Acute and Chronic Endometritis

Endometritis is an inflammatory condition of the endometrium, the inner lining of the uterus, which can be classified as acute or chronic based on the duration and histopathological characteristics. Acute endometritis is typically a recent, often severe inflammation characterized by neutrophilic infiltration, edema, and hyperemia of the endometrial stroma and glands, frequently associated with bacterial infection. Chronic endometritis is a persistent, low-grade inflammation with a mixed cellular infiltrate (lymphocytes, plasma cells, macrophages) and may involve fibrosis, glandular atrophy or cystic changes, and is often a sequel to unresolved acute infection or repeated uterine contamination. In the context of the estrous cycle, endometritis can occur at any stage but is particularly relevant during diestrus when progesterone dominates, promoting endometrial glandular secretion and creating a favorable environment for bacterial growth. The condition is a significant cause of infertility, embryonic loss, and systemic illness in bitches and queens, and can progress to pyometra if untreated. The classification also considers the underlying cause, such as bacterial, chemical, or hormonal, and the clinical presentation, which may range from subclinical to severe with systemic signs.

The primary etiological agents of endometritis are bacteria, with Escherichia coli being the most commonly isolated pathogen in both dogs and cats. Other aerobic bacteria include Streptococcus spp., Staphylococcus spp., Klebsiella spp., Proteus spp., and Pseudomonas spp. Anaerobic bacteria such as Bacteroides and Fusobacterium spp. may also be involved, especially in chronic cases. Mycoplasma and Ureaplasma species have been implicated in some cases. Viral causes are less common but may include canine herpesvirus, which can cause necrotizing endometritis in neonatal puppies and occasionally in adult bitches. Fungal endometritis is rare but can occur with systemic mycoses. Non-infectious causes include chemical irritation from intrauterine medications, foreign bodies, and hormonal imbalances, particularly hyperestrogenism or prolonged progesterone exposure. Iatrogenic causes include improper artificial insemination techniques, uterine catheterization, or obstetric manipulation. The pathogenesis involves bacterial adherence to endometrial epithelial cells, often facilitated by fimbriae and adhesins, and the production of toxins and enzymes that damage tissue. Progesterone upregulates endometrial receptors for bacteria and suppresses local immune responses, while estrogen can enhance uterine defense mechanisms. The presence of pre-existing endometrial hyperplasia or cystic endometrial hyperplasia (CEH) predisposes to infection.

Endometritis is a common reproductive disorder in intact female dogs and cats, with a higher prevalence in middle-aged to older animals (typically >6 years in dogs, >4 years in cats). Breed predispositions in dogs include those with a high incidence of pyometra, such as Golden Retrievers, Labrador Retrievers, Rottweilers, and Bernese Mountain Dogs, suggesting a genetic component. Nulliparous females are at increased risk, as are those with irregular estrous cycles or a history of mismating. The condition is more frequently diagnosed during diestrus, when progesterone levels are elevated, and in the postpartum period, when the cervix is open and the uterus is involuting. In breeding kennels, poor hygiene, inadequate nutrition, and stress can increase the incidence. The exact incidence is difficult to determine due to subclinical cases, but it is estimated that up to 25% of bitches may develop pyometra by 10 years of age, and endometritis is a precursor. In cats, the incidence is lower, but similar risk factors apply. The use of exogenous progestins for estrus suppression or contraception significantly increases the risk of endometritis and pyometra.

The pathophysiology of endometritis is complex and involves an interplay between hormonal milieu, bacterial virulence, and uterine defense mechanisms. During diestrus, progesterone stimulates endometrial glandular growth and secretion, and decreases myometrial contractility, leading to uterine stasis. Progesterone also suppresses the local immune response by reducing the number and activity of uterine leukocytes, particularly neutrophils and macrophages, and by decreasing the production of immunoglobulins. This creates an environment conducive to bacterial colonization and growth. Bacteria, particularly E. coli, adhere to endometrial epithelial cells via fimbriae and produce toxins that cause tissue damage and inflammation. The inflammatory response involves the release of cytokines, prostaglandins, and leukotrienes, leading to vasodilation, increased vascular permeability, and recruitment of neutrophils. In acute endometritis, there is intense neutrophilic infiltration, edema, and microabscess formation. If the infection is not resolved, chronic inflammation ensues, characterized by infiltration of lymphocytes, plasma cells, and macrophages, along with fibrosis and glandular atrophy. Chronic endometritis can lead to cystic endometrial hyperplasia (CEH), where the endometrial glands become dilated and filled with fluid, further compromising fertility. The inflammatory process can also extend to the myometrium and parametrium, leading to metritis and peritonitis. In severe cases, systemic inflammatory response syndrome (SIRS) and sepsis can develop, with endotoxemia from Gram-negative bacteria causing shock and multi-organ failure.

