Equine Uterine Disease

Rob Foster

Circulatory disease

Disorders of growth

Endometrial polyps

Estrada et al (2008) reported on one case of a uterine polyp that protruded through the vulva of a mare.

 

Estrada A, Ferrer MS, Brounts SH, Milligan MA, Lillich JD, DeBey B. Theriogenology Question of the Month Journal of the American Veterinary Medical Association (2008) 232: 10: 1473-1475.

Hyperplasia

Murphy et al (2005) reported on a 1 year old mare with what they called endometrial stromal hyperplasia. The histology was of diffuse fibrosis of the portion of endometrium.

Murphy JE, Frazer G, Munsterman A, Weisbrode S, Kohn C, Beard W. Endometrial stromal hyperplasia and mass formation in a yearling Quarter Horse. Equ Vet Educ 2005; 17: 159-162.

Neoplasia

Reports of neoplasia in the reproductive tract of mares is very rare.

Lopez et al (2017) reported an adenocarcinoma of the uterine body in a mare. There were metastases in the lungs, tracheobroncheal lymph nodes, marrow, bladder and ureters.

I have seen one case where the neoplastic cells infiltrated the myometrum to the serosa. The mare died of carcinomatosis about 12 months later.

Canisso et al (2013) reported on a mare with failure of pregnancy that had a uterine lymphoma.

 

Canisso IF, Pinn TL, Gerdin JA, Ollivett TL, Buckles EL, Schweizer CM, Ainsworth DM. B-cell multicentric lymphoma as a probable cause of abortion in a Quarter horse broodmare. Can Vet J. 2013; 54: 288-291.

Lopez C, Ciccarelli M, Gold JR, Tibary A. Uterine adenocarcinoma in Quarter Horse mare. 2018; 30: 640-644

Inflammation

Endometritis

Endometritis in the mare is different in many respects to that of other species. It primarily occurs after mating whereas other species tend to have postpartum endometritis.
After breeding, the endometrium is exposed to semen, bacteria and debris that ascend from the vagina.

There is a physiological response of the endometrium with mating. The important components are as follows:

1. Physical clearance and uterine tone
2. Mucociliary apparatus
3. Non-adaptive molecular immune response
4. Non-adaptive cellular immune response

Woodward and Troedsson (2015) and Morris et al (2020) reviewed the subject.

It appears that equine semen upregulates and downregulates certain cytokines. Upregulated are Il-1, and Il-8, and downregulated TNF alpha. (Fedorka et al 2017)

Herrera et al (2018) examined the histomorphometry of the endometrium of mares considered resistant or susceptible to persistent post breeding endometritis in mares. They found a relationship between evaluated endometrial histomorphometric characteristics of increased epithelial height, greater glandular density and greater glandular development during oestrus and persistent post-breeding endometritis.

Minkwitz et al (2019) did a detailed study of endometrial fibrosis by looking at immunohistochemistry for SMA, calponin, vimentin, desmin and GFAP. They found a myofibroblastic phenotype of stromal cell around fibrotic cell nests (SMA, calponin) and some vimentin staining of epithelial cells in these areas (myoepithelial).

Jasiński et al (2022) did not identify any increase in the NF-κB-signalling pathway in endometritis or endometrial fibrosis, but proinflammatory molecule pathways (IL-6 and MCP-1) were increased.

 

Fedorka CE, Scoggin KE, Woodward EM, Squires EL, Ball BA, Troedsson M. The effect of select seminal plasma proteins on endometrial mRNA cytokine expression in mares susceptible to persistent mating-induced endometritis. Reprod Domest Anim. 2017; 52: 89-96

Herrera M, Herrera JM, Cantatore S, Aguilar J, Felipe A, Fumuso E. Comparative histomorphological study of endometrium in mares. Anat Histol Embryol. 2018; 47 :153-158.

Jasiński T, Zdrojkowski Ł, Kautz E, Juszczuk-Kubiak E, Ferreira-Dias G, Domino M. The NF-κB-signalling pathway in mare's endometrium infiltrated with the inflammatory cells. Reprod Domest Anim. 2022; 57: 598-610.

LeBlanc MM, Causey RC. (2009) Clinical and subclinical endometritis in the mare: both threats to fertility. Reprod Domest Anim 2009; 44 Suppl 3: 10-22.

