Ovulation Induction

ovulation_inductionThorn BioScience LLC has sponsored several studies efficacy of sucrose acetate isobutyrate (SAIB), in horses. SABER™ Mate is presently developed for inducing ovulation within 48 hours in estrus mares with ovarian follicles 30 mm or greater, especially in mares with follicles between 30mm and 40mm.

The selection of an appropriate drug delivery system should be based on the pharmacokinetic and pharmacodynamic properties of the drug. Frequently, most of the emphasis is given to the pharmacokinetic characteristics of the drug including release rates, protein binding, and clearance rates while less attention is often given to the drugs pharmacodynamic properties such as the concentration-effect relationship. The importance of a drug’s pharmacodynamic properties is especially relevant in the case of natural hormones or synthetic analogs of natural hormones that target specific high affinity receptors to produce their effect.

In the case of GnRH or its analogs, this relationship is dependent on multiple elements including the target species, reproductive status of the target species and complex concentration /presentation-effect properties (i.e. pulsatile vs continuous administration) of the peptide and pituitary responsiveness to it. In the mare, current data suggest that ovulation induction treatment with potent analogs require multiple injections (2 to 4 at 12 hour intervals) of very low doses (40 m g buserelin)1 or a high dose ( 2.1 mg deslorelin) given as a slow releasing implant2 or using the SABER ™ Delivery System, a new biodegradable controlled release delivery system. 3-5

One Thorn BioScience backed study was designed to confirm the clinical effectiveness of the GnRH analog Deslorelin when administered using the SABER ™ Delivery System. The study was conducted in estrous mares with ovarian follicles 30 mm or greater, especially in mares with follicles between 30mm and 40mm, and will examine deslorelin’s ability to accelerate ovulation within 48 hours.

2. HISTORY AND RATIONALE

Nearly 28 years ago, Loy 6(1970) reported that only 55% of mares bred annually produce live foals. The most recent 1996 figures from “The Jockey Club” indicate that only 33,351 of 60,284, or 55%, of the thoroughbred mares bred during 1995 produced live foals7.. This is considerably lower than foaling rates of 76 to 84% which are achieved on farms where proper, extensive reproductive management is used8. Thus it seems that reproductive management has not improved much in the last 27 years. The extended estrus period, with ovulation at any time from 1 to 10 days after the beginning of estrus, has made reproductive management of mares time-consuming, expensive and most importantly, inefficient. Moreover, to most effectively manage the breeding stallion, mares should be mated or inseminated close to the time of ovulation.9,10 Therefore, development of an accurate economical method for the precise control of ovulation in the mare would greatly benefit reproductive management of broodmares and stallions.

Currently, a single injection of human chorionic gonadotrophin (hCG: 2000 to 3300 I.U.) has been demonstrated to be efficacious for hastening ovulation in mares 11-13. However, repeated use of hCG has been associated with decreased response12 and anti-hCG antibody formation14. Therefore, researchers have sought alternative nonantigenic substitutes for hCG for advancing ovulation in mares.

The ability of GnRH13, or its more potent analogs1-4 , to stimulate LH release has led to their use for ovulation induction. Unfortunately, a single treatment with GnRH or its more potent analogs have resulted in inconsistent induction of ovulation in mares6b,17,18. Multiple injections of a GnRH analog given at 12 hour intervals for an average of 3.8 injections resulted in effective ovulation induction1 . However, multiple injections are not considered practical. Recently, deslorelin, a potent GnRH analogue, delivered via a short term release implant2 or using the SABER ™ Delivery System, a new biodegradable controlled release delivery system,3-5 has been demonstrated to consistently advance ovulation within 48 hours in estrous mares having follicles 30 to 40mm in diameter.

REFERENCES

1. Harrison, L.A., Squires, E.L., and A.O. McKinnon 1991. Comparison of hCG, buserelin, and luprostiol for induction of ovulation in cycling mares. J. Eq. Vet Sci. 11:163-166.

2. Jochle, W, Trigg, T.E. 1994. Control of ovulation the mare with OVUPLANTÔ a short-term releasing implant(STI) containing the GnRH analogue Deslorelin Acetate. J Eq Vet Sci 44:632-644.(in Recommended Reviews).

