Hormones and Breeding

Home , Buserelin, Deslorelin, Histrelin, Luteolysis

IN-DEPTH: REPRODUCTIVE ENDOCRINOLOGY

Carlos R.F. Pinto, MedVet, PhD, Diplomate ACT

Author’s address: Theriogenology and Reproductive Medicine, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210; e-mail: [email protected]. © 2013 AAEP.

1. Introduction affected by PGF treatment to induce estrus. In The administration of hormones to mares during other words, once luteolysis takes place, whether breeding management is an essential tool for equine induced by PGF treatment or occurring naturally, practitioners. Proper and timely administration of the events that follow (estrus behavior, ovulation specific hormones to broodmares may be targeted to and fertility) are essentially similar or minimally prevent reproductive disorders, to serve as an aid to affected (eg, decreased signs of behavioral estrus). treating reproductive disorders or hormonal imbal- Duration of diestrus and interovulatory intervals ances, and to optimize reproductive efficiency, for are shortened after PGF administration.1 The example, through induction of estrus or ovulation. equine corpus luteum (CL) is responsive to PGF These hormones, when administered exogenously, luteolytic effects any day after ovulation; however, act to control the duration and onset of the different only CL Ͼ5 days are responsive to one bolus injec- stages of the estrous cycle, specifically by affecting tion of PGF.2,3 Luteolysis or antiluteogenesis can duration of luteal function, hastening ovulation es- be reliably achieved in CL Ͻ5 days only if multiple pecially for timed artificial insemination and stimu- PGF treatments are administered. For that rea- lating myometrial activity in mares susceptible to or son, it became a widespread practice to administer showing delayed uterine clearance. In this discus- PGF as a single bolus injection (subcutaneous or sion, we address the effects and potential indications intramuscular) only after 5 to 6 days after ovulation. for the different hormones available to the equine This common practice perhaps contributed to the practitioner working with broodmare reproduction. prevailing assumption that PGF treatments have only significant effects in mares with CL Ͼ5 days. 2. Prostaglandin F2␣ Mares with a CL Ͼ5 days undergo luteolysis when The administration of natural or synthetic prosta- treated with one single injection (subcutaneous or glandin F2␣ (PGF) analogues causes interruption intramuscular) of 5 to 10 mg of dinoprost trometh- of luteal function by luteolysis. The diestrus stage amine or 250 to 500 ␮g of cloprostenol (synthetic of the estrous cycle is then shortened leading to PGF analogue). In the United States, dinoprost onset of estrus. Characteristics of estrus and ovu- tromethaminea is the only PGF drug approved by lation are not different from that occurring in natu- the Food and Drug Administration (FDA) for use in ral cycles. The inherent fertility of mares is not horses, although the use of the racemic formulation

