If you're a breeder, frankly, it pays to be in the livestock business. Cattle, sheep, goats, and pigs all make life easy for those trying to produce young stock--they are all "facultative-induced ovulators," meaning that matings early in their estrous periods can accelerate their rate of ovulation. In practical terms, this means you can easily calculate the ovulation of a sow or ewe by the clock from the onset of estrus; which, for the breeder, is a huge advantage. It means a high success (pregnancy) rate with a single, correctly timed semen placement (whether by natural breeding or artificial insemination), and very little necessity for rectal palpation or ultrasound exams to determine follicle growth or impending ovulation.
Horses, by comparison, are considerably more cantankerous. Not only are mares not facultative-induced ovulators, they have proven to be one of the most difficult species in which to predict ovulation.
The nature and length of a mare's estrus (or "heat") can vary widely, as can the interval between the beginning of estrus and the release of an actual ovum from the follicle. Species differences in pituitary function (which controls the release rates of reproductive hormones such as follicle stimulating hormone, or FSH, and luteinizing hormone, or LH) are largely to blame.
For the breeder, this means it is extremely difficult to accurately predict when a mare is going to ovulate--so getting a mare in foal often entails a number of repeat visits to a stallion, not to mention a number of repeat visits from the veterinarian to do rectal palpations, ultrasounds, inseminations, and pregnancy checks; all of which, of course, costs time and money, and might still leave you with a barren mare at the end of the breeding season.
For this reason, therapies designed to reliably control ovulation in mares have been an essential part of the horse breeding business for almost a quarter-century. Human chorionic gonadotropin, or hCG, which mimics the function of LH in the mare's ovulatory response, is a familiar tool in any reproductive veterinarian's arsenal. A 2,500 I.U. injection, either intravenously or intramuscularly, given at the appropriate time in a mare's estrus, will induce ovulation within 24 to 48 hours.
But hCG is not without problems. Most significant is its tendency to produce "refractiveness," which is a reduced effectiveness with repeat use. Because hCG is a large and complex molecule, it tends to trigger an immunologic response in the mare. So if a mare fails to "catch" when first bred, and hCG is administered in successive heats, antibodies tend to bind to it, rendering it less and less effective.
Now there's a new drug on the horizon, which sidesteps the refractory response by mimicking the action of gonadotropin releasing hormone, or GnRH. GnRH plays a role earlier in the chain of command of ovulation than does LH--it's one of the hormones that stimulates the pituitary to produce FSH (for follicular growth) and LH (for ovulation and luteinization). This new synthetic version is a deca-peptide, meaning it is composed of only ten amino acids, which makes it comparatively tiny on a molecular scale and thus unlikely to trigger an immune response.
The mimic is called Deslorelin, and the peptide technology that led to its birth was developed in Australia, originally to stimulate ovulation in anestrous mares in winter. Dr. Wolfgang Jöchle, a noted independent pharmaceutical consultant researcher, initiated a number of studies in ten countries (including Brazil, Canada, Austria, the United States, and Germany) on Deslorelin, and was instrumental in its development, five years later, as a product called Ovuplant. What's unique about this product is its method of delivery--the drug is contained in a biodegradable, sustained release, subdermal implant, which is injected into the neck of the mare to induce ovulation within 48 hours. Already approved in Australia and Canada, USDA approval for release to veterinarians in the United States is being sought for the 1997 breeding season.
Field Studies and Findings
Patrick J. Meyers, DVM, a Canadian veterinarian who has been associated with the University of Guelph's renowned Equine Research Centre and Ontario Veterinary College, participated in studies of Ovuplant's effectiveness and safety both at the ERC and at Seelster Farms, a large Ontario Standardbred operation, in 1993 and 1994.
"I headed up eight or nine investigations with the product," he said, "the results of which were presented at the 1994 American Association of Equine Practitioners meeting in Vancouver. We summarized several studies in both Canada and the United States, encompassing approximately 187 mares of several breeds--Thoroughbreds, Standardbreds, Quarter Horses, Arabians, and Saddlebreds."
Earlier studies had already established an optimum dosage for Deslorelin. A pilot study in Australia, during the 1990-91 breeding season, exposed 77 "light-horse-type" mares to concentrations of the drug ranging from 1.3 mg and 1.6 mg, up to 2.2 mg; the results clearly indicated that the higher dosage, 2.2 mg, was most effective (95.7%) in producing ovulation within 48 hours (as compared to 16% of mares which ovulated within 48 hours on a placebo).