3. Burns, P.J., Thompson, Jr., D., Donadue, F, Kincald, L., Leise, B., Gibson, J., Swaim, R.,and A.J. Tipton. (1997) Pharmacodynamic Evaluation of the SABERÔ Delivery System for the Controlled Release of Deslorelin Acetate for Advancing Ovulation in Cyclic Mares. Proceed. Intern. Symp. Control. Rel. Bioact. Mater., Stockholm, Sweden. 24: 737-738 (in Recommended Reviews in Apendix B)

4. Fleury, J.J., Squires, E.L., Betschart, R., Gibson, J., Sullivan, S.,Tipton, A., and P.J. Burns (1998) Evaluation of the SABERÔ Delivery System for the Controlled Release of Deslorelin Acetate for Advancing Ovulation in the Mare: Effects of Formulation and Dose. Proceed. Intern. Symp. Control. Rel. Bioact. Mater., Las Vegas, NV. p.

(in Recommended Reviews in Apendix B)

5. Betschart, R., Fleury, J.J., Squires, E.L., Nett, T., Gibson, J., Sullivan, S., Tipton, A., and P.J. Burns (1998) Evaluation the SABER : Effect of Gamma Radiation. Proceed. Intern. Symp. Control. Rel. Bioact. Mater., Las Vegas, NV. p. Recommended Reviews in Apendix B

4. Loy, R.G. (1970). Management and other factors affecting breeding efficiency in mares. Proc. 3rd Techn. Conf. Artif. Insem. Reprod., Chicago, Illinois.

5. The Jockey Club 1996 Live Foal Percentages. The Blood Horse: Vol 39, 4794,1996

6. Ginther, O.J. (1992) Reproductive of the Mare: Basic and Applied Aspects. 2nd Edition, Equiservices, Cross Plains, Wisconsin. A p 508; b 262

7. Woods, J., Bergfelt, D.R. and O.J. Ginther. 1990. Effect of time of insemination relative to ovulation on pregnancy rate and embryonic loss rates in mares Eq. Vet. J. 22: 410-415.

8. McCarthy, P.F. and N. Umphenour 1992. Management of stallions on large breeding farms. In: Blanchard, T.L. and Varner, D.D. (eds) Stallion Management. Vet Clin. N. Amer. Equine Prac. 8: 219-236.

9. Loy R.G. and Hughes J.P. 1966. The effects of human chorionic gonadotropin on length of estrus and fertility in the mare. Cornell Vet 56:41-50.

10. Sullivan,J.J., Parker W.G. and Larson, L.L. 1973 Duration of estrus and ovulation time in nonlactating mares given hCG during three successive estrous periods. J AM. Vet. Med. Assoc. 63:895-898. (1973).

11. Voss J.L., Sullivan, J.J.,Picket, B.W., Parker, W.C., Burwash,L.D., and Larson,L.L.,1975. The effect of hCG on duration of oestrus, ovulation time and fertility in mares. J. Reprod.Fert. Suppl. 23:297-301.

12. Roser, J.J.,Kiefer B.L. and Evans,J.W. 1979. The development of antibodies to human chorionic gonadotropins following its repeated injection in the cyclic mare. J. Reprod.Fert.Suppl.173-179.

13. Ginther, O.J., and B.C. Wentworth 1974. Effect of a synthetic gonadotropin releasing hormone on plasma concentrations of luteinizing hormone in ponies. Am. J. Vet. Res., 35: 79-81.

14. Squires, E.L., Slade, N.P. and T.M. Nett. 1983. Effect of GnRH analogue on duration of estrus and secretion of gonadotrophins. Proc. 8th Eq. Nutr. Physiol. Symp. 273-279.

15. Irvine, D.S, Downey, Fr, Parker. W.G. and Sullivan, JJ. 1975 Duration of oestrus and time of ovulation in mares treated with synthetic GnRH (Ay24,031). J Reprod. Fert. Supp 23:279-283.

16. Wallace, R.A., Squires, E.L., Voss, J.L., Pickett, B.W. 1977 Effectiveness of GnRH or GnRh analogues in inducing ovulating and shortening estrus in mares. Abstr# 535 69th Annu Meet Anim Sci, Madison WI.