NOTES

AAEP PROCEEDINGS ր Vol. 59 ր 2013 331 IN-DEPTH: REPRODUCTIVE ENDOCRINOLOGY of d,l-cloprostenolb is very common among practi- thor’s clinical experience that mares that repeatedly tioners working with horse breeding, especially be- ovulate two or three follicles respond to a single cause of its longer half-life than dinoprost hCG treatment similarly to mares ovulating only tromethamine salt preparations—hours versus one follicle during estrus. Because hCG is avail- minutes, respectively. Conversely, in other coun- able in 10,000-IU vials, it is common to have equine tries (Europe, South America, etc), formulations of practitioners administering bolus doses of 2000 or the synthetic analogue cloprostenol are approved 2500 IU to optimize the use of each vial. Although and available for use in horses. In those countries, the author has successfully used vials that have the racemic d,l-cloprostenol and the more potent been reconstituted for several weeks, it is recom- formulation containing only the d-enantiomer clo- mended that reconstituted vials be used within 2 prostenolc are available; only 25 to 37.5 ␮g per mare weeks and kept refrigerated during that period. of d-cloprostenol is needed to induce luteolysis in Intramuscular or intravenous routes can be used to mares at least 5 days after ovulation.4 administer hCG in mares, but it seems, anecdotally, that fewer ovulation failures are seen in mares re- 3. Induction of Ovulation ceiving hCG intravenously than in mares receiving The ability to induce ovulation is one of the most it intramuscularly. For example, intramuscular important strategies used in breeding management. doses of 5000 to 10,000 IU should be avoided. The goal of inducing ovulation in breeding manage- Mares do have development of antibodies to the ment of mares is to induce ovulation within 48 human hormone, but the presence of antibodies does hours, preferably between 24 to 48 hours after treat- not appear to interfere with ovulation.7 Neverthe- ment. In mares monitored closely by palpation less, some authors do recommend not treating mares per rectum and ultrasonography, ovulation occurs with hCG more than once or twice during the same within 36 to 48 hours. This fact is particularly breeding season, whereas others (including this au- important for mares being managed for artificial thor) have used it successfully (ovulation within 48 insemination with frozen-thawed semen. For opti- hours from administration) in mares treated five to mal chances to predict outcome and increase efficacy 10 times during the same breeding season. of the treatment, regardless of the ovulation-inducing agent being used, induction of ovulation should 5. Gonadotropin-Releasing Hormones be attempted only in mares found unquestionably to be in estrus and with a growing follicle at least Ն30 Administration of simple gonadotropin-releasing mm in diameter. The most common hormones used hormone (GnRH) analogues (equivalent to the nat- to induce ovulation include human chorionic gonad- ural decapeptide GnRH) to cycling mares has failed otropin (hCG) and the gonadotropin-releasing hor- to consistently induce ovulation. Whereas doses of ␮ mone agonists (GnRH), which are discussed below. 