Persistent Mating-Induced Endometritis

Take Home Message: Persistentmating-induced endometritis in mares can often be managed effectively by using a combination of pharmaceutical agents, immunomodulation, and/or anatomical correction.

I. INTRODUCTION

Persistent endometritis in the mare has been categorized into the following conditions:¹

1. Sexually transmitted disease
2. Chronic infectious endometritis
3. Persistent mating induced endometritis
4. Chronic degenerative endometritis (endometrosis)

Although the etiology may differ, all of the above conditions may contribute to persistent mating-induced endometritis (PMIE), which in turn, poses a significant threat to fertility.

Mares that suffer from persistent mating-induced endometritis are referred to as “PMIE mares”, “susceptible” mares, “ fluid poolers”, and “DUC” (delayed uterine clearance) mares. This condition can be a result of either overproduction of intraluminal uterine fluid or inability to clear the fluid, or a combination of both. Unlike “resistant” mares that are capable of rapidly clearing inflammatory byproducts and fluid that result from in semination, these susceptible mares represent a population that fails to clear postmating fluid within the normal time period of 6-12 hours following breeding,² thus leaving an unfavorable uterine environment for embryo survival.³

The etiology of PMIE is multi-faceted; impaired physical and physiological pr ocesses both play a role. Uterine defense mechanisms, endometrial histoarchitecture and uterine anatomy are taken into consideration in management of the condition. All mares respond to the uterine deposition of spermatozoa and bacteria with the development of a physiologic endometritis, characterized by a rapid influx of polymorphonuclear neutrophils (PMNs). The activation of PMNs triggers the release of prostaglandin F2alpha that in turn causes myometrial contractions. The normal mare’s uterus responds by eliminating excess spermatozoa and inflammatory byproducts within 24 hours of contamination; the DUC mare’s does not. The DUC mare’s uterus often feels edematous and lacks t one. With age and repeated pregnancies, supportive ligaments of the reproductive tract weaken and some mares develop a heavy pendulous uterus that settles in a dependent position well over the pelvicbrim. It appears that fluid is not as easily expelled under these conditions. As well, the myoelectrical physiologic process is impaired in susceptible mares and fluid is retained, thereby stimulating further influx of inflammatory cells. This defective myometrial contractility, coupled with poor reproductive conformation, age-related vascular, glandular and lymphatic changes to the endometrium, and weakened mucocilliary clearance of debris, contributes to both chronic endometritis and delayed uterine clearance in the susceptible mare.

Mares with pathological conditions of the cervix are also at risk of mating-induced DUC. Age or injury-related fibrosis, intraluminal adhesions or congenital abnormalities of the mare’s cervix can be associated with failure to clear fluid.

The diagnosis of DUC is based on an ultrasound exam that shows intraluminal fluid that persists in the uterus for > 12 hours following insemination. Mares that are predisposed to this condition may demonstrate an abnormal pattern of edema during estrus. Excessive edema (Grade IV on a scale of 1-IV) and/or hypoechoic intraluminal fluid visible on ultrasonographic examination prior to ovulation suggests that a mare is likely to experience DUC following mating.⁴

These DUC mares represent a considerable source reproductive inefficiency and cost within the equine breeding industry. It has been estimated that as many as 10-15% of all broodmares develop this pathological response to the intrauterine deposition⁴ of spermatozoa.⁵ Many of these valuable mares face early retirement from the breeding population if they cannot be successfully treated.

The management of DUC depends on its etiology. Therapeutic options target improvement of reproductive anatomy, physiological function, immune defense and blood flow. 

II. ANATOMICAL CORRECTION

Poor perineal conformation can be secondary to weight loss, age, parity or a low body condition score, especially in heavily lactating mares. Improved perineal conformation may contribute to optimized reproductive efficiency, especially in older mares.

There are means other than weight gain to improve conformation of the external genitalia of the mare. Placement of a simple Caslick’s procedure or reconstruction of the perineal body using a Gadd or Pouret technique may prevent repeated inoculation of the cervix and endometrium. However, these surgeries alone are not likely to correct DUC, for gravity still pulls the pluriparous uterus over the pelvis in affected mares.