Minkwitz C, Schoon HA, Zhang Q, Schöniger S. Plasticity of endometrial epithelial and stromal cells-A new approach towards the pathogenesis of equine endometrosis. Reprod Domest Anim. 2019; 54: 835-845

Morris LHA, McCue PM, Aurich C. Equine endometritis: a review of challenges and new approaches. Reproduction 2020; 160: R95-R110.

Woodward EM, Troedsson MHT. Inflammatory mechanisms of endometritis . Equ Vet J 2015; 47: 384-389

Endometrial cytology

Equine theriogenologists use endometrial cytology as part of reproductive assessment of mares. The following references are of use.

Ferris RA, Bohn A, McCue PM. Equine endometrial cytology: Collection techniques and interpretation. Equine Vet Educ 2015; 27: 316-322

 

Endometrial biopsy

Biopsy of the endometrium in the mare is a process whereby each mare can be categorised into four groups with each having a probability of that mare giving birth to a live foal. Recent publications show variation in the grading by different pathologists, so this test should be used in conjunction with clinical assessments, and the reports should be read for specific factors that influence fertility.

The process I use is a modification of the Kenny and Doig system and each report I do is of a synoptic format to to provide a consistent, accurate and understandable description of the endometrial biopsy to provide part of the information required for classification. The full classification requires information on the mare including her clinical stage of cycle, any physical findings (such as exudates), whether she gave birth to a live foal the previous year, pertinent clinical information such as the presence of intrauterine objects, discharges and treatments. My reports are synoptic in type with a sentence or paragraph providing the following in order:

1. Provide comment about quality of sample.
2. Establish stage of cycle – determine if mismatch
3. Examine for fibrosis vs clustering
4. Examine for cells – neutrophils in tissue are significant.
5. Provide added value by making other observations including those of the lumen, luminal epithelium specifically, and any other changes that may influence fertility.
6. Note clinical features that influence pregnancy outcome, such as exudates/pyometra, stage of cycle, years without foaling, endometrial cysts (often not seen on biopsy as they are too big.

The general classification scheme that I use is as follows:

* Waelchi CVJ 31: 379 $ Kenny and Doig

Stage of Cycle

Anestral (Inactive)

Uterine luminal epithelium: cuboidal and hyperchromatic
Glands:as above
Stroma: minimal edema and hyperemia

Estral (estrogenic)

Uterine luminal epithelium: columnar nonciliated, pseudoapocrine, mitotic
Glands: straight, dilated lumen. No mitoses in deep glands, but in infundibulum
Stroma: marked edema and hyperemia
Neutrophils marginate but none in tissue

Early diestrus (progestagenic)

Uterine luminal epithelium: increased ciliated cells, nuclei more random
Glands: coiled, more complex and less lumen. Marked mitosis
Stroma: edema and hyperemia reduced, glands more closely packed
glandular tortuosity indicates greater progesterone.

20% of prooestral samples will have prooestral nests - differential accumulations of fluid in the endometrium.
surface epithelium height 15-20um in pro and diestrus, 30-40um in estrus. Luminal and duct epithelium is the first to change and the last to leave during oestrus.

Transition (Spring and autumn)
      

Killisch et al (2017) quantified changes in the endometrium considered normal for the transition period. These changes in the breeding (May to August in the Northern Hemisphere) period are considered maldifferentiation. "Irregular differentiation' was defined as variations in the height, staining quality and degree of dilation of endometrial glands especially when there is variation within a single biopsy. Regular differentiation was the norm in the breeding season

Usage of endometrial biopsy

There is considerable variation in the grades given by pathologists and where equine theriogenologists read their own biopsies, there is variation from the pathology report grade too. Westendorf et al (2022a) and Westendorf et al (2022b) show how much this can be. The variation in grading between pathologists is widely known.

Many equine theriogenologists look past the grade and read the pathology reports for specifics on the degree and type of inflammation, and on the fibrosis and other features. My approach to reporting endometrial biopsies is heavily influenced by this so I use a synoptic approach and I also concentrate on what I call "adding value". That is providing additional information based on my experience with correlating endometrial biopsy with such things as rectal palpation, ultrasound, and uteroscopy.