50 to 100 g of GnRH are sufficient to induce ovulation in cattle, doses as high as 1 to 4 mg have failed 4. Human Chorionic Gonadotropin to reliably induce ovulation in mares when admin- Human chorionic gonadotropind has been widely istered once or twice daily during estrus. Further- and extensively used as an ovulation-inducing more, only pulsatile administration (every hour) of agent because of its luteinizing hormone (LH)-like GnRH has been found to be effective in inducing activity. The hormone, hCG, is produced after be- ovulation in the mare; this method is, however, not ing extracted from urine of pregnant women. feasible for widespread clinical application. Since Chemically, hCG is a glycoprotein composed of an ␣- the chemical structure and peptide identification and a ␤-subunit; the ␣-subunit is similar to that of was reported in 1971, more than 2000 GnRH ana- human follicle-stimulating hormone (FSH) and LH; logues were synthesized in the following 15 years however, the ␤-subunit, despite containing the same after the 1971 report. Scientists working in re- amino acids present in the LH ␤-subunit, does have search and private pharmaceutical institutions an additional group of 23 amino acids and a high shared two main aims: (1) to create an analogue degree of sialylation that confers hCG a longer half- with high affinity for GnRH receptor binding and (2) life (several hours) than that of LH (20 to 30 min- to avoid or minimize enzymatic degradation by pro- utes). The hCG hormone is then lyophilized and teolysis. The GnRH molecule is susceptible to available in the United States in vials containing cleavage and inactivation by hypophyseal endopep- 10,000 international units (IU). Despite reports of tidases, especially between amino acids in position 5 mares being treated with hCG since 1939,5 hCG is and 6 and between 6 and 7. Another enzyme, car- not approved by the FDA for use in horses. Never- boxypeptidase, targets the bond between amino ac- theless, a single bolus dose of 1500 to 3300 IU is ids in positions 9 and 10. For these reasons, several typically sufficient to induced ovulation in mares GnRH synthetic analogues used in human and vet- during estrus, with distinct estrous uterine edema erinary medicine have (1) D-amino acid substitu- and with a viable, growing follicle Ͼ30 mm.6 tions in position 6 (glycine) and (2) the amino acid in Mares with more than one presumptive preovula- position 10 (another glycine) and its amide terminal tory follicle do not need to receive a double dose or a replaced by an ethylamide residue that is linked to second injection during that estrus. It is the au- the amino acid 9 proline.8

