Ovulation-inducing drugs beneficial when used in 'proper context'

source-image
Apr 01, 2001

Breeding season is in full swing and once again those difficult situations are starting to pop up.

The mare you are working on is in Florida. The stallion she is to be bred to is in New York. That particular stallion's shipped semen is really only good for about 36 hours, so, with shipping figured in, you do not have much room for error and would really like to be inseminating close to ovulation.

The stallion you manage is fully booked, leaving little room for re-breeds, so you are under pressure to increase timely first service; or the stud farm will only collect on alternate days and you may be getting the semen too soon or too late; or there are three mares, all cycling with follicles at different stages, for a stallion that is very difficult to collect. You would like to make one collection, split the semen, inseminate, and have a reasonable chance of getting these mares pregnant.

These are very familiar problems for this time of year and situations that can mean success or failure for your client's breeding program.

Drug response

Veterinarians have responded to these situations by using various drugs to influence a mare's cycle.

The standard agent used to induce or "speed up" ovulation has been hCG or human chorionic gonadatropin. This drug is given to mares with enlarging follicles and it serves to hasten the process of ovulation. Mares with follicles close to 40 mm or larger are often given this drug, and ovulation is generally expected within 48 hours. Many mares will ovulate sooner and some will ovulate later, so the practitioner must still try to inseminate as close to ovulation as possible. Wait too long and you've missed her. Inseminate too soon and she must be re-bred. Standard practice is to examine mares repeatedly and, when a follicle reaches appropriate size, to inseminate and give that mare hCG.

The mare must then be examined to ensure that ovulation occurs within the typical 48-hour window of sperm viability. If ovulation does not occur in that timeframe, then the mare must be re-bred.

Proven success

Human chorionic gonadatropin has been used successfully for many years and most practitioners feel comfortable with its use. Mares must be available for frequent ultrasound examinations for this protocol to work, however, and some mares can become refractory to repeated hCG use.

In 1999, the drug deslorelin acetate was approved for use in the United States. Deslorelin is a subcutaneous implant of a GnRH agonist marketed by Fort Dodge Animal Health under the name Ovuplant.

This drug was introduced with the claim that most mares would ovulate within a much smaller interval and that breeding could therefore be more tightly controlled.

Mares with a follicle greater than or equal to 35 mm in diameter will ovulate not sooner than 36 hours and generally not longer than 48 hours after administration of Ovuplant. And the reported numbers seem to back up these claims. Because different studies use different numbers of mares and different evaluation criteria, the actual percentages vary, but Fort Dodge reports that approximately 2 percent of mares given Ovuplant will ovulate within 36 hours of implantation. Between 86 and 95 percent of treated mares will ovulate between 36 and 48 hours and 5 to 10 percent of such mares will ovulate later than 48 hours post treatment.

This dramatic increase in the number of mares that will ovulate within a specific time post-treatment (between 36 and 48 hours) is the key point in the potential usefulness of this drug.

Palpation of a follicle greater than or equal to 35 mm allows the veterinarian to administer Ovuplant to the mare and then schedule breeding within the next 48 hours. Roughly 90 to 95 percent of these mares will ovulate within that timeframe and the DVM's job of ensuring that sperm and egg are present at the same time will have been done. Hopefully, a pregnancy will be the result of this crucial timing.

According to Drs. J. Morehead and T. Blanchard, many breeding farms actually prefer to administer ovulation-inducing drugs after the mares have been bred. Unforeseen problems such as injuries to stallions, semen shipments delayed in the mail, trailering problems and so forth can occasionally prevent a scheduled breeding. If drugs such as Ovuplant and hCG are not given until after breeding, then the likelihood of a mare ovulating too soon is eliminated.

Rumors, rhetoric

At first glance it would seem that Ovuplant would fit nicely into any equine reproductive program and may help improve the efficiency of breeding. However, following its first year of commercial use in the United States during 1999 some important information about deslorelin started to become available and the controversy began.

Researchers in Kentucky began reporting that some mares treated with Ovuplant that did not become pregnant on their first cycle showed a prolonged return to estrous. Reports of 35-day cycles began to appear. Some mares were rumored to have shut down completely and many practitioners therefore turned away from Ovuplant use. As usual, the truth lies somewhere between the rumors and the rhetoric.

Since that first year, much has been uncovered about the actual use and effects of deslorelin. Numerous studies have shown that deslorelin acetate administration is associated with decreased follicle stimulating hormone (FSH) during the diestrous period following ovulation.