Intrinsic predisposing factors include age, with older animals having reduced uterine defense mechanisms and increased likelihood of endometrial changes. Breed and genetic susceptibility play a role, as certain breeds have a higher incidence of CEH and pyometra. Nulliparity is a risk factor, as repeated estrous cycles without pregnancy lead to repeated exposure to progesterone and potential endometrial changes. Hormonal imbalances, such as hyperestrogenism or prolonged progesterone exposure from endogenous or exogenous sources, are significant. Congenital anomalies of the reproductive tract, such as uterine hypoplasia or cervical incompetence, can predispose to infection. Extrinsic factors include the administration of exogenous progestins for estrus suppression or treatment of false pregnancy, which can induce CEH and endometritis. Poor breeding management, including improper timing of mating, artificial insemination with contaminated semen, or unsanitary conditions during breeding or whelping, increases the risk. Stress, overcrowding, and poor nutrition can compromise the immune system. Postpartum uterine involution is a vulnerable period, and retained fetal membranes or dystocia can lead to endometritis. The presence of other reproductive diseases, such as vaginitis or cervicitis, can also predispose to ascending infection.

Clinical signs of endometritis vary depending on the severity and chronicity. In acute endometritis, signs may include vulvar discharge, which can be mucoid, purulent, or sanguineous, often with a foul odor. The discharge may be observed on the vulva or tail, and the animal may lick the perineal area. Systemic signs such as fever, lethargy, anorexia, and depression may be present, especially if there is concurrent metritis or sepsis. Abdominal pain may be evident on palpation, and the uterus may be enlarged and doughy. In chronic endometritis, clinical signs are often more subtle and may include intermittent or persistent vaginal discharge, infertility, failure to conceive, embryonic loss, or abortion. The animal may appear otherwise healthy, but there may be a history of repeated estrous cycles without pregnancy. On vaginal examination, the cervix may be open or closed, and the uterine horns may be palpably thickened. In cases of CEH, the uterus may be palpably enlarged and cystic. Behavioral changes such as increased thirst, urination, or lethargy may occur if systemic involvement is present. In severe cases, signs of sepsis, such as pale mucous membranes, tachycardia, and weak pulses, may be observed.

Differential diagnoses for endometritis include: 1) Pyometra: a severe, life-threatening uterine infection with accumulation of pus, often associated with closed cervix, systemic signs, and characteristic ultrasonographic findings of a fluid-filled, thickened uterus. 2) Metritis: inflammation of the uterine wall, often occurring postpartum, with systemic signs and a putrid vaginal discharge. 3) Vaginitis: inflammation of the vagina, which can cause discharge but is not associated with uterine pathology; diagnosis via vaginoscopy and cytology. 4) Cystic Endometrial Hyperplasia (CEH): a non-inflammatory condition characterized by cystic endometrial glands, often a precursor to pyometra; diagnosed via ultrasound and histopathology. 5) Pregnancy: early pregnancy can cause a mucoid discharge and uterine enlargement; differentiation via ultrasound and hormone assays. 6) Abortion or embryonic resorption: may present with vaginal discharge and a history of infertility; diagnosis via ultrasound and progesterone monitoring. 7) Uterine neoplasia: rare, but leiomyoma or adenocarcinoma can cause discharge and uterine enlargement; diagnosis via imaging and biopsy. 8) Foreign body in the reproductive tract: such as a retained fetal membrane or intrauterine device, can cause inflammation and discharge. 9) Coagulopathy or trauma: can cause sanguineous discharge, but history and other signs differentiate. 10) Hormonal imbalances, such as hyperestrogenism, can cause endometrial hyperplasia and discharge. Definitive diagnosis requires a combination of history, clinical signs, imaging, cytology, culture, and histopathology.