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Deslorelin Table 1. Comparative Rank Order Potency of Synthetic GnRH Ana- logues in Relation to Natural GnRH In contrast with the poor or limited efficacy of simple GnRH analogues, more potent GnRH synthetic an- GnRH Buserelin Deslorelin Histrelin alogues such as deslorelin have a predictable effect Relative potency 1 20 144 210 in inducing ovulation within 48 hours when administered as intramuscular injections or by means of subcutaneous implants. Deslorelin differs from the natural decapeptide GnRH in two amino acid substitutions: in amino acid position 6, where L-gly- approved deslorelin injectable formulation, 151 of cine has been replaced with the amino acid 168 (ϳ90%) mares treated in estrus with 1.8 mg of D-tryptophan, and in position 10, where glycine and deslorelin acetate (1 mL IM) ovulated on average 41 its amino terminal have been replaced by hours after treatment, whereas 111 of 134 mares N-ethylamide. (ϳ83%) treated with hCG (2500 IU IV) ovulated on 11 Ovulation rates after deslorelin administration average 44 hours after treatment. are comparable with those resulting from hCG ad- Histrelin ministration.9 Commercially, deslorelin became available as implants containing 2.1 mg of deslorelin Once an injectable form of deslorelin became FDA- acetate.d After being first available in Australia approved and commercially available, some com- and other countries, a deslorelin implante became pounding pharmacies began to accept requests to FDA-approved and available in the United States in compound another synthetic GnRH analogue, his- 1998. After being on the market for approximately trelin (or historelin). Histrelin is an even more po- two breeding seasons, it was anecdotally reported tent GnRH analogue than deslorelin (Table 1), but that occasionally, mares treated with the implant with similar clinical efficacy in inducing ovulation had prolonged interovulatory intervals, and some in horses as deslorelin or hCG. Histrelin differs actually had their reproductive cyclicity downregu- from the natural decapeptide GnRH in two amino lated for months. When exploring this issue, Mc- acid substitutions. In amino acid position 6, where L-glycine has been replaced with the amino acid Cue et al10 reported normal interovulatory intervals D-histidine, and in position 10, where glycine and in mares that had their implant removed once its amino terminal have been replaced by ovulation occurred. This phenomenon was later N-ethylamide. elucidated by the fact that prolonged delivery of Recently, a sustained-release (biorelease) formu- deslorelin would induce ovulation but its continu- lation of histrelin was found to effectively induce ous release would downregulate FSH and LH ovulation within 2 days after administration.12 secretion from the pituitary, resulting in prolonged The efficacy of histrelin treatment (0.5 or 1.0 mg interestrous intervals. Removing the implant after bolus injections) in inducing ovulation within 48 ovulation thus prevented sustained release of hours after administration has been found to be no deslorelin. Reportedly because of problems in man- e different from that promoted by hCG or deslorelin. ufacturing logistics, this deslorelin implant has not In a more recent study,13 a sustained-release (biore- been commercially available in the United States lease) formulation of histrelin was also found to since the early 2000s. Interestingly, side effects effectively induce ovulation within 2 days after ad- related to sustained deslorelin release have not been ministration. There were no differences among reported in Australia, where the drug originated maiden, barren, and foaling mares treated through- and still remains available there and in other out the ovulatory seasons; similarly, there were no countries. significant differences for the two doses used in that For several years, deslorelin was available either study, 0.25 and 0.5 mg, administered as single in- through importation from countries that manufac- e tramuscular bolus injections to mares in estrus. tured the deslorelin implant or through compounding The overall ovulation rate at 48 hours was 93% of injectable formulations of deslorelin (1.5 mg/mL; (43/46) and 85% (44/52) for doses of 0.5 mg and 0.25 dose 1 mL per mare administered intramuscularly). mg of histrelin, respectively. In summary, there Recently, an injectable controlled release form of does not appear to be differences in the efficacy, f deslorelin acetate (1.8 mg/mL) was approved by the relative to ability to induce ovulation, among deslo- FDA in 2010 for induction of ovulation in mares and relin, histrelin, and hCG. became commercially available in the United States in 2011. It contains 1.8 mg of deslorelin acetate Buserelin equivalent to 1.7 mg of deslorelin in a sucrose ace- Buserelin is another GnRH analogue that also con- tate isobutyrate and propylene carbonate matrix tains modification in the amino acid position 6 by that promotes controlled release of the drug. This having the natural occurring L-glycine replaced by formulation has been shown to induce ovulation at a tertiary butylated D-serine and the amino acid comparable rates of those from hCG or deslorelin 10 glycine and its amino terminal replaced by N- implant administrations. In the only published ethylamide, which is similar to the amino terminal peer-reviewed report on the efficacy of this FDA- modification present in deslorelin and histrelin.

