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Theriogenology 66 (2006) 126–134 www.journals.elsevierhealth.com/periodicals/the Contraception in felids Linda Munson * Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, 1 Shields Ave., Davis, CA 95616, USA Abstract Contraceptives are used for reversible reproductive control in genetically valuable wild felids, as permanent reproductive control in generic wild felids, and as an economically practicable means to control feral cats. The progestin contraceptives, megestrol acetate, melengesterol acetate, medroxyprogesterone acetate, and levonorgestrol (administered orally, in implants, or as depot injections), are effective in preventing pregnancy. However, long-term use is associated with endometrial hyperplasia, endometrial cancer, and mammary cancer. Gonadotropin releasing hormone analogs or luteinizing hormone vaccines that achieve contraception by suppressing ovarian or testicular function, do not have the adverse health effects of progestins. However, reliable reversibility has not been demonstrated, and male secondary sex characteristics may be suppressed. Bisdiamines also inhibit spermatogenesis and lower circulating testosterone concentrations in treated male cats. Porcine zona pellucida vaccines are ineffective contraceptives in felids and may cause serious health problems when combined with some adjuvants. Because of the limited availability of nonprogestin contraceptives and side effects associated with some agents, widespread application of contraception to felids has been curtailed. More non-steroidal methods of contraception should be tested in the future to provide alternatives for controlling reproduction in felids. Furthermore, all empirical information on contraceptive safety and efficacy should be assembled in a database to provide the knowledge needed by veterinarians and managers to determine benefits/risks of currently available contraceptives in felids, both domestic and wild. # 2006 Elsevier Inc. All rights reserved. Keywords: Contraception; Felid; Progestins; Deslorelin; Bisdiamines 1. Introduction The fecundity of many felid species has necessitated sterilization or contraception to prevent overpopulation. Whereas ovariohysterectomy or ovariectomy alone has been the method of choice for most domestic cats, reproductive management of threatened or endangered zoo-maintained felids requires safe and reversible contraception. The goal of felid conservation breeding programs in zoos is to retain at least 90% of the genetic diversity of a species over the next 100 years. Because space and resources are limited, zoo managers require * Tel.: +1 530 754 7567; fax: +1 530 752 3349. E-mail address: [email protected]. 0093-691X/$ – see front matter # 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.theriogenology.2006.03.016 contraception to limit reproduction of less geneticallyvaluable felids and to implement the conservation goals of species survival plans. Contraception as a form of reproduction control also is increasing in free-living wild felid and feral domestic cat populations, because of its preference by the public over lethal methods. If easily-delivered, safe, and effective contraceptives were readily available for domestic cats, catteries producing animals for the pet trade and some pet owners likely also would choose these methods over surgical sterilization. However, to date, widespread use of contraceptives has been limited in felids by safety concerns and the lack of effective choices. Few contraceptives are commercially available, and none have been approved by the Federal Drug Administration (FDA) for contraceptive use in felids. Thus, all L. Munson / Theriogenology 66 (2006) 126–134 contraceptive use in cats is extra-label (for FDA-approved drugs) or experimental (for unapproved methods). Most contraceptives were developed for humans and have only been tested for efficacy and safety in that species or a few laboratory animal species (usually rodents, the domestic dog, or non-human primates) [1]. Because reproductive function in the female cat (characterized by seasonal polyestrus and induced ovulation), differs considerably from that of the tested species, the effects of human contraceptives on felids are unknown. Drug metabolism in cats also differs from humans [2,3]. Therefore, whereas any surgical procedure or drug administration carries some risk, extra-label drug use in felids may pose special problems. Extra-label use of contraceptives will always be required for wild felids because controlled clinical trials are virtually impossible to conduct due to small population size and geographic disparity in location. While such clinical trials are feasible in the domestic cat, such testing requires considerable expense. Although some contraceptives have been tested for use in domestic cats (both as the target species and as a model for wild felids [4,5], conducting more studies should be a priority and ultimately would promote more large-scale contraceptive use in cats. Several excellent (albeit outdated) reviews of contraception in cats have been published [6–10]. This review intends to provide an update on current contraceptive methods and research in felids as a taxonomic group including both wild and domestic felids. While 127 permanent reproductive control can also be accomplished through sterilization, only reversible methods for preventing pregnancy will be included in this review. 