Ovulation induction and failure in mares: What’s new?

Human chorionic gonadotropin (hCG) is still the most used ovulation induction drug in the mare, at least in Europe. Doses of 750 to 3000 IU (administered subcutaneously, intramuscularly, and intravenously) have been proven to be successful at inducing ovulation within 48 h of treatment. However, it is well known that its efficacy decreases after the second treatment when administered in the same mare and season, due to the development of antibodies against hCG. In some mares, these antibodies may last for several years. Therefore, some studies have reported a reduction in the ovulatory response to hCG in aged mares (i.e. > 10 years old). As a result, the use of GnRH agonists has become popular as an alternative to hCG to induce ovulation in the mare. Several compounds of different potency, formulations and doses have been tried successfully in the mare for induction of ovulation. Deslorelin, buserelin, and histrelin have been used successfully as single treatment and are commercially available (either licenced for horses or humans) to induce ovulation in mares. Most recently, tripterolin has been shown to induce ovulation in mares as efficaciously as hCG or buserelin. The efficacy of GnRH agonists in inducing ovulation is reduced in spring transitional mares, as the LH pituitary reserves are low in non-cyclic mares. Therefore, in transitional mares, a combination of hCG and a GnRH agonist may be used to improve timely ovulation induction. In cyclic mares, higher doses of GnRH agonists are often needed when the drug is produced in a slow-release (long-acting) formulation (i.e. >1.25 mg per treatment; for example Ovuplant®: 2.1 mg; Sucromate®: 1.8 mg; BioRelease®> 1.25 mg, etc.). On the other hand, GnRH agonists formulated in saline or aqueous excipients can induce ovulation at a much lower dose. Buserelin (Suprefact®) at a dose as low as 125 μg (0.125 mg) in single treatment induced ovulation within 48 h in 85% of treated mares [1]. Although there have not been direct comparisons between hCG, GnRH agonists in aqueous and in slow-release formulations, it appears that hCG and GnRH agonists in aqueous solutions induce a slightly lower ovulatory response within 48 h when treated in a random population of mares (breeding stud, and varies between 78 and 90%) compared to slow-release formulations of GnRH agonists (deslorelin) which report ovulatory responses within 48 h from 87 to 93%, despite earlier start of treatment (i.e. follicular diameter at induction of ≥30 mm in diameter). However, the latter compounds are usually not available in many countries and their cost is high compared with hCG and other GnRH agonists licenced for humans (in aqueous formulations). Nevertheless, following the use of ovulatory induction drugs in mares, ovulatory failure or delayed ovulation are relatively common and frustrating outcomes. It is important to differentiate amongst these two outcomes, as the mechanisms underlying the causes are completely different. In the first place, and the most likely outcome, is the delayed ovulation. In this case, the ovulation induction drug is administered in what is believed to be the right moment: a growing dominant follicle of 35 mm or larger in diameter, from an estrous mare with obvious endometrial edema. However, the mare does not ovulate within the expected time frame after induction (36 to 48 h). On the contrary, the follicle continues to grow, and the endometrial edema remains similar or increases in intensity for an extra 24 to 96 h, before the follicle finally ovulates. This represents typically a 7 to 20% of induced cycles in cyclic mares, and the main reason for this is that the mare was too far from spontaneous ovulation to respond to the ovulatory drug, despite having a follicle size of what is considered enough to respond (and most mares would) to the ovulatory induction drug. The statistical analyses of large data sets of mares that did not respond to the ovulatory induction drug in a timely manner often show that the single most relevant factor was the follicle diameter at the time of induction (significantly lower diameter compared to that of responding mares). The percentage of delayed ovulations is significantly increased in transitional mares, before the first ovulation of the breeding season, owing to the reduced LH reserve of the pituitary in spring transitional mares. The second possible outcome is a true ovulatory failure, and this has two possible presentations. In the first presentation, the leading follicle on which the drug was administered and intended to induce ovulation, does not ovulate but undergoes atresia or “follicle regression”. These follicles are more commonly found in a) spring transition, b) mares with two major follicular waves (diestrous follicles), and less frequently c) in post-partum mares which after producing a dominant sized follicle during the foal heat, enter a temporary anestrous phase in which the follicle remains static or regresses. On such occasions, the regressing follicles do not luteinize despite showing a varying number of echoic specks within the antrum, and the mare feels anestrous on rectal palpation unless it has a CL (option b). The second presentation to a true ovulatory failure, is the development of a hemorrgahic anovulatory follicle (HAF), in which the oocyte is not released, and fertilization is not possible. This may occur in up to 5-8% of all cycles, with an increased incidence during the months of the peak breeding season (June-July in the N.H.). In fact, the ovulatory drugs function well, as the HAF cycles has the similar LH and estradiol hormonal patterns as ovulatory cycles. The HAF luteinizes and functions as a CL, producing progesterone, and therefore the mare enters a standard period of diestrus (13 to 16 days), after which the HAF regresses and the mare comes back in heat and a new dominant follicle can be induced. The aetiology of HAF still remains unknown. However, in an experimental model, they were reverted to ovulatory follicles by intrafollicular administration of PGE₂ and PGF_2α.

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