References

Evans TJ, Miller MA, Ganjam VK, Niswender KD, Ellersieck MR, Krause WJ, Youngquist RS. Morphometric analysis of endometrial periglandular fibrosis in mares. Am J Vet Res. 1998; 59: 1209-1214.

Gordon LR, Sartin EM. Endometrial biopsy as an aid to diagnosis and prognosis in equine infertility. J Equine Med Surg 1978; 2: 328–336

Kenney RM Cyclic and pathologic changes of the mare endometrium as detected by biopsy, with a note on early embryonic death. J Am Vet Med Assoc 1978; 172: 241–262

Kenney RM, P.A. Doig PA. Equine endometrial biopsy, Current therapy in theriogenology 2 WB Saunders, Philadelphia (1986), 723–729

Killisch R, Böttcher D, Theuß T, Edzards H, Martinsson G, Einspanier A, Gottschalk J, Schoon HA. Seasonal or pathological findings? Morphofunctional characteristics of the equine endometrium during the autumn and spring transition. Reprod Domest Anim. 2017; 52: 1011-1018

Ricketts SW, Alonso S. The effect of age and parity on the development of equine chronic endometrial disease. Equine Vet J 1991; 23: 189–192

Schlafer DH. (2007) Equine endometrial biopsy: enhancement of clinical value by more extensive histopathology and application of new diagnostic techniques? Theriogenology 2007; 68: 413-422.

Snider TA, Sepoy C, Holyoak GR. Equine endometrial biopsy reviewed: observation, interpretation, and application of histopathologic data.Theriogenology 2011; 75: 1567-158

Waelchli RO. Endometrial biopsy in mares under nonuniform breeding management conditions: Prognostic value and relationship with age. Can Vet J 1990; 31: 379-384

Watson ED, Sertich PL. Effect of repeated collection of multiple endometrial biopsy specimens on subsequent pregnancy in mares. J Am Vet Med Assoc 1992; 201: 438-440.

Westendorf J, Wobeser B, Epp T. IIB or not IIB, part 1: retrospective evaluation of Kenney-Doig categorization of equine endometrial biopsies at a veterinary diagnostic laboratory and comparison with published reports. J Vet Diagn Invest. 2022; 34: 206-214.

Westendorf J, Wobeser B, Epp T. IIB or not IIB, part 2: assessing inter-rater and intra-rater repeatability of the Kenney-Doig scale in equine endometrial biopsy evaluation. J Vet Diagn Invest. 2022; 34: 215-225.

 

Fibrosis

Endometrial fibrosis is the end result of multiple processes. It is an integral and important part of categorizing endometrial biopsies.

Zdrojkowski et al (2024) reviews aspects of endometrial fibrosis.

 

Zdrojkowski L, Pawliński B, Skierbiszewska K, Jasiński T, Domino M. Assessment of Connective Tissue in the Equine Uterus and Cervix: Review of Clinical Impact and Staining Options. Animals 2024; 14: 156

 

Foreign body

Glass balls are placed in the uterus of mares at ovulation to supress estrus. This is done to prevent prostaglandin F2alpha release and cause luteolysis. The corpus luteum is maintained and the mares may not cycle for up to 90 days. This luteostatic function is variable however.

Klein et al (2016) tried to determine the mechanism for failure of a mare to become pregnant when an intrauterine device was present. There found no difference in the number of inflammatory cells except for macrophages, and there was a difference in the amount of uteroferrin suggesting chronic inflammation.

Complications of placing a ball in the uterus include infertility (if the presence of the ball is unknown; this is the aim!), pyometra and trauma from rupture or fracture of the balls.

 

 

Klein V, Müller K, Schoon HA, Reilas T, Rivera Del Alamo MM, Katila T. Effects of Intrauterine Devices in Mares: A Histomorphological and Immunohistochemical Evaluation of the Endometrium. Reprod Domest Anim. 2016; 51: 98-104.

Turner RM, Vanderwall DK, Stawicki R. Complications associated with the presence of two intrauterineglass balls used for oestrus suppression in a mare. Equine Vet Edu 2015; 27: 340-343.

