ribes) Emelin isan indigenous’ benzoquinone plant used inAsia for the prevention of pregnancy Dixit and Bhargava, 1983). Oral treatment of embelin g 7 mg/kg every other day for 100 days) in male dos caused a significant decrease in testicular — and Variable degrees of spermatogenic ofp nly atthe spermatocyte state (absence Post-meiotic cells) (Dixit and Bhargava, 1983). 2 Scanned with CamScannerJournal of Canine Development & Research 2018 Within 8 months following discontinuation of embelin ingestion, normal spermatogenesis was restored. (b)Alpha-chlorohydrin Alpha-chlorohydrin is analkylating agent that causes of depletion spermatogenic elements from the seminiferous tubules. A single high dose (70 mg/kg) of a-chlorohydrin or chronic administration (Smg/kg body wt for 30days) inhibited spermatogenesis within 33 days in dogs. These effects were reversible within 100 days following treatment (Dixit et al., 1975). (c) Ketoconazole Ketoconazole is an inhibitor of cellular division and within 4-24 h of oral administration of ketoconazole (50-246 mg/kg) to male dogs, the motility of ejaculated sperm declined at an accelerated rate compared with control samples from the same animals (Vickery etal, 1985). The decline in spermatozoa motility was correlated with the presence of ketoconazole in the seminal plasma. Athigh doses, ketoconazole was poorly tolerated by the gastrointestinal tract and can cause hepatoxicity (Heiberg and Svejgaard, 1981). However, similar spermatostatic effects occurred following treatment with other orally administered 1 -substituted imidazole compounds in dogs without gastrointestinal and hepatic side effects (Good pasture et al., 1987). 5. Contraception devices (a) Barrier contraception devices in dogs Contraceptive vaginal lubricants used in women have been tested with canine semen. For example, RS-37367 is a non-surfactant imidazole oxalate with high spermatostatic potency when evaluated using ejaculated dog spermatozoa (Vickery et al., 1983). Exposure of canine spermatozoa to RS- 37367 for 5 min resulted in progressive immobilization that was not reversible even with extensive washing of the sperm (Vickery et al., 1983). In one study, 50% of bitches fitted with the device were bred and 25% became pregnant (Wildt and Seager., 1977). An IUD (Two intrauterine devices (IUDs- Y shaped) for canine contraception, commercially marketed by Biotumer Argentina SA, was highly effective in preventing pregnancy after breeding (Volpe eral., 2001). The manufacturer recommends leaving the IUD in place for? year (this isthe effective life of the electrolytic copper) (Volpe et al, 2001). Over 2-year interval, no side effects were observed, except for one bitch that developed persistent estrus that resolved when the device was removed (Volpe etal, 2001). The other IUD designed for dogs, Dog spiral (www.dogspiral.vet), consists of stainless steel spiral coated with copper, silver, or gold. However, IUDs are not practical for use in dogs due to the difficulty of transcervical cannulation. The general concem about the use of IUDs in dogs is the potential for a foreign body reaction resulting in uterine pathology (Nomura, 1997) because the basic mode of action of IUDs is to provoke a local inflammatory response. 6. Gene therapy (a) Gene silenceing technology ‘The gene silencing technology consists of using RNA interference to silence a gene required for fertility. The small inhibitory RNAs are delivered to the target cell through vectors such as the adeno- associated virus, as performed for gene therapy. In both rats and monkeys, good results were achieved by disrupting cyclicity. However, the delivery systems targeting specically the hypothalamus upon systemic administration still have to be found (Dissen et al., 2012 a,b). Conclusion It has been mentioned that some form of 23 Scanned with CamScannerJournal of Canine Development & Research 2018 contraception isa social necessity to prevent the production of unwanted pups and this highlights the variety of situations which have to be considered. Even when a decision has been reached, it may have to be modified because, for instance, it is found that a particular client is incapable of maintaining a dose regimen. 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