Immunotherapy for Broodmares

Endometritis has been the bane of many broodmares and their owners through the years. It frequently has been blamed for mares not becoming pregnant and, when they do conceive, for early embryonic death. The result has been serious economic losses when the disease strikes. Unfortunately, it strikes mares at operations around the world with frequency. About the only good news regarding the disease is that it is not life-threatening for the mare.

Now, there is more good news; there are new weapons to combat endometritis. These weapons are biologic products that enhance the horse's own immune system, and they are showing in preliminary studies to be valuable aids in clearing up endometritis in broodmares.

What Is Endometritis?

Endometritis is inflammation of the endometrium, which is the lining of the uterus. Basically, there are three categories of endometritis--acute infectious endometritis, chronic uterine infection, and persistent mating-induced endometritis.

Acute infectious endometritis is most apt to be found in older mares that have had a number of foals. The mare's reproductive system is designed to protect against the invasion of infectious agents, but as she ages, this defense system often develops flaws, such as the vulva becoming lax and allowing harmful bacteria to make their way into the uterus and set up shop. Urine pooling in the reproductive tract can also be implicated.

Chronic uterine infection shows up in mares that have a wide range of degenerative changes, such as the development of scar tissue and cysts within the uterus. Many of these mares become poor candidates for breeding because the damage within the uterus is permanent.

Persistent mating-induced endometritis is a major factor in mares failing to conceive and in causing early embryonic death when they do. The inflammatory response within the uterus when a mare is bred by natural cover or artificial insemination is a natural one. In normal circumstances, the mare's body will clear the inflammation naturally and pregnancy is the outcome. However, in many cases, the mare for some reason is unable to rid her uterus of the buildup of fluid and contaminants. This can render the uterus uninhabitable when the fertilized egg arrives.

A clear and succinct explanation of what occurs has been provided by Jonathan F. Pycock, BVetMed., PhD, DESM, MRCVS, a reproduction specialist from England who has spoken widely on the subject and has authored numerous articles and books. In a paper titled "The Dirty Mare," Pycock had this to say:

"Semen is deposited directly into the uterus when mares are bred. This means that bacterial and seminal components, as well as debris, contaminate the uterus, and that results in uterine inflammation. It was previously thought that the inflammatory response to breeding was due to bacterial contamination of the uterus at the time of insemination. It's now accepted that the sperm themselves, as well as bacteria, are responsible for the acute inflammatory response in the equine uterus after insemination.

"A transient uterine inflammation following insemination is useful and serves to clear the uterus of excess sperm and debris associated with breeding," he continues. "In most mares, this transient endometritis resolves spontaneously within 24 to 48 hours so that the environment of the uterine lumen is compatible with embryonic and fetal life.

"However, if the endometritis persists more than four or five days (some equine reproduction experts say as few as two or three days) after ovulation, this is incompatible with embryonic survival," Pycock added. "These mares are referred to as susceptible, and they develop a persistent endometritis.

"The physical ability of the uterus to eliminate bacteria, inflammatory debris, and fluid is known to be the critical factor in uterine defense," he states. "It is a logical conclusion that any impairment of this function, i.e., defective uterine contractility, renders a mare susceptible to persistent endometritis."

(Editor's Note: For more information on endometritis see article on page 63.)

A New Era

The first challenge for veterinarians dealing with endometritis is to correctly diagnose the condition. The use of ultrasound has played an important role. Complicating the situation is the fact that a number of mares show no signs of endometritis before mating, but the condition flares up in the wake of breeding and the mare is unable to resolve it on her own.

Through the years, the prime weapons to combat endometritis have included oxytocin to assist in contracting the uterus to eliminate fluid, antibiotics to clear up infection, and lavage to flush away debris.

Additional help has arrived in the form of biologic weapons that stimulate the mare's own immune system to combat endometritis. There is still much to learn about these immunostimulants, as little research has been conducted on these drugs. However, information provided by the few studies undertaken is all on the positive side. There have been definite positive results without adverse side effects.

One significant study has been conducted in Argentina, and another has been completed at the University of Tennessee in collaboration with researchers in Kentucky. Results of the Argentine study have been published. An abstract concerning the U.S. study is available, but a complete report on the research awaits publication and is not available to the lay press.