Fungal endometritis

Beltaire KA, S. H. Cheong SH, Coutinho da Silva MA. (2012) Retrospective study on equine uterine fungal isolates and antifungal susceptibility patterns (1999–2011) Eq Vet J 2012 44: 84-86      Aspergillus and Candida

Postpartum metritis

Metritis in the pathology world is inflammation of the uterus, and is endometritis plus myometritis. In the clinical domain it is different. The terminology is endometritis after birth is postpartum metritis. This section refers to the clinical syndrome of inflammation of the uterus after parturition. It can be endometritis or metritis.

The type of bacteria cultured from 45 cases of postpartum metritis were recorded by Ferrer and Palomares (2018) and include multiple isolates (62% of cases). Escherichia coli, Klebsiella spp, and Enterobacter spp.were the common gram positive bacteria. Streptococcus zooepidemicus was the most common gram positive bacterium.

 

Ferrer MS, Palomares R. Aerobic uterine isolates and antimicrobial susceptibility in mares with post-partum metritis. Equine Vet J. 2018; 50: 202-207.

Pyometra

Pyometra is defined as pus in the uterus. It is uncommon. Affected horses seldom have systemic signs, but they do have a vaginal discharge.

McCarthy reported on a case that was a 10 week old filly that, when born, had placentitis. Streptrococcus equ zooepidemicus and Streprococcus dysgalactiae equisimilus was cultured from the discharge.

 

McCarthy MB. Townsend KS. Johnson PJ. LaCarrubba AM. Voelkl DL. Volkmann DH. Occurrence of a vaginal septum in a foal diagnosed with pyometra. Equ vet Edu 2021; 33: e273-e279.

Neoplasia

Lymphoma

A mare with a multinodular uterine mass was found to have lymphoma with a uterine manifestation. It was a B cell tumor.

Claes A, Ball BA, Liu IKM, Vaughan B, Highland MA, Brow JA. Uterine B cell lymphoma in a mare. Equine Vet Edu 2015; 27: e5-e8.

Pneumouterus

Livesey LC, Carson RL, Stanton MB. (2008) Postpartum colic in a mare caused by pneumouterus Vet Rec.162: 626-627

Segmental aplasia

Brown JA, Hodder ADJ, Benak J, Ball BA (2007) Uterus unicornis in two mares. Aust vet J 85: 371-374
2 mares both missing a horn – one left, one right

Torsion

J Amer Vet. Med Assoc 220: 349-353
Chronic torsion in 2 mares
Jung C, Hospes R, Bostedt H, Litzke LF (2008) Surgical treatment of uterine torsion using a ventral midline laparotomy in 19 mares. Australian Vet J 86: 272-276.
Clockwise 9 and anticlockwise 10, 360 (3), 270 (3), 180 (7) and less than 180 (6).
Half had GI disease including colitis, impactions, torsions
13 foaled at term and 2 aborted. The rest died in the perioperative period.

Miscellaneous disease

Retained fetal membranes

Rapacz-Leonard et al (2015) found that oxytocin receptor expression as indicated by immunohistochemistry was reduced in mares with RFM. It is likely that reduced receptors is the reason for atony of the uterus and subsequent RFM.

Rapacz-Leonard A, Raś A, Całka J, Janowski TE. Expression of oxytocin receptors is greatly reduced in the placenta of heavy mares with retained fetal membranes due to secondary uterine atony. Equine Vet J. 2015; 47: 623-626.

Rupture of uterine artery

Periparturient hemorrhage from rupture of the uterine artery affects mares around the time of birth.

Rupture of the uterine artery with hemorrhage into the mesometrium, with or without extension into the abdominal cavity. The latter situation commonly results in the death of the mare from exsanguination. The uterine artery near the rupture commonly contains pre-existing chronic degenerative changes.

It is a disease of older mares, and especially older multiparous mares. The age range is 5 up with the average about 14.

In a study of 73 cases, 14 mares had prepartum hemorrhage and the rest were postpartum. 14 had dystocia.

Pascoe RR. Rupture of the utero-ovarian or middle uterine artery in the mare at or near parturition. Vet Rec. 1979; 104: 77.

Arnold CE, Payne M, Thompson JA, Slovis NM, Bain FT. Periparturient hemorrhage in mares: 73 cases (1998-2005). J Am Vet Med Assoc. 2008; 232: 1345-1351.

In mares, in which these changes have been studied by endometrial biopsies, the luminal and glandular epithelium becomes cuboidal and the glands are straight during the winter anestrous period, but there is considerable individual variation in the degree of atrophy mares develop.