2. General methods of preventing pregnancy Contraception in its broadest sense is preventing the birth of offspring while maintaining the potential for fertility. Contraception can be achieved by preventing gamete formation, conception, or implantation, as well as by disrupting pregnancy (causing resorption or abortion). Contraceptives are more widely used in females where the intricately orchestrated events leading to oogenesis, ovulation, gamete transport, and implantation are more easily disrupted than is spermatogenesis in the male. Reproductive cyclicity and gametogenesis in both sexes can be disrupted by administrating exogenous hormones that interfere with the normal hypothalamic/pituitary/gonadal axis, prevent hormonal synthesis or release, or interfere with endocrine activity at the tissue level. Spermatogenesis also can be directed arrested by some chemicals. Fertilization can be averted by physically blocking the reproductive tract, altering the uterine milieu necessary for sperm movement, or interfering with sperm–egg binding necessary for fertilization. Specific examples of these concepts are outlined below, and the commerically-available contraceptives are listed in Table 1. Table 1 Commercially-available contraceptives for felids Contraceptive Brand name Source Method of delivery Progestins Megestrol acetate Megestrol acetate Medroxyprogesterone acetate Medroxyprogesterone acetate Melengesterol acetate Levonorgestrol Ovaban1 Megace1 Provera1 Depo-Provera1 Nonea Norplant1 Schering-Plough Bristol-Meyers Squibb Pfizer Inc. Pfizer Inc. ZooPharm Wyeth-Ayerst PO PO PO IM Implant Implant Androgen Mibolerone a Cheque1 Drops Pfizer Inc. PO GnRH analogs Deslorelin Leuprolide acetate Leuprolide acetate Suprelorin1 None Lupron Depot1 Peptech Animal Health ZooPharm TAP Pharmaceuticals Implant IM depot IM depot Immunocontraceptive Porcine zona pellucida vaccineb Porcine zona pellucida vaccineb SpayVac1 None TerraMar Environmental Research Ltd Zoo Montana IM IM Chemical contraceptive Bisdiamine WIN 18,446 Fertilysin1 SAF Bulk Chemicals, Milwaukee, WI PO a b Mibolerone can be hepatotoxic and thyrotoxic in felids. PZP vaccines have not been proven effective in felids. 128 L. Munson / Theriogenology 66 (2006) 126–134 3. Methods of administration Contraceptives for felids are available as implants, depot injections, pills or liquid for oral administration, powder for mixing with food, or as vaccines. Regimens may differ according to the timing of first treatment, whether coinciding with the active reproductive period, preceding this period, or during anestrus. Many felid species are seasonally polyestrous [11], even in a controlled laboratory environment (Munson, unpublished). Therefore, contraception may be necessary only during the breeding season. However, it is unknown if reproductive function will simply be postponed, leading to fertility after contraception withdrawal, and the potential birth of offspring during a less optimal season of the year for raising young. To prevent this uncertainty and complication, most contraceptives are given to felids throughout the period in which reproductive suppression is desired. Ideally, the treatment regimen is initiated during anestrus to minimize the dose needed for reproductive suppression and to avert exposure to endogenous steroids that can cause lesions in reproductive organs. 4. General safety concerns Designing contraceptives that are effective and reversible, yet safe, has been the primary challenge for felids. Agents that disrupt endocrine function sufficiently to halt reproduction have the potential to adversely affect hormone target tissues and disturb metabolic homeostasis. Immunocontraceptives that target egg and sperm antigens have the potential to incite immune-mediated damage in other organs [12,13]. Chemicals that block spermatogenesis are rarely specific to this process and can cause toxicity in other organs [14]. For each population or individual animal, these potential and actual risks need to be assessed and then weighed against the contraceptive benefits. The specific side effects in felids are included under each category of contraception reviewed below. 