AAEP PROCEEDINGS ր Vol. 59 ր 2013 333 IN-DEPTH: REPRODUCTIVE ENDOCRINOLOGY The moderate potency of buserelin (Table 1) perhaps tractions. Because delayed uterine clearance is may explain why a single administration of a labeled commonly seen in mares with persistent mating- dose of buserelin (40 to 100 ␮g per mare) is not induced endometritis, oxytocin is one important sufficient to induce ovulation in mares. For many therapeutic option for treating abnormal intrauter- years, buserelin (not available in the United States, ine accumulation of fluid. Despite oxytocin’s rela- except through compounding pharmacies) has had tively short-life of ϳ7 minutes, it appears that its limited use and efficacy in inducing ovulation only biological effect far exceeds this time. For that rea- when used in daily or twice-daily injections for 2 to son, treatment protocols varying from two to four 4 days. This protocol probably has prevented vet- daily treatments have been shown to be relatively erinarians and horse owners from favoring its use in efficacious in promoting uterine clearance. Boluses brood mare management. In contrast with this doses of 10 to 20 IU administered subcutaneously, knowledge, Levy and Duchamp14 (2007) recently intramuscularly, or intravenously are frequently showed that much higher doses than those origi- used to treat mares with mating-induced intra- nally used resulted in ovulation rates comparable to uterine fluid accumulation. Oxytocin treatments that of hCG. In that study, 6 mg of buserelin was are administered during estrus before or after ovu- injected subcutaneously to cyclic mares, resulting in lation, with treatments scheduled to not coincide 89% to 95% ovulation rates that did not differ from with breeding to avoid interfering with sperm trans- hCG administration (86%). Considering the rela- port, especially if given shortly after artificial in- tive potencies of deslorelin, histrelin, and buserelin semination, for example, Ͻ4 hours. Recently, our (Table 1), we calculate that buserelin is at least 7 laboratory reported on the pharmacokinetics of car- and 10 times less potent than deslorelin and histre- betocin, a long-acting oxytocin analogue.15 Carbe- lin, respectively. This may partially explain why in tocin has a half-life of ϳ17 minutes. Carbetocin is this study a buserelin dose ϳ60 times greater (6000 available and approved for use in horses in several ␮g versus 100 ␮g) than that recommended in veter- countries but not in the United States. Despite its inary commercial preparations of injectable busere- longer half-life than oxytocin, multiple daily treat- ling was able to effectively promote ovulation in ments may still be required for optimal effects in treated mares at a similar rate reported for hCG, promoting uterine clearance as is required with oxy- deslorelin, and histrelin. tocin or PGF. A direct comparison between oxyto- Veterinarians should use the FDA approved prod- cin’s and carbetocin’s ability to promote uterine ucts for this indication. Certain compounded prod- clearance has not been reported for in vivo treat- ucts can vary significantly in potency and stability. ment in mares. Currently, it not known whether Consequently results may vary substantially. There the reported prolonged half-life of carbetocin would can also be legal and ethical issues with using a translate into a greater and/or more productive bio- compounded product when there are FDA approved logic response than oxytocin in mares that may re- products available in the appropriate dosage form quire prolonged myometrial stimulation. Steckler and with the appropriate indication. et al16 have recently reported on the results of a comparison of oxytocin versus carbetocin in eliciting 6. Ecbolic Hormones for Treatment of Delayed contractions in ex vivo uterine tissues collected from Uterine Clearance mares at different reproductive stages (eg, anestrus, In general, the use of ecbolic hormones to correct estrus, and diestrus). The results indicated that deficiencies or weakness in myometrial contractions the effect of oxytocin on equine myometrial tissue commonly seen in mares with delayed uterine clear- was greater during anestrus and diestrus than dur- ance and susceptible to endometritis are safely ing estrus, whereas carbetocin appeared to elicit initiated at 4 to 8 hours after artificial or natural myometrial contractions independent of the repro- insemination to avoid interferences with sperm ductive status; however, there were no differences transport that could affect fertility. These treat- between their ability to induce myometrial contrac- ments are then continued at the discretion of the tions in the ex vivo strips of myometrial tissues. prescribing veterinarian; ecbolics are often administered twice daily or more often if necessary and Prostaglandin F2␣ depending on the recorded response for an individ- In addition to being known for its luteolytic actions, ual mare. Commonly used ecbolics in broodmares PGF is also an effective promoter of myometrial include oxytocin and PGF. contractions. Because of its longer half-life than oxytocin, especially the synthetic PGF analogue clo- Oxytocin prostenol (ϳ2–3 hours), PGF has been favored by Oxytocin is a nonapeptide synthetized in the mag- equine practitioners, especially for use in mares that nocelullar neurons in the hypothalamus that extend anecdotally appear to be refractory or do not respond their axons into the neurohypohysis, where it is appropriately to oxytocin treatment. Cloprostenol stored until released into the blood stream for does elicit less vigorous myometrial contractions biological action. Oxytocin has several known than oxytocin but for prolonged periods. For exam- physiologic effects, such as milk ejection, promoting ple, one study reported that oxytocin induced strong maternal behavior, and inducing myometrial con- myometrial contractions that lasted ϳ30 minutes,