Another pilot study of 140 Hanoverian broodmares in Germany and the United States established the optimum time to administer Deslorelin. After Deslorelin implants of either 1.5 mg or 2.25 mg were administered, 93% of the mares ovulated within 48 hours--a result comparable to the control group which were given hCG. However, the size of the existing ovarian follicle proved to be the crucial factor, not the time in the estrous period. The study determined that a follicle size of 30 mm or larger (determined by ultrasound and/or rectal palpation) was significant in the drug's effectiveness, and all further studies were based on that benchmark.
As Meyers pointed out, Ovuplant is not really designed as a "home ovulation kit" for breeders.
"A veterinarian's participation is still very necessary in order to pinpoint when the follicle is at the correct size to administer the drug," he said. "Personally, I like to wait until the follicle is at least 35 mm in diameter. And, of course, it's not just the size that matters--an experienced veterinarian will also be able to tell, by palpation, when the follicle is 'soft' enough to be ready to go."
He noted that the optimum size of the follicle might vary a bit from mare to mare--the larger the mare, the more he leans towards the 35 mm mark.
Further studies in North America and Europe established Ovuplant's safety. Throughout the five-year series of studies, the injection sites for the drug were carefully examined for signs of reactions, and very little adverse effect was recorded. In all, the injection sites of some 967 mares were examined on a daily basis for seven days following treatment, and the difference between reactions from an injection of the drug and an injection of a placebo implant was not statistically significant.
"The implanting tool comes in a self-sealed, sterile package," noted Meyers, "but it is a 12-gauge needle, which is a fairly large bore. So, the injection site does tend to leave a little hole, which heals up pretty well in a day or two. In the odd horse, we noted a little localized swelling, which went away in two to three days, but there were no signs of allergic reaction to the drug or its medium (which the Canadian distributor, Ayerst, calls an "inert matrix," the formula for which is closely guarded)."
A series of studies in 1991 and 1992 determined that Ovuplant had no adverse effect on actual pregnancy rates (which ranged from 80.0% to 97.1% after treatment with the drug, not statistically different from the study's control group). Nor did the use of Deslorelin have any impact on pregnancy loss, foal vitality, lactation, or the incidence of twinning. These same studies also uncovered the welcome news that mares did not develop a tolerance (or refractiveness) to Ovuplant with repeated use.
The effectiveness of Ovuplant is dependent on it being administered at the right time, i.e., when an ovarian follicle reaches at least 30 mm in diameter. Outside of that parameter, its impact on ovulation is considerably less. In a Brazilian study of Thoroughbred mares, one farm that administered Ovuplant at the correct time reported an 82.1% incidence of ovulation within 48 hours, while another farm that used Ovuplant incorrectly (i.e., too early or too late) reported only 69.3% of mares ovulating within that timeframe.
Ovuplant, marketed in Canada by Ayerst Laboratories (Guelph, Ontario), actually comes as a tiny cylinder, 3.6 mm long and 2.3 mm in diameter, and containing 2.1 mg of Deslorelin (as Deslorelin acetate), pre-loaded in a sealed, disposable syringe with a 12-gauge needle. It is administered sub-cutaneously (just under the skin) in the neck of the mare midway between the head and the shoulder--in roughly the same area one would give an intramuscular injection. Over a period of about a week, it is slowly lysed by the horse's natural hydrolytic enzymes, and completely dissolves. The drug itself is only released for 48 hours or so, posing no threat to a new pregnancy.
"The implant is a completely novel technology," noted Meyers. "It's totally biodegradable--unlike most other implants people are familiar with, such as (the human contraceptive) Norplant. What's really exciting is the enormous potential this slow-release technology has for other applications, such as the administration of antibiotics and vaccines. It's going to work its way into every aspect of the animal health industry very soon."
Ovuplant's effectiveness is very comparable to that of the more traditional hCG therapy. Both have demonstrated excellent consistency in inducing ovulation within 48 hours of use, although Meyers noted that he personally finds Ovuplant "more potent than hCG."
One advantage of Ovuplant's method of administration over hCG is the way the slow release of Deslorelin mimics the way LH is slowly released by the anterior pituitary gland.