In both cases, research involves studying the effects of immunostimulants in jump-starting the mare's own immune system.

The investigators used two products that are commercially available. One is sold under the trade name EqStim Immunostimulant, and it is made available by Neogen Corporation, whose life sciences division is based in Lexington, Ky. The other is Settle, which is offered by Bioniche Animal Health, a Canada-based company with marketing subsidiaries in the United States, Canada, Europe, and Australia. Settle is the only immunostimulant approved by the FDA specifically for the treatment of uterine infections.

The EqStim study was the subject of discussion during the 2006 Society for Theriogenology convention in St. Paul, Minn. John Steiner, DVM, Dipl. ACT, of Hagyard Equine Medical Institute in Lexington, and a collaborator on the study, says EqStim has shown promise as therapy for mares with endometritis and that no adverse effects were noted. The key ingredient in EqStim is the inactivated bacterium Propionibacterium acnes (a skin-dwelling organism that is involved in causing acne). Steiner said that EqStim is considered an adjunct therapy to be used in conjunction with more conventional approaches, such as lavage, oxytocin, and antibiotics.

The lead researcher in the study was Barton Rohrbach, VMD, MPH, Dipl. ACVPM, associate professor in the college of veterinary medicine at the University of Tennessee. Another collaborator on the study was Peter Sheerin, DVM, Dipl. ACT, of Rood and Riddle Equine Hospital in Lexington. Sheerin presented an abstract of the study at the Ninth International Symposium on Equine Reproduction held in 2006.

In the abstract, Sheerin reported that 112 broodmares with a diagnosis of persistent endometritis were enrolled in a double-blind randomized clinical trial.

Sheerin and his colleagues based their diagnoses of endometritis on whether there was a high concentration of neutrophils (an indicator of infection) on cytology.

"Mares were randomly assigned to receive either the experimental treatment (EqStim) or a placebo on Days 0, 2, and 6 of treatment," he said in the abstract. "Demographic information, reproductive history, and any treatments given were recorded for each mare. Breeding dates, results of pregnancy examinations, and adverse reaction to P. acnes or placebo were recorded."

Sheerin reported that neither EqStim nor the placebo caused any adverse effects. The overall pregnancy rate for the 112 mares was 78% for those treated with EqStim and 68% for the controls treated with the placebo.

Sheerin concluded, "When adjusting for extraneous factors in a multivariable model, the odds of mares bred within 30 days of the start of treatment becoming pregnant on the first cycle bred were 3.5 times greater for treated than control mares. For mares treated and bred two days or less prior to treatment, or anytime during or after treatment, those receiving P. acnes were 3.7 times more likely to become pregnant than were the control mares given the placebo.

"These data suggest that P. acnes is a safe and effective treatment to increase the first estrous cycle and overall pregnancy rate in mares with persistent endometritis," stated Sheerin.

EqStim is not a new kid on the block. It was introduced in 1988 and has been utilized primarily as an immunostimulant to combat respiratory problems. It has been administered either orally or intravenously (IV).

The pathogen frequently implicated in endometritis is Streptococcus zooepidemicus, and an immunostimulant introduced during the 2005 breeding season to combat it is Settle, which can be administered either IV or intrauterine (IU). Settle was first introduced to veterinarians at the 2004 American Association of Equine Practitioners convention in Denver, but research on the treatment had been ongoing for four previous breeding seasons, according to Bioniche Animal Health officials.

While EqStim's prime ingredient is comprised of inactivated and naturally occurring whole P. acnes bacteria, Settle's salient component is cell wall fractions of nonpathogenic Mycobacterium spp. Both of the bacterial products are capable of stimulating the equine immune system.

The immunostimulants activate macrophages (immune cells that engulf foreign substances, dead cells, and other debris), induce the production of cytokines (proteins released by cells that affect the interactions between cells), and have a positive effect on B and T lymphocytes (white blood cells), all of which figure into the body's effort to produce antibodies that battle invading infectious agents.