334 2013 ր Vol. 59 ր AAEP PROCEEDINGS IN-DEPTH: REPRODUCTIVE ENDOCRINOLOGY whereas cloprostenol induced low-amplitude myo- asone administered at the time of artificial insemi- metrial contractions that lasted 4 to 5 hours. This nation was safe and effective for modulating sustained effect is particularly desirable to enhance persistent mating-induced endometritis in suscepti- lymph flow and consistent intraluminal evacuation ble mares; the glucocorticoid treatment decreased of accumulated fluid (inflammatory transudate). endometrial edema, accumulation of intraluminal Despite its indisputable efficacy as an ecbolic hor- uterine fluid and its turbidity, without altering the mone, the use of PGF during estrus, especially in amount of polymorphonuclear cells seen in prepara- the early post-ovulatory period, was found to tran- tions obtained from endometrial cytology. Ferris siently affect luteal function. Some studies con- and McCue22 studied the effects of multiple (twice firmed this effect on luteal function that was daily for 5 days) glucocorticoid treatments (pred- followed by a resurgence in CL function.17,18 It is nisolone or dexamethasone in mares during early unknown whether this early effect in suppressing estrus. They reported that mares treated with luteal function would affect the fertility of treated dexamethasone showed reduced uterine edema and mares. For this reason, if PGF is to be used as an ovulation rate (40% versus 83%, respectively) than ecbolic to treat delayed clearance during estrus and mares treated with prednisolone. In addition, only early postovulatory period, it is important that two of five dexamethasone-treated mares had unal- equine practitioners remain cognizant of its effects tered LH hormonal profiles, whereas five of six on luteal function. Most mares so treated should mares treated with prednisolone had LH surges have resurgence in luteal function and not have within normal limits. The differences noted be- deleterious effects on their luteal function and sub- tween dexamethasone and prednisolone may derive sequent fertilities.19 Moreover, our laboratory has from their differences in relative potencies in rela- recently reported that the effect of PGF administration to cortisol (dexamethasone ϭ 30; pred- tion on early luteal function can induce luteolysis nisolone ϭ 4). Nevertheless, it is unlikely that a or antiluteogenesis, depending on the duration of single treatment with dexamethasone as prescribed treatment after ovulation and on dosage used.3 by Bucca and Carli21 would result in ovulation fail- For these reasons, treatments with PGF during es- ure as only mares with multiple, daily treatments trus should not continue beyond 24 hours after ovu- with dexamethasone have been shown to have al- lation. Whenever indicated, low doses of PGF (eg, tered endogenous LH release that resulted in signif- 62.5–125 ␮g cloprostenol or 1.25 mg dinoprost), icant ovulation failures. It is important, however, which are capable of inducing uterine contractions, to ensure that mares being treated with glucocorti- are recommended for treating mares with delayed coids during estrus are also treated with ovulation- uterine clearance. inducing agents to prevent any potential negative effects of glucorticoid agents in the hypothalamic- 7. Modulation of Mating-Induced Endometritis With hypophyseal axis that may result in anovulation. Steroids Bucca et al23 provided supporting evidence to the Endometritis after artificial insemination or mating efficacy of associating induction of ovulation with is one important cause of infertility especially in glucocorticoid treatment in mares susceptible to per- mares susceptible to persistent mating-induced sistent post-mating endometritis. Mares treated endometritis. In addition to therapies aimed at with a single bolus intravenous injection of 50 mg of combating endometritis by use of intrauterine or dexamethasone within 1 hour of breeding and con- systemic antibiotic treatment and stimulation of current induction of ovulation with 1500 IU of hCG myometrial function through administration of ec- exhibited normal ovulation rates (ϳ97% of mares bolic hormones (mainly oxytocin and PGF), another ovulated within 48 hours). The minimal dose of strategy is to control or modulate the exacerbated prednisolone and dexamethasone to combat inflam- inflammation response seen in these mares. mation in mares during estrus has yet to be Dell’Aqua et al20 first reported on the efficacy of determined. prednisolone treatment of mares during estrus that 8. Conclusions benefited from the glucocorticoid modulatory effects on barren mares afflicted with endometritis. A Several pharmacologic agents are now available for significantly higher pregnancy rate was seen in bar- use in the breeding management of broodmares. ren mares treated 5 times with 0.1 mg/kg of pred- Strategic utilization of hormones to induce estrus nisolone acetate (ϳ50 mg per mare) administered and ovulation and to modulate/prevent inflam- every 12 hours with four treatments occurring be- matory processes in mares susceptible to mating- fore artificial insemination (AI) and one at AI. induced endometritis and delayed uterine clearance In 2008, Morris reported promising results used can significantly affect the outcome of breeding the same protocol described by the Dell’Aqua, except by increasing the odds of timed ovulation and she used a dose of 200 mg of oral prednisolone per pregnancy. 21 mare. More recently, Bucca et al, reported on the References and Footnotes use dexamethasone given as a single bolus admin- 1. Oxender WD, Noden PA, Louis TM, et al. A review of pros- istration of 50 mg per mare at time of breeding. taglandin F2alpha for ovulation control in cows and mares. In that study, the authors concluded that dexameth- Am J Vet Res 1974;35:997–1001.