5. Female contraceptives 5.1. Contraceptives that disrupt hormonal cyclicity, folliculogenesis, gamete transport, or endometrial receptivity 5.1.1. Progestins Commercially available progestin contraceptives include megestrol acetate [MA; Ovaban1 (tablets), Schering-Plough, Lafayette, NJ; Megace1 (oral sus- pension), Bristol-Meyers Squibb, Princeton, NJ], medroxyprogesterone acetate [MPA; Provera1 (oral tablets) or Depo-Provera1 (injectable), Pfizer Inc., Groton, CT], melengestrol acetate [MGA implant, ZooPharm, Fort Collins, CO), and levonorgestrel [LNG, Norplant1 (implant), Wyeth-Ayerst, Chazy, NY]. The specific mechanism (or mechanisms) by which progestins effectuate contraception is unknown. Proposed mechanisms include: (1) negative feedback on the hypothalamus and pituitary gland leading to suppression of GnRH, FSH, or LH secretion and failure of folliculogenesis and/or ovulation; (2) altered motility of the tubular tract causing failed oocyte transport and fertilization; or (3) altered receptivity of the endometrium resulting in implantation failure. Neither the potent progestin, MGA, in zoo felids [15], nor LNG in the domestic cat [16] suppressed follicular development or ovulation, suggesting that hypothalamic and pituitary suppression is not the means by which these agents effect contraception. In general, progestins promote endometrial growth and secretion, as well as smooth muscle relaxation in the uterus [17–19]. Therefore, altered uterine motility and endometrial receptivity are the likely mechanisms for progestin-induced contraception. Megestrol acetate has been used to suppress estrus in domestic cats and to reduce litter numbers in feral cats in Europe [20–24]. This product also has been used as an oral contraceptive in zoo-held felids [American Zoo and Aquarium Association Contraceptive Advisory Group (AZACAG) Database]. Treatment regimens differ depending on whether treatment is initiated during anestrus, estrus, or diestrus. In the anestrous domestic cat, an initial dose of 2.5–5 mg/day for 3–5 days has been recommended, followed by 2.5–5 mg/ week [7,21,25–27]. Cats in estrus may require a higher dose (5 mg/day until estrus stops, then 2.5–5 mg/week, PO) [25]. The recommended dose for diestrous cats is 2.5 mg/day PO [27]. Treated cats should be separated from adult males for at least 1 week to assure efficacy. Recommended duration of treatment ranges from 2 to18 months, followed by a period of normal estrous cycles before treatment is repeated [25]. Most MA-treated cats return to estrus within a few days. Medroxyprogesterone acetate has been used as a contraceptive for the domestic cat (companion or feral), as well as felids maintained in zoos [8,22,28]. An oral dose of 5 mg/day or a 25–100 mg injection is recommended for the domestic cat [7]. Estrus is suppressed for 2–4 months using the injectable form [7], although treatment every 6 months has also been recommended [22]. In zoo felids, an injection of 5 mg/ L. Munson / Theriogenology 66 (2006) 126–134 kg body weight is recommended every 2 months (AZACAG recommendations at: http://www.stlzoo.org/ contraception). A MPA dose of 1000 mg (IM) followed by a 500 mg (total) injectable bolus every 3 months also has been effective in suppressing estrus in lions [29]. Melengestrol acetate has been the most widely used contraceptive in zoo felids, because it provides longterm, reliable and reversible contraception in all zoo felid species tested (AZACAG dtabase) [29]. MGA also has been used to control reproduction in free-ranging lions [30]. This agent is administered in a silastic implant (Dow Corning, Hemlock, Michigan 48626), placed SC or IM, providing continual exposure to a potent progestin [31]. This practical method of delivery has been invaluable for reproductive management of non-domestic felids. If left in place, a single implant (containing 3–40 mg MGA/kg body weight; usual dose of 20 mg/kg) can prevent pregnancy reliably for at least 2 years. Smaller cats appear to require a higher dosage (E. Plotka, personal communication). Levonorgestrel (16 mg in a silastic implant) has been used to prevent pregnancy in domestic cats for up to 1 year [16]. Nine of ten LNG-treated cats subsequently became pregnant, demonstrating reversibility after a single year of treatment. Safety and reversibility have not been evaluated after long-term use in a controlled study. Although progestins have proven to be reliable and affordable contraceptives for felids, there have been significant adverse reactions in every species evaluated, a factor that should be considered before use. The same activities that make progestins effective contraceptives (by altering endometrial growth and glandular secretion and by promoting myometrial relaxation) are the basis for the serious side effects noted in many progestintreated felids. These