In the mare, semen is ejaculated directly into the uterus and induces a transient postcoital endometritis. Such post-mating endometritis is recognized in most species. Infectious agents tropic for the uterus include T. foetus and C. fetus or pyogenic cocci and coliforms of low pathogenicity.

Uterine infection frequently occurs in mares both following foaling and after coitus by α-hemolytic streptococci, Klebsiella pneumoniae, Escherichia coli and Taylorella equigenitalis, the contagious equine metritis organism. The endometritis is usually mild, but the impact on fertility can be substantial.

However, the presence of neutrophils in the stroma of the endometrium is evidence of inflammation in the mare. The best indication of endometritis in all species consists of accumulations of plasma cells and foci of lymphocytes in the stroma. Resolution of this type of endometritis may occur with no more residue than a few cystic glands with periglandular fibrosis (Fig. 4.56), although during its course it may be responsible for early embryonic mortality. If the endometritis is more severe or persists for a longer time, the cumulative damage to the endometrium may render the mare sterile.

Contagious equine metritis is a venereal disease of mares caused by Taylorella equigenitalis, a gram-negative, microaerophilic coccobacillus. The disease produced by this organism does not appear to be significantly different from other common infecting organisms of the mare’s genitalia. The interest in this disease stems from its apparently abrupt appearance in horse-breeding establishments in England in 1977 and its rapid spread to equine studs around the world. Strict control measures seem to have limited its spread and the clinical disease is now rare.

The disease causes temporary infertility in mares and a mucopurulent discharge that lasts 2–3 weeks. The organism can persist in infected mares for several months, and recovered mares represent an important reservoir of infection. Stallions transmit the organism by genital contact but do not develop clinical disease.

Pyometra in the mare differs from the disease in the bitch and the cow in several particulars. While some cases develop following difficult parturitions with infections, as they do in cattle, many do not. Remarkably, most mares continue to cycle during the disease, and the hormonal influences that are so marked in the bitch, queen, and cow are much less important in the mare.

In some mares, cervical adhesions and closure may lead to pyometra, but in most instances the purulent material collects without demonstrable cervical closure, and in some cases the cervix is fully dilated. Copious amounts of pus can be discharged under such circumstances, particularly during estrus. Pyometra in the mare seldom leads to evidence of systemic disease, although some mares develop mild anemia.

The length of the estrous cycle appears to be related to the severity of the endometrial damage. In rare cases, where the endometrial damage is severe, the cycles are prolonged with long luteal phases due to delayed or inadequate prostaglandin F_2α release. Mares with less severe endometritis have normal or shortened cycles.

A variety of organisms may be present in pyometra in the mare: Streptococcus zooepidemicus is the most common, but E. coli, Actinomyces spp., Pasteurella spp., and Pseudomonas are often present.

This potent chorionic gonadotropin in mares stimulates ovarian corpora lutea to develop, and these maintain the pregnancy until approximately 126–140 days, when the fetal chorion takes over the production of progesterone. If the conceptus dies after day 35 of gestation, the cups persist and continue to secrete chorionic gonadotropin, accessory corpora lutea are produced, and the mare fails to return to estrus and continues for a variable period in a state of pseudopregnancy.

In the mare, it is typically one of twin fetuses that is mummified. Mummification may also occur in mares receiving progesterone in the early stages of gestation in order to prevent abortion associated with failure of endometrial cup development and subsequent failure of accessory corpora lutea formation and thereby progesterone production

A syndrome of abortion reached epidemic proportions in the spring of 2001 and to a lesser extent in 2002. It is of major concern to the equine industry in various states but especially in Kentucky. Several hundred late-term fetuses were examined. Most were aborted or stillborn at term or several weeks before term, well preserved, and enclosed within the placenta. There were few or no premonitory signs of illness in the mares. Lesions observed in the fetus included hyphema and little or no inflation in the lungs. Hemorrhages were frequently observed on the chorion, amnion and amniotic segment of the umbilical cord, pleura, and heart. The surface of the amniotic segment of the cord was dull gray to yellow, roughened, and thickened by stromal edema. On microscopic examination, the amniotic cord had bacteria on the surface and where there was loss of epithelium there were light to heavy infiltrations of neutrophils and macrophages. Similar light infiltrates were seen in the stroma of the allantochorion.