The diagnostic algorithm for endometritis begins with a thorough history and physical examination, including assessment of reproductive status, estrous cycle stage, and any previous breeding issues. A complete blood count and serum biochemistry profile are performed to evaluate for systemic inflammation, leukocytosis, and organ function. Vaginal cytology is collected to assess the stage of the estrous cycle and to identify inflammatory cells, bacteria, and epithelial cells. Serum progesterone measurement is crucial to determine the stage of the cycle and to assess for luteal function. Abdominal ultrasonography is the primary imaging modality, allowing evaluation of the uterine size, wall thickness, luminal contents, and ovarian structures. The presence of intraluminal fluid, endometrial thickening, or cystic changes supports the diagnosis. Radiography may be useful in late pregnancy or to detect fetal mineralization, but is less sensitive for uterine pathology. If the cervix is open, a uterine culture and sensitivity can be obtained via a guarded swab or by flushing the uterus with sterile saline. Endometrial biopsy, either via transcervical catheterization or during surgery, provides a definitive histopathological diagnosis and can differentiate acute from chronic endometritis. In cases of suspected CEH or neoplasia, biopsy is essential. Additional tests such as PCR for specific pathogens (e.g., Brucella canis) may be indicated in breeding animals. The algorithm should be systematic, starting with non-invasive tests and progressing to more invasive procedures as needed.

Laboratory findings in endometritis often reflect systemic inflammation. Hematology may reveal leukocytosis with a left shift, characterized by an increased number of neutrophils, including band cells, and toxic changes in neutrophils. In chronic cases, mild anemia may be present. Serum biochemistry may show hyperglobulinemia due to chronic inflammation, and in severe cases, azotemia and elevated liver enzymes may indicate sepsis or multi-organ dysfunction. Hypocalcemia can occur in postpartum metritis. Serum progesterone levels are typically elevated during diestrus, which is the most common time for endometritis to develop. Estrogen levels may be low. Vaginal cytology during diestrus shows a predominance of parabasal and intermediate cells, with few superficial cells, and the presence of neutrophils and bacteria. In acute endometritis, there may be a large number of neutrophils, often with degenerative changes. In chronic endometritis, the cytology may show a mixed population of inflammatory cells, including lymphocytes and plasma cells. Uterine culture and sensitivity are essential to identify the causative organism and guide antibiotic therapy. E. coli is the most common isolate, and susceptibility testing is important due to increasing antimicrobial resistance. Urinalysis may reveal proteinuria or bacteriuria if there is concurrent urinary tract infection. In cases of suspected brucellosis, serology or PCR is performed.

Abdominal ultrasonography is the most valuable imaging modality for evaluating endometritis. In acute endometritis, the uterus may be enlarged, with a thickened, hypoechoic endometrium and the presence of intraluminal fluid, which may be anechoic or echogenic depending on the cellular content. The uterine wall may appear irregular, and there may be increased vascularity on Doppler examination. In chronic endometritis, the endometrium may be hyperechoic with cystic structures, indicative of CEH. The uterine lumen may contain small amounts of fluid. Ultrasonography can also assess the ovaries, identifying corpora lutea or follicles, and can rule out pregnancy. Fetal heart rate, if pregnant, can be measured; a rate below 160 beats per minute indicates fetal distress. Radiography is less sensitive but may show uterine enlargement or fetal mineralization after day 42-45 of gestation. In cases of pyometra, radiographs may show a tubular soft tissue opacity in the caudal abdomen. CT and MRI are rarely used but can provide detailed images of the reproductive tract, especially in cases of neoplasia or complex pathology. Vaginoscopy can be performed to visualize the vaginal mucosa and cervix, and to collect samples for cytology and culture. It can help differentiate vaginitis from endometritis by assessing the presence of discharge originating from the cervix.

Vaginal cytology is a key diagnostic tool. During diestrus, the cytology shows a shift from superficial cornified cells to parabasal and intermediate cells, with the presence of neutrophils and bacteria. In acute endometritis, there is a marked increase in neutrophils, often with degenerative changes, and intracellular bacteria may be seen. In chronic endometritis, the cytology may show a mixed inflammatory infiltrate, including lymphocytes and plasma cells, and the presence of macrophages. Endometrial biopsy, obtained via transcervical catheterization or during surgery, provides definitive histopathological diagnosis. Acute endometritis is characterized by neutrophilic infiltration of the endometrial stroma and glands, edema, hyperemia, and microabscess formation. Chronic endometritis shows infiltration of lymphocytes, plasma cells, and macrophages, along with fibrosis, glandular atrophy, and possibly cystic dilation of glands (CEH). Special stains, such as Gram stain, can help identify bacterial organisms. Histopathology is also essential to rule out neoplasia and to assess the severity of endometrial changes, which can guide treatment and prognosis. In cases of CEH, the glands are dilated and lined by hyperplastic epithelium, and there may be intraluminal fluid accumulation.

