Patrick W. Concannon, MS, PhD, DACT (Hon)
Dept. Biomedical Science, College of Veterinary Medicine, Cornell University
Ithaca, NY, USA
Nonsurgical contraceptive measures include permanent or temporary pharmaco-castration of males, reversible and nonreversible estrus prevention in females, estrus suppression in females, and pregnancy prevention or termination after unwanted mating. As for females, no new products for estrus prevention or suppression have been introduced in the last decade, other than revised formulations and new brands of progestins previously marketed. In fact, contraceptive options in bitches have decreased in some countries with the recent withdrawal of the androgen mibolerone (Cheque Drops©) as an estrus preventative. However, an implant product providing down-regulating amounts of a potent GnRH-agonist has recently been approved as male dog contraception in New Zealand and Australia, and efforts are underway to obtain approval as a contraceptive in bitches as well, as well as application to cats. Depending on price and regulatory hurdles, the product is likely to become available in many countries in the next decade. There are significant advances in protocols and products available for termination of unwanted pregnancies, including extra-label uses of prostaglandin, of PG analogs, of dopamine agonists, and of dexamethasone in selected situations; additionally, the anti-progestin aglepristone is approved and sold with an indication of pregnancy termination in some countries. The goal of non-surgical contraception in males has advanced on two fronts: the above-mentioned GnRH-agonist implant technology, and a new product that provides testis-necrosing doses of a metallic salt injected directly into the testes.
Progestin administration remains the widest available method of cycle prevention in dogs. They are marketed with an indication for use in female dogs, and in some countries there may be an indication or suggested doses for use in cats. In all cases, progestin administration is intended to produce an artificial luteal phase (i.e., circulating progestin mimicking the normal post-estrus profile of progesterone); during this period a new ovarian cycle will not occur and following it a normal anestrus period is reinitiated. The progestin acts at the hypothalamic-pituitary level, primarily preventing increases in GnRH (and thus gonadotrophin) secretion that would otherwise occur as the stimulus for the next follicular phase and proestrus. Oral formulations are given daily; depot-injectable formulations, by single injections; extended therapy in either instance is by repeating the treatment at 2-5 month intervals, based on manufacturers recommendations. Generic progestin formulations marketed under various brand names in different countries include oral megestrol acetate, depot-injectable medroxy-progesterone acetate (MPA), oral MPA, depot-injectable proligestone, and others. The number of trade names under which each is marketed is large and expanding as these compounds go off patent and are produced as new brand names of the generic drug, often with the progestin identified only by a chemical name that is not typically used but is scientifically synonymous with the more commonly used chemical or generic name. MPA can validly be identified by any one 16 synonymous chemical formulas (e.g., 6-alpha-methyl-4-pregnene-3, 20-dion-17-alphaol acetate; 17-alpha-Acetoxy-6-alphamethylpregn-4-ene-3,20-dione) and an additional 14 generic drug names (e.g., MPA, mespirenone, NSC-26386, farlutin), in addition to 12 or more product brand names (e.g., Promone, Depo-promone, Perlutex, Repromap, Supprestal, Gestovex, etc). The situation is just as complex with megestrol acetate, as it has over 40 different chemical, generic, and trade names, and the number of brand names continues to increase as generic drug companies produce their own brands of same formulations. Unfortunately, doses and treatment protocols vary among manufactures, often markedly and incorrectly, and caution should be exercised because of the modest margin of safety as regards known side effects.
There is likely no universally safe and effective dose of any of the progestins in either dogs or cats. In both species, effective dose can in some individuals result in uterine disease or diabetic-like symptoms. In dogs, reported possible side effects seen with recommended doses but more often with higher than recommended doses include mammary hyperplasia and mammary tumors, elevated Growth hormone and acromegalic changes, diabetes, adrenocortical suppression, masculinization of female fetuses, local skin reactions, and behavior changes including increased appetite with weight gain. Nevertheless, many bitches tolerate recommended doses well, without side effects. Of primary concern is the potential to cause cystic endometrial hyperplasia and resulting pyometra, especially if the dose is excessive and/or administered in late proestrus, estrus or the luteal phase, where interaction with a prior elevation in estrogen can magnify potential effects on the uterus. Administration in dogs should be limited to confirmed anestrus or very early proestrus. The latter should be confirmed by vaginal cytology as owners often recognize proestrus too late for safe or even effective administration. Administration late in proestrus can result in induction of a fertile ovulation rather than suppress the impending ovulation. In cats, spontaneous ovulations can occur, and the hormonal and cycle status of the queen should be confirmed before initiation of treatment. Contra-indications include pregnancy, and any history of reproductive tract, mammary or liver disease.