"HCG is given as a 2,500 I.U. bolus," said Meyers, "which is a big slug of hormone all at once. The GnRH analogue (Deslorelin) in Ovuplant mimics the natural physiology of the mare much more closely."
Ayerst's statistics on Ovuplant include such notable numbers as: a 30% reduction in estrus length (over untreated mares); a 32% reduction in number of breedings per estrus; a 43% reduction in number of estrous periods per mare before a pregnancy is achieved; and a 51% reduction in the number of breedings per season a mare has to undergo to get in foal.
Richard Donnelly, director of marketing at Ayerst Laboratories, is enthusiastic about Ovuplant, which was introduced on the Canadian market in February of 1996.
"The most important thing (about Ovuplant) is its incredible consistency," he said. "It can save the breeder a considerable amount of time and money."
Those savings add up in terms of fewer repeat breedings, fewer palpations and ultrasounds, and fewer days of boarding and mare care to ensure a pregnancy.
"The feedback we've had has been outstanding," Donnelly added. "We feel this product is an important step in equine medicine."
Stallion owners, too, can benefit from the use of Ovuplant on their clients' mares, according to Donnelly.
"It's an excellent product to use along with insemination by frozen semen," he said. "It makes it much easier to coordinate the arrival of the container and the scheduling of your veterinarian."
Meyers also noted that it has become popular on breeding farms where stallions are heavily booked (such as some racing and Quarter Horse stables).
"These farms can't afford to use their stallions more often than absolutely necessary, and Ovuplant can cut down on repeat breedings," he said.
Chris Vanbussel is the farm manager at Seelster Farms, one of the participants in the Canadian trials on Ovuplant.
"In action, we found it very similar to hCG," he said, "except for the 'time capsule' format. I'm not one to use hormone therapy except in certain rare circumstances anyway, but if you're trying to limit your breedings or are transporting semen from a distance, it probably has a place in your program. I think it will be more useful for the small breeder than for (large) operations like mine, but it's important to note that it doesn't replace rectal palpation."
Research into Ovuplant's original purpose, to stimulate anestrus mares into estrus, is also ongoing. Donnelly says that no label claims have yet been made, but that initial results look promising.
One of the glaring disadvantages of Ovuplant is the price. Compared to hCG, which is based on technology that is at least 25 years old and is quite reasonably priced (at an average cost of about $15 to $20 U.S. per dose), Ovuplant might cost double or triple that. Currently in Canada, it might cost the breeder $65 or more (Canadian dollars).
"Small breeders tend to be shocked by the price of it," agreed Meyers. "But the extra cost is justified by the results. To me, the drug makes more sense than hCG, both in terms of practicality and physiology. And if you're going to save on mare care, breedings, and vet care, it's not an outrageous price to pay."
Donnelly noted that many breeders might begin with the more reasonably priced hCG, then use Ovuplant as a second line of defense should hCG not produce the desired results.
"Fifteen to twenty bucks for hCG is a good deal, and the drug does a good job," he said. "It's been around a long time, and people have confidence in it."
But informal field testing has indicated that Ovuplant's slow-release technology might elicit a better ovulatory response from "difficult" mares which might not have responded well to hCG.
"Ovuplant's been great for those really 'tough' mares," noted Donnelly. "It's been a super test for the product."
Like Vanbussel, however, he too emphasizes that "palpation is really a necessary part of the process."
What's the bottom line? Ovuplant might be a valuable ingredient in your breeding program in the future--provided you are prepared to respect its parameters. Like any medication, it's not a miracle worker; but the technology used to develop it might have far-reaching applications in the near future. Ayerst's sister company in the United States, Fort Dodge Laboratories/Animal Health, has applied for USDA approval for Ovuplant, and hopes to make it available for American breeders for the 1997 breeding season.
About the Author
Karen Briggs is the author of six books, including the recently updated Understanding Equine Nutrition as well as Understanding The Pony, both published by Eclipse Press. She's written a few thousand articles on subjects ranging from guttural pouch infections to how to compost your manure. She is also a Canadian certified riding coach, an equine nutritionist, and works in media relations for the harness racing industry. She lives with her band of off-the-track Thoroughbreds on a farm near Guelph, Ontario, and dabbles in eventing.