Drs. McCue, Farquhar and Squires of the Equine Reproductive Laboratory at Colorado State University have stated that this decreased FSH serum concentration may lead to decreased follicular development and a delay in the subsequent emergence of a dominant follicle. This produces an increase in the time required for return to estrus. Their study showed that Ovuplant treated mares had an average interovulatory interval of 25.6 days compared to 22.9 days for mares not given deslorelin.

A similar study by Drs. Morehead and Blanchard showed that 80 percent of Ovuplant treated mares had cycles of 18-25 days while 97 percent of untreated mares had cycles of that length. Nineteen percent of deslorelin treated mares had cycles longer than 25 days and no untreated mares had cycles that long.

These two studies point out two facts. Treatment with Ovuplant seems to delay return to estrus in mares and there are numerous ways to measure and report this observation so the actual numbers may vary. Fort Dodge's own studies confirm that there is a delay of two to five days in return to estrus when mares are treated with Ovuplant.

Dr. Paul Schober of Peptide Animal Health in Australia takes a more practical approach to this information.

As a proponent of Ovuplant, Schober feels that "a few days delay in return to estrous is the consequence of using a drug that may be able to help a veterinarian better time an important breeding and obtain a pregnancy."

While the consequences of delayed return to estrous and lost breeding time cannot be overlooked, Schober feels that the pluses and minuses of Ovuplant use must be weighed for each individual mare and each situation.

Dr. R. Holder of Haggard, Davis and McGee in Lexington, Kentucky agrees and states that, "essentially it is a good product that works but it does have a side-effect (prolonged return to estrus)."

A few days delay in return to estrus may be an acceptable "consequence" of this product's use, but what of those mares showing cycles of 30 days or more?

Schober addressed this question and pointed to research at numerous farms that showed that there was a small percentage of mares that had severely prolonged cycles (greater than 30 days) regardless of treatment.

One Standardbred farm in Maryland reported that five untreated mares out of 200 horses had cycles of longer than 30 days. Mares treated with Ovuplant showed tremendous variation in the percentage of severely prolonged cycles. One Thoroughbred farm in Kentucky reported no cycles over 25 days while one Standardbred farm also in Kentucky reported 30 percent of mares with cycles over 25 days.

Researchers have been searching for some other factor or factors that may explain this variability. None has been identified to date. Schober feels that perhaps the mares selected for these studies are a "biased" population. To explain, he uses the example of a farm with 100 broodmares. Of these horses roughly 20 percent are "problem breeders" for whatever reason. All of the mares are given Ovuplant and bred on their first cycle. Using a generous figure, assume 70 percent become pregnant. This leaves 30 open mares, of which, he feels, likely almost 15 may be from the original 30 problem mares.

The statistics for return to cycle then include a high percentage of mares that have some problem unrelated to Ovuplant use. To carry this thought out one more cycle, Schober assumes that 20 mares become pregnant out of the 30. This leaves 10 mares of which, it is likely all 10 are original "problem" mares. Any information for the next cycle will be from a very selective population that may have any number of factors influencing return to estrus.

Schober backs up this analysis with data from field studies on a number of farms which show that the percentage of mares with excessively prolonged return to estrus does not vary between treated and non-treated horses.

"The very long ones are always there," says Schober.

Other interesting facts

A few other interesting facts have been brought up concerning deslorelin.

No research has shown that Ovuplant use has actually "shut down" cycles in the horse and Schober confirms that one would have to use more than 10 times the dose to fill all the receptors and get enough "down regulation" of FSH to effectively shut down ovarian cyclical activity.

Research in this area of Ovuplant pharmacology may well lead to a product that is of benefit to equine practitioners in a totally different way. Studies are under way that may produce a product that can be used in show horses to keep them from cycling during the show season. Many progesterone-based products are currently available for this purpose but they are not always effective for certain mares.

Injectable Depo-Provera and progesterone implants may not last very long in some mares and liquid progesterone requires daily handling and dosage.

The development of a deslorelin implant that can effectively stop cyclical activity may be beneficial and well accepted by certain sections of the horse show community.

Ultimate goal

The ultimate goal of the equine veterinarian during breeding season is to get mares bred.

No one works on a broodmare thinking about her return to estrus. Positive thinking would say that she would get pregnant the first time. But this is not always true and attention must be paid to the consequences of a return to estrus.

Deslorelin is a beneficial product when used in the right context and when the potential problem of longer cycles associated with its use has been taken into account. The argument over Ovuplant use should no longer be whether it causes prolonged return to estrus or not, or exactly how many days longer that estrus is. These questions have been reasonably answered. The only argument now is whether this drug is appropriate for your particular situation

Holder's advice, perhaps, sums up the best approach to Ovuplant use.

"It is a good product," he states. He cautions, however, that clients must be counseled on its possible downsides. End of argument.