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2. Barker C, Echeverria, Davis M, et al. Effects of different 15. Schramme AR, Pinto CR, Davis J, et al. Pharmacokinetics

doses of PGF2␣ on luteal function and on the subsequent of carbetocin, a long-acting oxytocin analogue, following in- estrous cycle. Anim Reprod Sci 2006;94:207–209. travenous administration in horses. Equine Vet J 2008;40: 3. Rubio C, Pinto CR, Holland BE, et al. Anti-luteogenic and 658–661.

luteolytic effects of PGF2a during the post-ovulatory period in 16. Steckler D, Naidoo V, Gerber D, et al. Ex vivo influence of mares. Theriogenology 2008;70:58. carbetocin on equine myometrial muscles and comparison 4. Cuervo-Arango J, Newcombe JR. Relationship between with oxytocin. Theriogenology 2012;78:502–509. dose of cloprostenol and age of corpus luteum on the luteolytic 17. Nie GJ, Johnson KE, Wenzel JG, et al. Effect of adminis- response of early dioestrous mares: a field study. Reprod tering oxytocin or cloprostenol in the periovulatory period on Domest Anim 2012;47:660–665. pregnancy outcome and luteal function in mares. Theriog- 5. Day FT. Ovulation and the descent of the ovum in the fallo- enology 2003;60:1111–1118. pian tube of the mare after the treatment with gonadotropin 18. Troedsson MH, Ababneh MM, Ohlgren AF, et al. Effect of hormones. J Agric Sci Camb 1939;29:459–469. periovulatory prostaglandin F2alpha on pregnancy rates and 6. Bollwein H, Braun J. Follicular dynamics after treatment luteal function in the mare. Theriogenology 2001;55:1891– with hCG for ovulation induction in mares. Tierarztl Prax 1899. Ausg G Grosstiere Nutztiere 1999;27:47–51. 19. Bergfelt DR, Pierson RA, Ginther OJ. Regression and re- 7. Roser JF, Kiefer BL, Evans JW, et al. The development of surgence of the CL following PGF2alpha treatment 3 days antibodies to human chorionic gonadotrophin following its after ovulation in mares. Theriogenology 2006;65:1605– repeated injection in the cyclic mare. J Reprod Fertil Suppl 1619. 20. Dell’Aqua JA, Papa FO, Lopes MD, et al. Modulation of 1979;27:173–179. acute uterine inflammatory response after artificial insemi- 8. Andreyko JL, Marshall LA, Dumesic DA, et al. Therapeutic nation with equine frozen semen. Anim Reprod Sci 2006;94: uses of gonadotropin-releasing hormone analogs. Obstet Gy- 270–273. necol Surv 1987;42:1–21. 21. Bucca S, Carli A, Buckley T, et al. The use of dexametha- 9. Meinert C, Silva JF, Kroetz I, et al. Advancing the time of sone administered to mares at breeding time in the ovulation in the mare with a short-term implant releasing the modulation of persistent mating induced endometritis. GnRH analogue deslorelin. Equine Vet J 1993;25:65–68. Theriogenology 2008;70:1093–1100. 10. McCue PM, Farquhar VJ, Carnevale EM, et al. Removal of 22. Ferris RA, McCue PM. The effects of dexamethasone and deslorelin (Ovuplant) implant 48 h after administration re- prednisolone on pituitary and ovarian function in the mare. sults in normal interovulatory intervals in mares. Theriog- Equine Vet J 2010;42:438–443. enology 2002;58:865–870. 23. Bucca S, Carli A. Efficacy of human chorionic gonadotropin 11. Ferris RA, Hatzel JN, Lindholm ARG, et al. Efficacy of to induce ovulation in the mare, when associated with a deslorelin acetate (SucroMate) on induction of ovulation in single dose of dexamethasone administered at breeding time. American Quarter Horse mares. J Equine Vet Sci 2012;32: Equine Vet J Suppl 2011;40:32–34. 285–288. 12. Lindholm ARG, Ferris RA, Scofield RB, et al. Comparison of aLutalyse, Pfizer Animal Health, Kalamazoo, MI 49001. deslorelin and histrelin for induction of ovulation in mares. bEstrumate, Merck Animal Health, Summit, NJ 07091. J Equine Vet Sci 2011;31:312–313. cGenestran, FORTE Healthcare Limited, Naul, Dublin, Repub- 13. Voge JL, Sudderth AK, Brinsko SP, et al. Comparison of lic of Ireland. efficacy of two dose rates of histrelin to human chorionic dChorulon, Merck Animal Health, Millsboro, DE 19966. gonadotropin for inducing ovulation in broodmares. eOvuplant, Zoetis Canada, Kirkland, QC H9J 2M5 Canada. J Equine Vet Sci 2012;32:208–210. fSucromate is a product of and manufactured by Thorn BioSci- 14. Levy I, Duchamp GA. single subcutaneous administration ence, Louisville, KY, a division of CreoSalus; it is marketed by of buserelin induces ovulation in the mare: field data. Re- Bioniche Animal Health USA, Inc, Athens, GA 30601. prod Domest Anim 2007;42:550–554. gReceptal®, Intervet Ltd., Upper Hutt, New Zealand.

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