Cultures of the fetus and placenta yielded non-β-hemolytic Streptococcus spp. and/or Actinobacillus spp. in 50% and 20% of the specimens cultured. Similar bacteria were also cultured from lung, stomach content, and placental membranes. Microscopic lesions included funisitis, amnionitis, pneumonia, fetal bacteremia, and sometimes chorionitis. Further investigations supported unusually warm weather and rate of change from cool to warm as major factors, which correlated with increased bacterial growth and Eastern tent caterpillar (ETC) development. In a controlled study, investigations involving the feeding of ETC to pigs caused abortion. A similar study in mares revealed that abortion occurred only on feeding of the insect exoskeleton, and that hair remnants resembling ETC setae were embedded in the submucosa of the digestive tract of aborting gilts and of an aborting mare.  Studies of a similar disease caused by processionary caterpillars show that the setae penetrate the intestine after ingestion and subsequently migrate to the pregnant uterus by direct penetration. With them go bacteria that induce infection of the pregnant uterus and fetus and placenta.

This disease, caused by actinomycete bacteria, is found sporadically throughout the world, with a few similar cases reported elsewhere. All ages and breeds of mares are affected. The mare shows no outward signs of illness, except, as with other near-term abortions, premature development of the mammary gland and lactation may occur. Infection is cleared early and rebreeding has not been accompanied by problems. The bacteria involved are gram-positive branching filamentous organisms, and include at least 3 different genera of bacteria: Crossiella equi, Streptomycin, and three species of Amycolatopsis. No risk factors have been identified, nor has the condition been reproduced.

The virus is spread by aerosolization of respiratory secretions among closely associated animals. Stallions are probably the most important means of spread, as they shed the organism in semen for a short or very long period, even for life, and transmit the disease sexually. There are minimal consequences of sexually acquired infection with little effects on conception rate, unless a mare is infected in the late stages of gestation, in which case she may abort. Stallions that are shedding the organism should not be used for breeding unless they are bred to seropositive mares that have received the organism from either vaccination or natural infection. In contrast, while mares may spread the virus during their illness or shortly after, they generally do not remain carriers and after recovery neither mares nor stallions shed the virus in nasal passage secretions, urine, or blood. Most horses develop long-term immunity to EAV after natural infection of the virus.

which are caused to abort by this infection, are not ill, and the organism does not persist for long in the uterus after abortion. However, the same mare may abort successive pregnancies, a fact which suggests that the uterus can be reinfected from some endogenous asymptomatic focus. A. equuli can occasionally be found in the intestine and tissues of healthy animals, and also as an opportunist in pathological tissues such as verminous thromboses. It is, however, seldom of significance in adult animals, although septicemic infections have been observed.

 In the live mare and stallion during the early stages of disease, the presence of EAV may be determined by culture or PCR assay of swabs taken from nasopharynx and conjunctiva, from white blood cells, or from semen. The virus may be recovered from semen or revealed by breeding unexposed mares, which may then develop a fever or become clinically ill. Serological tests are available to detect previously infected animals. Samples for culture from the conceptus should include placenta, lung, and spleen. Diagnosis can also be obtained by immunohistochemistry, virus isolation, and PCR-based tests.

Contagious equine metritis, caused by Taylorella equigenitalis, is a sexually transmitted disease of horses. As discussed above in the section on endometritis, acute infection of mares causes purulent endometritis and cervicitis. In mares that have become carriers, the Taylorella organisms reside within the crypts and fossa of and around the clitoris. Although the mare’s clitoral area, shown in Figure 4.104, is grossly normal, she had large numbers of Taylorella coccobacilli within the clitoral fossa that was associated with only a mild lymphocytic reaction. An atypical Taylorella sp. also capable of causing transient endometritis and endometritis has been isolated from donkeys in the USA.

Mastitis in mares is rare. They are seldom used as dairy animals and therefore do not have the usual environmental exposure and mechanical injury that accompanies milk harvesting. Bacteria cultured from lactating mares are similar in spectrum to other species, and include streptococci and staphylococci. Mastitis is recognized as excessive swelling of a mamma in a lactating mare. Lesions are similar to those in other species.