Two key studies on the effectiveness of Settle in the treatment of endometritis were conducted at the Universidad Nacional del Centro de la Provincia de Buenos Aires in Tandil, Argentina.

Thirty endometritis-susceptible broodmares were selected for the first study. All 30 mares were deliberately infected with S. zooepidemicus and all developed endometritis.

The mares were then divided into four groups--10 were treated with Settle by IV injection; 10 were treated with Settle by IU instillation; five were treated with an IV placebo, and five were treated with an IU placebo. The mares were given a single dose of Settle.

Dragan Rogan, DVM, MSc, PhD, who heads up research and development for Bioniche Animal Health, had this to say about the results: "One hundred percent of the control mares still had a bacterial endometritis at Day 7, whereas those mares treated with mycobacterial cell wall formulation (MCW, or Settle) were cured of the endometritis in 55% of the cases after 24 hours and 75% after seven days. The known ability of MWC to enhance the non-specific immunological response during the early phase of mare infection has proven to have a significant therapeutic effect. The immediate reduction of the uterine bacterial load unequivocally suggests that Settle is a fast, safe, and effective treatment for equine endometritis."

A second study at the same institution involved administering Settle to mares that were to be bred on foal heat (the mare's first heat period following the birth of her foal) to determine whether the immunostimulant could improve pregnancy rates.

Used in the study were 81 Argentine Saddle Horse mares. Thirty-eight of them received a placebo and 43 received Settle. In the placebo group, nine of the 38 (24%) became pregnant when bred on foal heat, and in the Settle-administered group, 28 of 43 (65%) became pregnant on foal heat.

The lead researcher in that study was Elida Fumuso, DVM, PhD, a veterinarian at the Universidad Nacional del Centro de la Provinicia de Buenos Aires. She concluded: "Settle administered the day after foaling promoted a significantly higher pregnancy rate, a dramatic pathogen-dependent decrease in bacterial contamination in the endometrium, and a significant decrease in the number of endometrial inflammatory cells presented at foal heat. Furthermore, the Settle treatment has demonstrated to be a safe, intravenous, non-antibiotic therapy for nursing mares."

Equine reproductive experts are quick to say that one of the best weapons against endometritis is proper mare management. Cleanliness and sanitary conditions are high on this list. However, for those mares that develop endometritis despite the best of efforts, there is more in the veterinary arsenal than existed in the past, thanks to these relatively new biologic weapons.

Most veterinarians and researchers, such as Ed Squires, MS, PhD, who heads up equine reproductive research at Colorado State University, welcome the arrival of the new biologic weapons, but view the products as adjunct therapy.

"Immunostimulants are new tools that the veterinarian now has," Squires said, "but most veterinarians are advising that they be used in conjunction with conventional therapy."

Take-Home Message

Mare owners might see their veterinarians applying immunostimulant therapies to mares with known reproductive issues.

While there is still much to learn, preliminary research has shown positive implications for these types of therapies.


Bioniche Animal Health suggests the following as appropriate timing for administering Settle. Administer the drug:

  • When the uterine infection is diagnosed and while awaiting culture and sensitivity test results.
  • In conjunction with local or systemic antibiotic treatments.
  • The day after foaling (or at the first sign of estrus) in known endometritis-susceptible mares or mares recognized as difficult breeders.
  • At the time of retained placenta removal (and/or at the first heat of mares with history of retained placenta or delayed expulsion).
  • The day after foaling (or at first natural heat, or foal heat) in mares with poor reproductive tract conformation.
  • At diagnosis of uterine inflammation or poor uterine involution.
  • At the time of natural breeding or artificial insemination.
  • Immediately prior to shipping mares for breeding to expensive stallions.
  • The day after foaling to ensure earlier maintenance of uterine health, facilitate earlier breeding when mares are late in the season, or to increase conception at the foal heat.--Les Sellnow

About the Author

Les Sellnow

Les Sellnow is a free-lance writer based near Riverton, Wyo. He specializes in articles on equine research, and operates a ranch where he raises horses and livestock. He has authored several fiction and non-fiction books, including Understanding Equine Lameness and Understanding The Young Horse, published by Eclipse Press and available at or by calling 800/582-5604.

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