Treatment of endometritis depends on the severity, the animal's breeding status, and the presence of systemic signs. In mild, acute cases in breeding animals, medical management may be attempted. The goals are to eliminate the infection, promote uterine evacuation, and preserve fertility. Antibiotics should be selected based on culture and sensitivity, and administered for at least 2-3 weeks. Commonly used antibiotics include amoxicillin-clavulanic acid (12.5-25 mg/kg PO q8h), cephalexin (15-30 mg/kg PO q8h), or enrofloxacin (5-10 mg/kg PO q12h) in combination with amoxicillin for anaerobic coverage. To promote uterine evacuation, prostaglandin F2alpha (PGF2α) can be used, but it is contraindicated in pregnant animals. Dinoprost (Lutalyse) is administered at 0.1-0.25 mg/kg SC q12h for 2-5 days, or cloprostenol (Estrumate) at 1-2 μg/kg SC q48h. These agents cause luteolysis and myometrial contraction, expelling uterine contents. However, they can cause side effects such as vomiting, diarrhea, and restlessness. Alternatively, aglepristone (Alizin) at 10 mg/kg SC on days 0, 1, and 2, is a progesterone receptor antagonist that can be used to terminate diestrus and facilitate uterine clearance. It is particularly useful in cases of CEH. In addition, cabergoline (0.005 mg/kg PO q24h for 5-7 days) can be used to lower prolactin and progesterone levels. Oxytocin (0.5-2 IU/kg IM or SC) can be given to stimulate uterine contractions, but it is more effective in the presence of estrogen and is often used postpartum. Supportive care includes fluid therapy, anti-inflammatories, and nutritional support. In severe cases, or in non-breeding animals, ovariohysterectomy (OHE) is the treatment of choice, as it removes the source of infection and prevents recurrence. In cases of pyometra, OHE is often life-saving. Postoperative care includes antibiotics and pain management. In breeding animals with chronic endometritis, surgical intervention may be necessary if medical therapy fails, but the prognosis for fertility is guarded.

The prognosis for endometritis depends on the severity, chronicity, and underlying cause. In acute, uncomplicated cases that are treated promptly and appropriately, the prognosis for recovery is good, and fertility may be preserved if the endometrium is not severely damaged. However, the recurrence rate is high, especially if predisposing factors such as CEH are present. In chronic endometritis, the prognosis for fertility is guarded to poor, as the endometrial damage may be irreversible. The presence of CEH significantly reduces the chances of successful pregnancy. In cases that progress to pyometra, the prognosis is guarded, with a mortality rate of 4-20% even with surgical treatment. Negative prognostic indicators include closed-cervix pyometra, systemic signs, azotemia, and peritonitis. After OHE, the prognosis is excellent for resolution of the disease, but the animal is permanently infertile. For breeding animals, the prognosis for future fertility is best if the condition is detected early and treated aggressively, with a focus on preserving endometrial health. Serial monitoring of progesterone and ultrasonography can help guide breeding management.

Follow-up care for endometritis is essential to ensure resolution and to monitor for recurrence. After medical treatment, a recheck examination should be performed within 2-4 weeks, including vaginal cytology, ultrasonography, and possibly a uterine culture to confirm clearance of infection. Serum progesterone should be monitored to assess the stage of the estrous cycle and to ensure that luteolysis has occurred if PGF2α or aglepristone was used. If the animal is intended for breeding, the next estrous cycle should be monitored closely, and breeding should be timed based on progesterone and vaginal cytology. Ultrasonography should be performed during proestrus and estrus to assess uterine health and to detect any residual fluid or endometrial changes. If the animal is not for breeding, OHE is recommended to prevent recurrence. After OHE, the animal should be monitored for surgical complications, such as infection or dehiscence, and a recheck is typically scheduled at 10-14 days postoperatively. In cases of chronic endometritis, long-term management may involve repeated treatments and careful breeding management. The owner should be educated on the signs of recurrence and the importance of early intervention.