In North America the only drug so marketed is Ovaban, 5 and 20 mg tablets, by prescription only, for use in dogs only, not more than successive cycles of use, not before or during first estrus cycle (i.e., pubertal proestrus), for postponement of estrus; administration in anestrus, at 0.25 mg/lb body weight per day for 32 days administered orally, intact, or crushed and mixed with food; administration in proestrus at 1 mg/lb per day for 8 days-administered orally, intact, or crushed and mixed with food. There is no indication for use in cats. The nearly-or quasi-equivalent metric doses and protocols for dogs, and those usually but not always recommended in European products are, for anestrus, 0.5 mg/kg/day for 32 days or 40 days, and for proestrus, 2.0 mg/kg/day for 8 consecutive days. In some countries there are products with an indication for use in prepubertal bitches and during pubertal proestrus; likewise, there may be indications for use in cats at doses of 5 mg/cat every 2 weeks or 2.5 mg/cat per week, or 5 mg/cat/ day for 4 days, then 5 mg once every 2 weeks It has been suggested that dosing in cats, as in dogs, if considered, should incorporate a dose per unit body weight, such as 0.5-1 mg/kg or less, assuming previously recommended dose would be sufficient for 5 kg or larger cats; dosing by body weight might limit the occurrence of side effect sin smaller cats. Dose response studies for cats have not been published. Where oral MPA is marketed, there are similar anestrus and proestrus protocols, with recommended doses that have not been subjected to dose-response studies that have been published.
Greater caution should be exercised with depot injectable progestins, as the treatment cannot be quickly discontinued in the event of overdosing or idiosyncratic occurrences of side effects. Conservative does are on the order of 2.5-3 mg/kg every 5-6 mos. in dogs, and 2-mg/kg/5 mo. in cats. Animals should be monitored for potentially debilitating side effects. Anecdotal reports suggest that experiences with proligestone are not very different from those with MPA, including the potential for undesirable reproductive and metabolic side effects. The typical product, i.e., Covina© or Delvosteron© Intervet 100 mg/ml is recommended by the manufacturer to be administered at doses of 10 to 33 mg/kg, given to bitches at 0, 3 and 7 months of treatment, and subsequently at 5-month intervals.
In zoo-maintained exotic carnivores silastic implants of melengestrol acetate were used for many years but resulting uterine disease has reduced interest in their use. In dogs and cats, implants of progesterone, androgen and synthetic progestins have been shown capable of providing cessation of cycles, but studies of safety have been limited. One concern is whether the implants can provide steady state release with first order kinetics as opposed to burst release in the initial weeks. Implants of levo-norgestrel (Norplant) marketed for human sue, as well as equivalent implants made with generic levonorgestrel have been show to have a contraceptive efficacy in female cats but not dogs at doses that were multiples of the human dose on a body weight basis. Recently, silastic implants of a new design and containing a synthetic progestin have been reported to have first-order release kinetics when placed subcutaneous in dogs or cats and to provide safe and effective estrus cycle prevention for at least 2 years, without side effects. (Verstegen et al., 2004; Verstegen, personal communication).
Mibolerone is no longer marketed in the U.S. Performing dogs and working dogs are often subjected to high doses of synthetic androgens or testosterone esters are a mode of contraception, notwithstanding the potential anabolic effects that may accompany treatment. Clinicians should be aware of such drug abuse in dealing with animals with signs of masculinization, elevate hematocrits, adrenal suppression, and persistent anestrus.