Uteropexy, on the other hand, lifts the ventrad-angled uterus dorsad and can be performed through laparoscopic imbrication of the mesometrium. Following this surgery on 5 pluriparous barren mares, the authors reported that the surgery was successful in returning the uterus to a normal horizontal position in all 5 mares and 3/5 mares became pregnant in the same year without receiving other treatment.⁶

Correction of cervical abnormalities can also improve pregnancy rates in these compromised mares. The use of a prostaglandin E1 analogue, misoprostol,^a has been shown to be effective,³ for 30 minutes-2 hours, for inducing mild cervical dilation. Tablet(s) (200ug) may be inserted directly in to the distal cervical os, and/or pulverized and mixed into a sterile lubricant for application on the external cervix. There have also been anecdotal reports of improvement in cervical dilation using topical BuscopanR. In the author’s experience, patient and persistent manual dilation can be equally effective in cervical dilation. In mares that appear to have cervical incompetence and/or luminal adhesions (secondary to trauma during foaling, breeding or iatrogenic injury) surgical correction may be explored. In 2/3 mares undergoing a cervical wedge resection for correction of pyometra, not only did the pyometra resolve, but also embryos were later recovered.⁷

III. UTERINE LAVAGE

Dilution and physical removal of inflammatory byproducts can be accomplished with uterine irrigation, beginning as early as 4 hours after insemination, without deleterious effects on pregnancyrates.⁸ As well, uterine lavage can also be performed safely 1 hour prior to insemination.⁹ Serial liters of sterile fluid are introduced into the uterus through a Foley-type catheter and then immediately removed. This procedure is repeated until recovered effluent is clear. Lactated Ringers Solution (LRS) appears to be the fluid of choice, in comparison to other irrigation fluids, because it appears to be associated with significantly less neutrophil migration into the uterus following infusion (Miller, C unpublished).

IV. ECBOLIC DRUGS

By far, the most common treatment for DUC in mares involves the use of ecbolic agents as early as 4 hours after breeding. Administration of these drugs has shown to be effective in promoting uterine clearance in compromised mares.^10-13 Small doses of oxytocin (5-25 IU) increase intrauterine pressure and physical clearance of postbreeding uterine fluid and debris.¹⁴ Doses of oxytocin that exceed 25 IU have been associated with a decrease in pregnancy rate,¹⁵ possibly due to a change in the contractile pattern of the uterus, resulting in in effective fluid expulsion.

In some affected mares, there commended small doses of oxytocin are ineffective in uterine clearance. Explanations for the failure to respond to oxytocin may include the dependent position of the uterus relative to the pelvic brim, a closed or damaged cervix, oxytocin receptor unresponsiveness, and/or the short duration of effect of oxytocin. Treatment with a prostaglandin analogue, cloprostenolb (250ug i.m.) has been shown to provide a significantly longer duration of uterine contraction^16,17 and has been effective in some of these mares that fail to respond appropriately to treatment with oxytocin.³

However, the use of cloprostenol as an ecbolic agent carries its own risks in mares. Some mares respond to even small doses of closprostenol administration with side effects such as sweating, abdominal discomfort and diarrhea. Although these effects are self-limiting and of short duration, they are undesirable. More importantly, studies have shown that cloprostenol can be used only during a very small window of time in the periovulatory period without adversely affecting the size of the corpus luteum, progesterone levels, and pregnancy rates.^18-20

Carbetocinc, an oxytocin analogue with a half-life 4X as long as oxytocin, has been recommended as a treatment for mares with delayed uterine clearance that fail to respond to other ecbolic agents.^3,21 In women, carbetocin has been shown to be effective in both the prevention and treatment of postpartum hemorrhage.^22,23 In horses, following IV administration of 0.175 mg carbetocin, Schramme et al²⁴ reported that the half-life of carbetocin is greater than 2X the half-life re ported for oxytocin (17.2 versus 6.8 minutes, respectively). In a study that compared administration of oxytocin (10 IU IV) and carbetocin (0.280 mg IM) in mares 7 days postovulation, it was reported that although plasma oxytocin concentration were not different between treatments, the peak concentration appeared almost 20 minutes later in mares that received carbetocin. Furthermore, the duration of peak concentration was almost three-fold higher in the mares that received carbetocin than those that received oxytocin.²⁴

In addition to its longer half-life, carbetocin may be an effective ecbolic agent through other mechanisms. It appears to elicit a different contractile pattern than oxytocin in the mare. The pattern of propagation of uterine contraction in response to oxytocin has been shown to be different between reproductively sound mares versus mares with delayed uterine clearance.²⁵ [...]