effects may be confounded and accentuated by concurrent exposure to endogenous estrogens (that up-regulate progesterone receptors) and/ or progesterone [32,33], because many progestintreated felids continue to cycle and ovulate [15]. Progestins also alter glucose metabolism, suppress adrenal cortical function, and promote growth of the mammary gland. Together, these actions can have profound effects on general and reproductive health. Although most progestin-induced uterine lesions only cause infertility, mammary and uterine cancers, pyometra, or diabetes can be fatal. In the domestic cat, MA treatment has been associated with development of endometrial hyperplasia and pyometra [22,34,35]. MA treatment also has been associated with fibroadenomatous mammary gland hyperplasia [25,36–39], a change that regresses 129 when treatment is discontinued. Additionally, MA and MPA treatment increases the risk of mammary cancer in cats [40–42], as well as hair loss and xanthomatosis [22,39,43]. Some young adult cats treated with levonorgestrel had mild endometrial lesions, but no changes in mammary tissue after 1 year of exposure [16]. In zoo felids, MGA or MA exposure significantly increased the risk of developing marked endometrial hyperplasia, endometrial mineralization and hydrometra [44–46]. Although not life-threatening, these conditions would likely cause infertility and are irreversible. Furthermore, felids treated with MGA developed more serious endometrial hyperplasia earlier in life than untreated animals [44]. Some MGA-treated felids with endometrial hyperplasia also developed endometrial polyps, endometritis and pyometra, [44] conditions that likely would also result in infertility. Furthermore, most felids with endometrial cancer and leiomyosarcoma have been treated earlier with MGA or MA [47–50], suggesting a causative role of progestins in these cancers. MGA exposure also increases the risk of zoo felids developing mammary cancers, most of which progress rapidly, metastasize widely, and are fatal [51]. Metabolic abnormalities (such as diabetes) occur in some progestin-treated domestic and wild cats [46,50] because these steroids can antagonize the actions of insulin, elevate growth hormone and have direct glucocorticoid effects [22,46,52–54], all of which can increase serum glucose [16,55] and cause glucosuria [56]. Glucocorticoid suppression has been reported in MA- and MPA-treated, but not MGA- or LNG-treated cats [29,52,57]. Androgenization, manifested by the development of a mane, has also occurred in a few progestin-treated lionesses [29]. Weight gain also occurs in progestin-treated felids [16,39]. Whether this is a direct effect of the anabolic actions of progestins or secondary to decreased activity from estrus suppression is not known. 5.1.2. Mibolerone Mibolerone (Cheque1 Drops: Pfizer) is an androgen that blocks pituitary LH release, thereby suppressing gonadal function [27]. Mibolerone at an oral dose of 7– 8 mg/day has suppressed estrus in captive jaguars, lions and leopards [58]. However, concerns about increased aggression and masculinization (including mane growth in female lions) have limited its use in zoo animals [27,58]. In the domestic cat, a dose of 50 mg/day prevents estrus, but causes masculinization [59], while lower doses have been ineffective [59]. Because mibolerone also can be hepatotoxic and thyrotoxic in 130 L. Munson / Theriogenology 66 (2006) 126–134 cats at the contraceptive dose, its use in felids has been discouraged [60]. 5.2. Contraceptives that disrupt the hypothalamicpituitary-gonadal axis 5.2.1. GnRH agonists Steroid hormones of ovarian derivation or from exogenous sources all promote pathological growth of endometrial and mammary tissue in felids. So a contraceptive that suppresses ovarian steroid production would be ideal for cats. One such candidate is the GnRH agonists, small-sized proteins that, when given exogenously, override endogenous pulsatile GnRH that normally regulates pituitary FSH and LH secretion. Treatment with gonadotropin agonists initially provokes folliculogenesis and ovulation, which then is followed by protracted ovarian quiescence. There are two commercial sources of GnRH agonist, deslorelin [Suprelorin1 (implant), Peptech Animal Health, Australia] and leuprolide acetate [luprolide (slow-release injectable) ZooPharm; Lupron Depot1 (injectable),TAP Pharmaceuticals]. Deslorelin implants are available in 5 mg (for animals 30 kg) and 10 mg (for animals 30 kg) doses. Five mg implants have been effective for 6–2 months, and 10 mg implants for up to 2 years in zooheld felids (AZACAG recommendations). Deslorelin has been proven effective and safe in the domestic cat, and only the limited availability restricts more widespread use [4]. This product, delivered in a 6 mg subcutaneous implant to 10 