Available data suggest that 3 and possibly 4 different GnRH agonists have been shown to suppress gonadal activity in both male and female doges, to have a high margin of safety, to be fully reversible whether administered in adults or beginning prior puberty. The drugs are all decapeptides that represent modifications of the natural GnRH via substitution of one or more natural or synthetic amino acids resulting in potencies 100-200x that of GnRH. Formulation and marking of a commercial product involves or will involve implants to be placed s.c. via a needle/trochar, and which will release effective systemic concentrations for 6 mo. to one year or more. The agonists, when administered continuously, act by causing a protracted down-regulation of the GnRH receptors on gonadotrophin-secreting cells of the pituitary, following a brief period of up-regulation that causes a transient increase in LH and FSH (an effect sufficient to induce estrus in anestrus bitches). The resulting chronic suppression of LH and FSH concentrators results in suppression of gonadal hormone secretion and gametogenesis--a chemo-castration effect in males and a protracted anestrus in females, in each case reversible. Peptic, Australia has gained approval of sale of its implants of the GnRH analog deslorelin analog by the relevant authorities in Australia and New Zealand under the name Suprelorin©. The registered product claims efficacy for at least 6 months in 98% of male dogs as contraception, and use a treatment for benign prostatic hyperplasia (BPH) and as and as an aid in the control of unacceptable behavior. The expectation is to produce an implant with an efficacy per implant that last for one year, and to gain approval for the product being indicated for use as a cycle-preventing contraceptive in female dogs.
One caveat in using GnRH agonists in females is the concern of inducing a fertile estrus at the start of the treatment period, which is a typical response unless the animals are less than 3-5 months of age or have elevated progesterone concentrations (i.e., are within 1 month of a prior estrus or are pretreated with a progestin). Intervet researchers have reported on a formulation of an GnRH-agonist that is a modification of the human drug nafarelin, and the azaglynafarelin is formulated in a controlled release device, Gonazon-CR©. It safely and efficiently prevented puberty in female dogs throughout the treatment period of 1 year beginning at 4-5 months of age. Prevention of puberty did not appear to affect body weight or growth compared to controls in the study. The potential for this product to also come to the veterinary market also seems very promising.
In the U.S. the FDA has approved the product Neutersol© (Addison Biological Laboratories) developed by Technology Transfer, Inc. The injectable solution contains 13.1 mg/ml zinc as zinc gluconate that is neutralized to pH 7.0 with L-arginine. The indication is for intra-testicular injection to produce sterilization in 3-10 month old male dogs, the volume injected into each testicle being based on testicular width as determined by measuring each testicle at its widest point using a metric caliper. More than 99.5% of animals studied became sterile, but testosterone levels we only reduced by approximately 50%. Marketing is to both private practices and to animal welfare faculties with an interest in reducing the per overpopulation problem in the U.S. The claim is that by using fine needle injections, the procedure is tolerated by dogs without sedation, and that the side effects are usually minor. Local reactions included the expected testicular swelling, and in some cases pain with biting and licking at the scrotum, swelling of the prepuce and irritation, ulceration, and/or infection of the scrotum. Systemic reactions included an increase in the white blood cell count, vomiting, anorexia, lethargy and diarrhea. Withdrawal of food for 12 h pre injection is suggested. Scrotal swelling without pain may persist for a few months.
