Etiology

• In order to understand the etiology of persistent post-breeding endometritis, it is necessary to understand the normal physiological mechanisms which occur in the mare’s uterus following breeding, since persistent post-breeding endometritis is the failure (either underactivation or uncontrolled activation) of these mechanisms.
• Following breeding, mares need to eliminate those sperm cells which do not pass through the utero-tubal junction into the oviduct and other debris from the uterus, in order to leave the uterus in a non-inflamed state, ready to receive the embryo when it descends into the uterus from the oviduct 5.5-6 days post-ovulation.
• This clearance is normally achieved by a combination of lymphatic drainage, myometrial contractions (physical expulsion), and a non-specific immune response (necessary because a specific immune response with a memory would have a detrimental effect the fertility of any subsequent breedings).
• Thus all mares undergo a transient inflammatory reaction within the uterus (endometritis) following breeding - this is a normal physiological mechanism. The inflammation is triggered by sperm cells, which activate complement in uterine secretions. This causes complement factor C5 to cleave into C5a and C5b. This cleavage acts as a chemotactic signal to polymorphonuclear leukocytes (PMNs), causing an influx of PMNs into the uterine lumen Polymorphonuclear (PMN) score table.
• These activated PMNs bind to sperm cells, by ligand binding and possibly also by extruding their (the PMNs’) DNA to form extracellular neutrophil traps (NET). The PMNs phagocytose sperm cells and bacterial contaminants from breeding.
• It is proposed that the activated PMNs also release prostaglandin F2α, which promotes myometrial contractions, thus physically removing inflammatory products and fluid from the uterus.
• In normal mares, the inflammation (endometritis) subsequently subsides. Seminal plasma (i.e. the non-sperm and non-gel component of the ejaculate) has a role to play in limiting the duration of physiological post-breeding endometritis by suppressing complement activation, PMN chemotaxis and phagocytosis.
• The use of spermatozoa with reduced seminal plasma (as in frozen/thawed semen or sperm 'packed' from fresh semen by centrifugation) results in a more marked and prolonged inflammatory response, because seminal plasma is a modulator of sperm-induced inflammation and protects viable spermatozoa from opsonization and phagocytosis.
• In mares which are susceptible to persistent post-breeding endometritis (around 10-15% of broodmares), some part of this normal physiological mechanism of post-breeding inflammation, physical clearance and subsequent dampening of the inflammation fails (see Pathophysiology below).

Predisposing factors

General

• Older mare, either maiden or pluriparous.
• Mares bred with frozen/thawed semen.

Specific

• Cervix which fails to dilate during estrus Cervix: fibrosis.
• Pendulous uterus.
• Failure of myometrial contractility, ie failure of physical clearance of intrauterine fluid.
• Failure of normal suppression of normal physiological inflammatory reaction to breeding.
• Poor lymphatic drainage, eg due to endometrial degeneration/fibrosis Endometrium: fibrosis.
• Possibly, angiosis, ie endometrial vascular degeneration.

Pathophysiology

• In mares which are susceptible to persistent post-breeding endometritis, one or a combination of the following factors results in a failure of the normal physiological mechanism for dealing with the insult to the uterus which breeding represents:
• Failure of physical clearance mechanisms
  • Pendulous uterus meaning that intrauterine fluid cannot be moved towards the cervix by the contracting myometrium, due to gravity.
  • Lack of myometrial contractility.
• Failure of suppression of the normal inflammatory reaction to breeding, by 24-48 h post-breeding.

• There is an inter-relationship between disruption of normal mechanisms of inflammation and myometrial contractility. During inflammation, nitric oxide is synthesized by inducible nitric oxide synthase. In mares susceptible to persistent post breeding endometritis, there is an increase in NO production following breeding compared to non-susceptible mares. Nitric oxide has a relaxing effect on smooth muscle, ie inhibits myometrial contractility.
• Prolonged inflammation and prostaglandin release can cause premature lysis of the corpus luteum with resulting progesterone deficiency and embryo mortality.
• The persistent inflammatory reaction within the uterus and the failure of normal physical clearance combine to set up a vicious cycle of intra-uterine fluid-production. The persistence of intrauterine fluid can:
  • Act as a culture medium for bacteria introduced into the uterus prior to breeding, eg due to poor perineal conformation, at the time of breeding, or post-breeding, eg during the course of intrauterine treatments. Thus, what is primarily a disruption of normal physiological mechanisms can exacerbate or progress into bacterial endometritis Uterus: endometritis – bacterial.
  • Possibly, result in a failure of a mucociliary clearance mechanism which usually promotes uterine clearance post-breeding, by overhydrating the mucus, thus disrupting its viscosity and elasticity and preventing it from functioning normally to traps particles and facilitate their clearance via carriage by ciliary cells.

Timecourse

• Post-breeding endometritis is initiated within 30 min of breeding.
• In normal mares, it is self-limiting by 24-48 h post-breeding
• In ‘susceptible’ mares, it continues beyond this time frame and may persist until the embryo descends into the uterus at 5.5-6 days post-ovulation.