IN-DEPTH: REPRODUCTIVE ENDOCRINOLOGY
The moderate potency of buserelin (Table 1) perhaps may explain why a single administration of a labeled dose of buserelin (40 to 100 g per mare) is not sufficient to induce ovulation in mares. For many years, buserelin (not available in the United States, except through compounding pharmacies) has had limited use and efficacy in inducing ovulation only when used in daily or twice-daily injections for 2 to 4 days. This protocol probably has prevented vet- erinarians and horse owners from favoring its use in brood mare management. In contrast with this knowledge, Levy and Duchamp14 (2007) recently showed that much higher doses than those origi- nally used resulted in ovulation rates comparable to that of hCG. In that study, 6 mg of buserelin was injected subcutaneously to cyclic mares, resulting in 89% to 95% ovulation rates that did not differ from hCG administration (86%). Considering the rela- tive potencies of deslorelin, histrelin, and buserelin (Table 1), we calculate that buserelin is at least 7 and 10 times less potent than deslorelin and histre- lin, respectively. This may partially explain why in this study a buserelin dose 60 times greater (6000 g versus 100 g) than that recommended in veter- inary commercial preparations of injectable busere- ling was able to effectively promote ovulation in treated mares at a similar rate reported for hCG, deslorelin, and histrelin. Veterinarians should use the FDA approved prod-
ucts for this indication. Certain compounded prod- ucts can vary significantly in potency and stability. Consequently results may vary substantially. There can also be legal and ethical issues with using a compounded product when there are FDA approved products available in the appropriate dosage form and with the appropriate indication.
6. Ecbolic Hormones for Treatment of Delayed Uterine Clearance
In general, the use of ecbolic hormones to correct deficiencies or weakness in myometrial contractions commonly seen in mares with delayed uterine clear- ance and susceptible to endometritis are safely initiated at 4 to 8 hours after artificial or natural insemination to avoid interferences with sperm transport that could affect fertility. These treat- ments are then continued at the discretion of the prescribing veterinarian; ecbolics are often adminis- tered twice daily or more often if necessary and depending on the recorded response for an individ- ual mare. Commonly used ecbolics in broodmares include oxytocin and PGF.
Oxytocin
Oxytocin is a nonapeptide synthetized in the mag- nocelullar neurons in the hypothalamus that extend their axons into the neurohypohysis, where it is stored until released into the blood stream for biological action. Oxytocin has several known physiologic effects, such as milk ejection, promoting maternal behavior, and inducing myometrial con-
334 2013 Vol. 59 AAEP PROCEEDINGS
tractions. Because delayed uterine clearance is commonly seen in mares with persistent mating- induced endometritis, oxytocin is one important therapeutic option for treating abnormal intrauter- ine accumulation of fluid. Despite oxytocin’s rela- tively short-life of 7 minutes, it appears that its biological effect far exceeds this time. For that rea- son, treatment protocols varying from two to four daily treatments have been shown to be relatively efficacious in promoting uterine clearance. Boluses doses of 10 to 20 IU administered subcutaneously, intramuscularly, or intravenously are frequently used to treat mares with mating-induced intra- uterine fluid accumulation. Oxytocin treatments are administered during estrus before or after ovu- lation, with treatments scheduled to not coincide with breeding to avoid interfering with sperm trans- port, especially if given shortly after artificial in- semination, for example, 4 hours. Recently, our laboratory reported on the pharmacokinetics of car- betocin, a long-acting oxytocin analogue.15 Carbe- tocin has a half-life of 17 minutes. Carbetocin is available and approved for use in horses in several countries but not in the United States. Despite its longer half-life than oxytocin, multiple daily treat- ments may still be required for optimal effects in promoting uterine clearance as is required with oxy- tocin or PGF. A direct comparison between oxyto- cin’s and carbetocin’s ability to promote uterine clearance has not been reported for in vivo treat- ment in mares. Currently, it not known whether the reported prolonged half-life of carbetocin would translate into a greater and/or more productive bio- logic response than oxytocin in mares that may re- quire prolonged myometrial stimulation. Steckler et al16 have recently reported on the results of a comparison of oxytocin versus carbetocin in eliciting contractions in ex vivo uterine tissues collected from mares at different reproductive stages (eg, anestrus, estrus, and diestrus). The results indicated that the effect of oxytocin on equine myometrial tissue was greater during anestrus and diestrus than dur- ing estrus, whereas carbetocin appeared to elicit myometrial contractions independent of the repro- ductive status; however, there were no differences between their ability to induce myometrial contrac- tions in the ex vivo strips of myometrial tissues.
Prostaglandin F2 In addition to being known for its luteolytic actions, PGF is also an effective promoter of myometrial contractions. Because of its longer half-life than oxytocin, especially the synthetic PGF analogue clo- prostenol (2–3 hours), PGF has been favored by equine practitioners, especially for use in mares that anecdotally appear to be refractory or do not respond appropriately to oxytocin treatment. Cloprostenol does elicit less vigorous myometrial contractions than oxytocin but for prolonged periods. For exam- ple, one study reported that oxytocin induced strong myometrial contractions that lasted 30 minutes,
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