domestic cats, effectively suppressed ovarian follicular activity for 4–14 months (the latter coinciding with study termination). No adverse effects were noted except weight gain. However, eight of 10 cats did not fully return to normal cycling by the end of the study [4]. Therefore, although GnRH agonists have not been associated with significant adverse health effects in the cat, it remains unclear if reproductive cyclity returns after the administered dose is depleted. Deslorelin is now being used in captive-held wild felids, such as the clouded leopard (Neofelis nebulosa) and cheetah (Acinoynx jubatus), and no adverse effects have been noted to date [61,62]. However, the priority for GnRH agonist research is a prospective and systematic assessment of reversibility in both the domestic cat and representative wild felid species. 5.2.2. LH receptor vaccination There has been one study examining the potential of vaccinating the domestic cat against the LH receptor using a silastic, subcutaneous implant [63]. Estrous behavior was suppressed and corpus luteum function was reduced for 395–516 days without affecting normal estradiol concentrations [63]. Further studies testing the efficacy, safety and reversibility of this immunocontraceptive approach are warranted. 5.3. Contraceptives that prevent sperm–egg interactions Most immunocontraceptives tested in felids have targeted the zona pellucida (ZP) antigens that mediate sperm binding to the egg (native porcine zona pellucida, PZP; Jay Kirkpatrick, Zoo Montana; SpayVac1, TerraMar Environmental Research Ltd.) [64–67]. A disadvantage of this technique is that the cats continue to cycle, producing endogenous ovarian steroids that increase the risk of uterine and mammary gland disease [42,44,68]. The immunogenicity of ZPs also is low because these antigens are viewed by the immune system as ‘‘self’’. To enhance the immune response, they are usually administered with potent adjuvants [69,70], some of which have been associated with sarcomas in domestic cats [71]. Several clinical trials testing the efficacy of PZP vaccines have been conducted in the domestic cat, and poor contraceptive success has been achieved despite a robust antibody response. One study tested SpayVac1 with Freund’s complete adjuvant (FCA) or alum in 8–12 week old domestic kittens, and all vaccinated animals became pregnant in spite of high anti-PZP titers [64]. In another study using PZP with FCA in adult cats, only one of five became pregnant [65]. In a third trial using carbopol as the adjuvant, equivalent numbers of vaccinated and control cats became pregnant (L. Munson, unpublished). Taken together, these results indicate that PZP vaccination does not provide adequate contraception in the domestic cat. Lack of efficacy may be due to antigenic differences between feline and porcine ZPs that limit the blocking effect of anti-PZP antibodies in the cat [72]. Several safety trials with PZP vaccines have also been conducted in both zoo felids and the domestic cat to determine if anti-PZP antibodies cause immunemediated damage to the ovaries [66,67]. Although no ovarian lesions were noted, marked local reactions occurred at the vaccination site in all individuals vaccinated with PZP in FCA or Freund’s incomplete adjuvant [66,67]. Some domestic cats injected with FCA with or without PZP developed systemic granulomas and associated hypercalcemia [66]. Poor efficacy and considerable safety concerns make PZP an L. Munson / Theriogenology 66 (2006) 126–134 unattractive alternative for controlling reproduction in felids. 6. Male contraceptives 6.1. Contraceptives that arrest spermatogenesis by disrupting the hypothalamic/pituitary/testiscular axis The GnRH agonists, deslorelin [Suprelorin1 (implant)] and leuprolide acetate [luprolide (slowrelease injectable)] have been tested for contraceptive effects in the male domestic cat and certain wild felids. Both spermatogenesis and testosterone production depend on pituitary LH and FSH secretion, which is suppressed in the presence of continuously high GnRH agonist concentrations. Spermatogenic arrest has been achieved in domestic cats using deslorelin, and a 6–12 mg deslorelin implant successfully inhibits fertility in the cheetah and lion after a 6 week delay, largely by suppressing spermatogenesis [62]. In these felids, 5 mg implants have been effective for 6–12 months and 10 mg implants for up to 2 years (AZACAG recommendations). Male aggressive behaviors are reduced in some animals, but not territorial behavior (AZACAG database). Testosterone-dependent secondary sex characteristics, such as mane growth in lions, were also diminished. The latter effect may be of concern to some managers who desire majestic-appearing lions. Finally, because males treated with these GnRH agonists may continue to copulate, co-housed females will remain at risk for developing diseases associated with prolonged endogenous progestin exposure. 