CURRENT RESEARCH: NEW MODES OF CONTRACEPTION
These include reports of several promising approaches intended to interfere with GnRH action, with function of pituitary gonadotrope cells responsible for secretion of LH and FSH, or with the action of LH on the ovary. Such approaches include presentation of GnRH or GnRH-like peptide multimers and/or protein conjugates as vaccines in protocols using new and more readily acceptable, less irritating adjuvants; delivery of a GnRH-vaccine expressed by modified virus; administrations of GnRH-peptides with GnRH or GnRH-agonist linked to a cytotoxin and/or membrane-active lytic peptide, intended to result in gonadotrope cell uptake of the cytotoxin and cell destruction; and use of a vaccine for immunization against bovine LH-receptor presented via silastic implants and serial booster injections, intended to prevent ovarian cells from responding properly to endogenous LH. Additional vaccine approaches include myriad proposed methods for immunization against the peri-oocyte zona pellucida proteins, especially ZP3, using as immunogen either a purified ZP protein or crude ZP preparation with one of many proposed acceptable but potentially sufficiently effective adjuvant or carrier system,
PREGNANCY TERMINATION AND PREVENTION: EXTRA-LABEL DRUG USE
Many of the protocols involve the extra label use of drugs marketed for use in other species, or for other indication in small animals, ideally along with ultrasound to confirm efficacy. These include natural prostaglandin F2a (PGF) at doses of 20-100 ug/kg, i.m. or sac., at a minimum of 2 times per day, to effect, and, various PGF-analogs marketed for use in large animals (e.g., Cloprostenol injections every 2 days, to effect), given after confirmation of pregnancy in dogs. Higher doses required in cats have been less well studied. Likewise, dopamine agonists including cabergoline marketed in some countries for suppression of lactation; given orally daily after day 30 (and to effect) in prolactin-suppressing doses will cause luteolysis and terminate pregnancy. In dogs, immunosuppressive oral doses of dexamethasone () given for 10 days will terminate pregnancy probably by mimicking mechanisms similar to those that occur naturally at parturition, and may be justified in certain locales and circumstances; the induced adrenal suppression is reversed immediately upon withdrawal. Recently, combination therapies of PGF or PGF-analog in conjunction with a dopamine agonist (cabergoline or bromocriptine) were show to have high efficacy and the potential to utilize lower amounts of the drugs and minimize side effect. These protocols have been reviewed in detail (Wanke et al, 2002, www.ivis.org).
The progesterone receptor antagonist aglepristone is currently marketed in a limited number of countries in Europe and South America, e.g., Alazine ©, Virbac France, 30 mg/ml, with an indication for termination of pregnancy any time after mating. Doses of 10 mg/kg administered twice, with an interval of 24 h, have been reported to terminate pregnancy given en at day 15, 30 or 34 of pregnancy. The protocol and findings have been reviewed in detail (Fieni et al, 2001, www.ivis.org)
1. Baldwin CJ, Peter AT, Bosu WT, Dubielzig RR.. Lab Anim Sci 1994 Jun;44(3):261-9. The contraceptive effects of levonorgestrel in the domestic cat.
2. Concannon, P.W. (1995). Contraception in the dog. In: The Veterinary Annual, No. 35, Blackwell Scientific, Oxford, 35: 177-187.
3. Concannon, P., England, G., Verstegen, J., Farstad, W. and Linde-Forsberg, C. and Doberska, C. (Eds.) Advances in Dog, Cats and Exotic Carnivore Reproduction. Proc. Third International Symposium Canine and Feline Reproduction. J. Reprod. Fert. Suppl. 57. Journal of Reproduction and Fertility, Cambridge., 2001.
4. Concannon, P. 2002. Ovarian cycle suppression in dogs and cats. In: Kirk's Current Veterinary Therapy, Vol. 15 (Bonagura, J. eds), W.B. Saunders, Philadelphia.
5. England, G (1998) Pharmacological control of reproduction in the bitch. Ch. 16 in Manual of small animal reproduction and neonatology. G. Simpson, G E England, M J Harvey (Eds) Brit. Sm Anim Vet Assn., Birmingham. Pages 198-218
6. Griffin, B., Boyle, S., Jochle, W. , and Baker, H. Summaries. International Symposium on Nonsurgical Methods for Pet Population Control, April 19-21, 2002 , Callaway Gardens, Pine Mountain, Georgia.
7. Romagnoli, S. and Concannon, P. 2003. Clinical use progestins in bitches and queens: A review. In: Recent Advances in Small Animal Reproduction (Concannon, P., England, G., Verstegen, J., Linde-Forsberg, C., Eds). International Veterinary Information Service (www.ivis.org)
8. Verstegen , J. (Ed.) 2004. Program Book, 5th Symposium Canine Feline Reproduction, Embu das Artes, Sao Paulo, Brazil.
9. Wanke, M., Loza, M., Monachesi, N. and Concannon, P. (1997). Clinical use of dexamethasone for termination of unwanted pregnancy in dogs. J. Reprod. Fert., Suppl. 51: 233-238.