Julie K. Levy, DVM, PhD, DACVIM
Maddie's Shelter Medicine Program College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
The World Health Organization estimates that the international dog population is approximately 10% of the human population and that about 75% of these dogs are homeless strays, community dogs, or feral. Without care, these dogs suffer from malnutrition, disease, and early death. In some countries, events such as an increase in human rabies deaths or fatal dog attacks may result in large-scale dog destruction campaigns by inhumane methods such as shooting, poisoning, beating, drowning, or electrocution. While the proportion of unowned free-roaming dogs in the Unites States is much lower, several million dogs are destroyed in animal shelters each year because they are unclaimed.
Increasingly, it is recognized that dog removal campaigns have only a transient impact on dog populations and the problems associated with them. In contrast, large-scale sterilization of unowned street dogs has successfully decreased their population, improved their welfare, and diminished their negative impacts on society. According to the World Health Organization, rabies control in particular relies on mass vaccination of dogs, not removal. In the largest report to date, 24,986 dogs were surgically sterilized and vaccinated against rabies during an anti-rabies campaign in Jaipur, India between 1994 and 2002. At the time of reporting, 65% of the female dogs were sterilized and the total dog population had declined by 28%. Importantly, there were no human rabies cases in the last 2 years of the project, whereas human rabies fatalities continued to be reported in areas that were not involved in the sterilization campaign.
Surgical sterilization meets the needs of preventing dog reproduction, but its delivery in most of the world is limited by costs and availability of advanced veterinary services. With evidence that dog welfare, public health, and environmental protection are improved by mass sterilization and vaccination programs, it is imperative to develop programs that are capable of delivering large-scale contraception to dogs humanely, efficiently, with minimal technical requirements, and low cost. The availability of a long-acting immunocontraceptive vaccine which could be administered by lay technicians in the field would be a powerful tool for dog population control. Since fertility control in free-roaming species is aimed at the level of the population, and not at individual animals, it not essential that every immunized animal be rendered infertile.
For over 30 years, researchers have been studying methods to control reproduction. Tremendous advances have been made in recent years with many successes in the human and wildlife fields. During this time, a few scientists have been working to apply these technologies to cats and dogs. In 2000, the Alliance for Contraception in Cats and Dogs (ACCD) was established in order to focus and direct these efforts in order to expedite the development of contraceptive drugs and vaccines specifically for cats and dogs.
Since then, ACCD has held three international symposia to facilitate interaction of interested individuals and to encourage exchange of ideas and research results. The Third International Symposium on Non-Surgical Contraceptive Methods of Pet Population Control was held in November 2006 and was attended by 120 attendees and 38 speakers from nine countries. Speakers presented the latest data and information on contraceptive drugs and vaccines under development, discussed the market for contraceptive products, and explored the role of veterinarians in acceptance and effective introduction of contraceptives and non-surgical sterilants. Participants developed action plans and formed collaborative teams to respond to challenges and opportunities in the field.
Contraceptive drugs and vaccines work by exerting a targeted pharmacological effect or prompting an immune response that blocks some component of the animal's reproductive system, resulting in infertility. The ideal contraceptive product would rapidly induce permanent sterilization, eliminate breeding behavior as well as fertility, and provide at least as many health benefits as surgical sterilization, while requiring only a single dose. Furthermore, the ideal product would be effective in dogs and cats of both sexes and all ages, and be safe and easy to administer. At this time, no single product is able to fulfill all of these criteria; however several promising products are under development. Even if the ideal formulation cannot be produced, safe products that induce sterility in dogs or cats, male or female, will be valuable tools in the fight against pet overpopulation.
Several factors have impeded progress in the development of long-acting contraceptives for dogs. Importantly, there has long been a shortage of funds to support research that benefits homeless animals and only a small number of scientists around the world devoted to this line of investigation. The need to keep end-user treatment costs very low for widespread use in developing nations and for homeless dogs has made it unattractive for major pharmaceutical company investment. The need to use animals in research studies for development of new treatments has dampened participation and support by some in the animal welfare field.