6.2. Chemical contraceptives that directly arrest spermatogenesis Several chemicals, such as gossypol, dinitropyrroles and carbamates, can cause male infertility through multiple mechanisms [14], but most have other toxic effects, making them unacceptable as contraceptives. The bisdiamine compounds (amebicidal drugs that target male germinal epithelium) are an exception and appear to have no harmful systemic effects [73]. A safety and efficacy trial in the male domestic cat demonstrated that 150 mg/kg of the bisdiamine WIN 18,446 (Fertilysin1, SAF Bulk Chemicals, Milwaukee, WI, USA) administered daily in food causes near complete spermatogenic arrest in all treated individuals without damage to spermatogonia [5]. These effects were completely reversible, 131 and no adverse effects on general health, blood parameters or behavior were noted. However, serum testosterone concentrations were significantly lower in treated versus control males. Whether this reduction was sufficient to cause loss of secondary sex characteristics is unknown. Testosterone concentrations returned to normative levels within 3 months of treatment cessation. Although bisdiamines appear safe and effective for male cats, they can induce serious teratogenic effects in pregnant females [74], so administration must be done with care to assure only males receive the drug. The final limitation to this approach is that the cost of bisdiamines is currently prohibitive for most veterinary uses. 6.3. Contraceptives that block sperm outflow: vas plugs Occlusive silicone casts of the vas deferens have been tested for felids as a reversible alternative to vasectomy (L. Zaneveld, personal communication). Although sperm outflow is blocked (thereby achieving the contraceptive goal), local inflammatory reactions occur due to exuded sperm at the site of plug placement, making reversibility unlikely (L. Munson, unpublished). Furthermore, the necessity for skilled microsurgery makes application of this technique impractical. 7. The AZA Wildlife Contraception Center and the Contraceptive Health Surveillance Center The AZA Wildlife Contraception Center at the St. Louis Zoo http://www.stlzoo.org/contraception and the Contraceptive Health Surveillance Center at the University of California at Davis centralize information on the efficacy and adverse effects of contraceptives in zoo and wild animals. The Contraceptive Health Surveillance Center also maintains a database of published information on adverse reactions in domestic animals. Information on contraceptive safety is obtained from pathological evaluations of reproductive tracts from both untreated and contraceptive-treated zoo and wild mammals. Lesion prevalence and severity are then compared between treated and untreated populations to determine if contraceptive exposure is a risk factor for lesion development. Through this surveillance, spontaneous gynecologic diseases can be distinguished from those exacerbated by exogenous compounds. Protocols and forms for submission can be found at the American Association of Zoo Veterinarians website: http:// www.aazv.org/secure/cagpathologysurvey.htm. 132 L. Munson / Theriogenology 66 (2006) 126–134 8. Summary Progestins continue to be the most available and affordable contraceptive for females, but serious side effects resulting in permanent infertility or even death, are common. The PZP vaccines used to date do not appear to be effective, and the adjuvants may not be well tolerated in cats. However, prospects for safe and effective felid contraception for both females and males have improved over the last decade as a result of clinical trials testing GnRH analogs, LH-R vaccines, and bisdiamines. Commercial availability of these nonprogestin methods continues to be a problem, because manufacturing and marketing costs can rarely be covered by the limited veterinary market. However, smaller companies, such as ZooPharm and Peptech, are responding to this important need for safer, effective felid contraceptives. Clinical trials testing the efficacy and safety of nonsteroid contraceptives for male cats, such as indenopyridines, should be a high priority for research. Clinical trials assessing contraceptive safety of new bioengineered contraceptives should also be conducted in cats as these drugs become available. The domestic cat serves as a valuable model for wild felids in any contraceptive trial. Surveillance for immediate as well as long-term adverse effects of currently available contraceptives also should be conducted at the national/international level to determine contraceptive safety through off-label use outside of a formal clinical trial. 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