Clinical pearls: 1) Always measure serum progesterone to stage the estrous cycle; a progesterone >2 ng/mL indicates diestrus, and >5 ng/mL is consistent with a functional corpus luteum. 2) In pregnant bitches, a fetal heart rate <160 bpm is a sign of fetal distress and may indicate impending abortion. 3) When using PGF2α, be prepared for side effects such as vomiting, defecation, and restlessness; pre-treatment with antiemetics may help. 4) Aglepristone is a safer alternative to PGF2α in cases of CEH, as it does not cause luteolysis but blocks progesterone receptors. 5) Always perform a culture and sensitivity before starting antibiotics, as resistance is common. 6) In postpartum metritis, oxytocin can be used to promote uterine involution, but it is ineffective if the cervix is closed. Pitfalls: 1) Do not use PGF2α in pregnant animals, as it will cause abortion. 2) Avoid the use of corticosteroids in cases of endometritis, as they can suppress the immune response and worsen the infection. 3) Do not rely solely on vaginal cytology to diagnose endometritis, as it can be normal in chronic cases. 4) Do not delay surgical intervention in cases of closed-cervix pyometra, as it can be fatal. 5) Do not use antibiotics without culture and sensitivity, as this can lead to antimicrobial resistance. 6) Do not breed an animal with a history of endometritis without confirming uterine health via ultrasound and cytology.

Current drug protocols for endometritis are based on Plumb's Veterinary Drug Handbook and theriogenology guidelines. Antibiotics: Amoxicillin-clavulanic acid (12.5-25 mg/kg PO q8h) for 14-21 days; Cephalexin (15-30 mg/kg PO q8h) for 14-21 days; Enrofloxacin (5-10 mg/kg PO q12h) for 14-21 days, often combined with amoxicillin (20 mg/kg PO q8h) for anaerobic coverage; Doxycycline (5-10 mg/kg PO q12h) for 14-21 days, especially for Mycoplasma. Prostaglandin F2α: Dinoprost tromethamine (Lutalyse) at 0.1-0.25 mg/kg SC q12h for 2-5 days, or 0.25 mg/kg SC q24h for 3-5 days; Cloprostenol (Estrumate) at 1-2 μg/kg SC q48h for 2-3 treatments. These are contraindicated in pregnancy. Aglepristone (Alizin) at 10 mg/kg SC on days 0, 1, and 2, repeated if necessary. Cabergoline (Galastop) at 0.005 mg/kg PO q24h for 5-7 days. Oxytocin (Pitocin) at 0.5-2 IU/kg IM or SC, can be repeated q2-4h, but only if the cervix is open. Calcium gluconate (10% solution) at 0.5-1.5 mL/kg IV slowly, for hypocalcemia, with cardiac monitoring. Supportive care: IV fluids (Lactated Ringer's solution) at maintenance rates, anti-inflammatories such as carprofen (2.2 mg/kg PO q12h) or meloxicam (0.1 mg/kg PO q24h) for pain and inflammation, but avoid NSAIDs if renal function is compromised. In cases of sepsis, consider broad-spectrum antibiotics and intensive care.

Evidence-based literature on endometritis in dogs and cats is limited but growing. Key studies include: 1) A retrospective study by Hagman et al. (2006) on pyometra in dogs, which identified E. coli as the most common pathogen and found that age, breed, and cystic endometrial hyperplasia were significant risk factors. 2) A study by Verstegen et al. (2008) evaluated the use of aglepristone for the medical treatment of pyometra and CEH, showing a success rate of 80-90% in open-cervix cases, with a recurrence rate of 10-20%. 3) A study by England et al. (2007) on the use of PGF2α for the treatment of endometritis in bitches, demonstrating that low-dose protocols were effective in promoting uterine evacuation and resolving clinical signs. 4) A consensus statement from the European Society for Small Animal Reproduction (EVSSAR) on the management of pyometra and endometritis, recommending OHE as the treatment of choice for non-breeding animals, and medical management with aglepristone or PGF2α for breeding animals with open-cervix disease. 5) A study by Fieni et al. (2014) on the use of cabergoline in combination with aglepristone for the treatment of pyometra, showing improved outcomes. 6) A study by Smith et al. (2013) on the diagnostic value of ultrasonography in differentiating CEH from pyometra, finding that uterine wall thickness and luminal content echogenicity were useful predictors. 7) A meta-analysis by Jitpean et al. (2017) on the prognosis of pyometra, identifying azotemia and systemic inflammatory response syndrome as negative prognostic indicators. These studies underscore the importance of early diagnosis, appropriate antimicrobial therapy, and consideration of surgical intervention in severe cases.