New Products: Contraceptive Drugs and Vaccines
Zinc gluconate (Neutersol®/ EsterilSolTM/Infertile®) is the first permanent, non-surgical method of sterilization for companion animals. It is currently licensed for use in the U.S. for chemical castration of puppies 3-10 months of age, although it has been shown to be effective in adult dogs and cats as well. It is delivered via an intratesticular injection, which results in sclerosis of the testes and permanent sterility. It is 99% effective and very safe. The precise mechanism of action is unknown; the testicles atrophy over weeks to months following injection, resulting in a 70-90% reduction in testicular size in very young puppies and 50% in older dogs (atrophy may not be symmetrical). Sterility may take up to 60 days in postpubescent males. In most cases, zinc gluconate can be administered without sedation. FDA studies showed that zinc gluconate reduces but does not abolish testosterone production, and its effects on hormone dependent diseases and behaviors have not been established. However, studies have revealed a significant decrease in prostate size in zinc gluconate-injected dogs versus controls. The only significant safety concern is the development of scrotal ulcers at the injection site in a small percentage of dogs. This appears to be most commonly observed in large adult dogs (an off-label use) and may be related to poor injection technique allowing some of the chemical to contact the scrotal tissues. Injection site reaction rates are similar to rates of wound complications in surgically castrated dogs, but use of zinc gluconate avoids adverse events or deaths associated with the use of anesthesia. This product is a useful option in veterinary practice as well as animal shelters. The obvious advantage is that it eliminates the need for anesthesia and surgery and saves substantial time. While available previously for a short time from Addison Laboratories, Neutersol was used successfully by programs in the U.S. (including one event in which 200 dogs were sterilized in one day) and abroad (including a 10,000 dog study conducted by the head of the Mexican VMA which demonstrated safety and efficacy in dogs over 10 months of age). A new product with a slightly different formulation of zinc gluconate with DMSO has recently been released in Brazil under the brand name Infertile®).
A deslorelin implant (Suprelorin®) is approved and available for use in male dogs in Australia, New Zealand, and the EU. Deslorelin is a GnRH agonist. When GnRH agonists are given continually at low doses, they suppress pituitary function. This action results in safe, reversible contraception. Down-regulation of GnRH receptors at the gonadotropin-producing cells of the anterior pituitary reversibly blocks the production and release of the gonadotropins LH and FSH. Without their stimulating effects, gonads cease to produce gametes (egg cells and sperm) and female and male sex hormones. Therefore, all reproduction-related body functions and behavior cease until the block is removed. This method was discovered more than 30 years ago, and has since been used to treat human prostate cancer patients. An implant containing 5 mg deslorelin provides contraception for 12 months. As in human subjects, adverse effects have not been observed in dogs and cats. However, one complication of GnRH agonists that is not observed with GnRH antagonists is that they may trigger a single estrus cycle when first implanted due to an initial stimulatory effect on GnRH receptors. The duration of contraception may vary beyond one year among individuals. Treatment can be safely repeated.
An azagly-nafarelin implant (Gonazon®) is approved (but unavailable) in the European Union for one-year, reversible contraception for female dogs. Limited data in cats indicated that queens had suppression of estrus over three years. This raises the possibility that the product might be useful in the control of feral cat populations, although the expense involved in manufacturing GnRH agonist implants may be a limiting factor. Canine Gonadotropin Releasing Factor Immunotherapeutic is a new anti-GnRH vaccine from Pfizer that has conditional FDA approval. Created and licensed for treatment of benign prostatic hyperplasia (BPH), the product results in suppression of testosterone release in male dogs for at least six months and can be repeated.
Other Approaches Under Development
GonaCon®: Dr. Lowell Miller and Kathy Fagerstone of the National Wildlife Research Center of the USDA presented data on the GnRH vaccine GonaCon, developed and tested for use in several wildlife species. Data are being submitted to the EPA initially for approval for use in deer and other cervids. Pilot studies in dogs by Drs. Brenda Griffin and Henry Baker at Auburn University revealed severe injection site reactions and inconsistent suppression of fertility in male beagles. Evaluation in cats by Dr. Julie Levy at UF has yielded more promising results, and a majority of female cats responded to a single injection with more than three years of infertility. Injection site reactions consisting of a small subcutaneous lump occurred after two years in a few cats, several of these resolved spontaneously.
ChemSpay®: Dr. Loretta Mayer of Senestech/Northern Arizona University is studying early stage technology for permanent sterilization of female dogs and cats. The drug is an industrial chemical that has been shown to deplete the ovarian follicles and cause sterility in rodents. This is a totally new approach and is exciting for its potential for permanent sterility. Dr. Mayer is currently working on dose levels and formulation for single-treatment application. Dr. Levy is currently investigating the use of this compound in female cats.
Found Animals (www.foundanimals.org) is privately operating foundation, formed by prolific inventor, entrepreneur and billionaire, Dr. Gary Michelson. The foundation addresses the causes and consequences of pet overpopulation through innovative strategies and community partnerships and works to develop sustainable, scalable animal welfare business models. Found Animals has announced the availability of $50 million in support of research for nonsurgical contraception in dogs and cats and a $25 million prize for the scientist who develops a single-dose permanent contraceptive treatment that is efficacious in both male and female dogs and cats. Research grant proposals are being accepted from scientists world-wide.
The Alliance for Contraception in Cats and Dogs (ACC&D) has a mission is to expedite the successful introduction of methods to non-surgically sterilize dogs and cats and to support the distribution and promotion of these products to humanely control cat and dog populations worldwide. ACC&D's Board of Advisors include leading scientists, veterinarians and animal health industry experts as well as senior executives from world leading animal welfare organizations.