DEFINITION
Pyometra is the term for an accumulation of purulent material within the uterus, while cystic endometrial hyperplasia (CEH) is the result of repeated stimulation of the endometrium by progesterone.
Pyometra is a common disorder in bitches, but can also affect the females of other companion animals, such as cats, rabbits, ferrets, guinea pigs and hamsters.
For years, pyometra in the bitch was considered a direct consequence of CEH; more recently, in the light of various clinical and anatomopathological findings, there has been a tendency to classify pyometra and CEH as distinct conditions, even though pyometra continues to be included as a part of the “cystic endometrial hyperplasia - pyometra” complex. In fact, CEH can be followed not only by the development of pyometra, but also by mucometra, hydrometra and haematometra, depending on the type of fluid accumulation within the uterine lumen (mucoid, serous, and blood, respectively). These latter conditions are distinguished from pyometra by a lack of significant systemic effects. Pyometra, which typically affects sexually intact bitches and is observed predominantly during dioestrus, is classically divided into open-cervix pyometra and closed-cervix pyometra, with clinical pictures that vary very greatly between the two and range from an almost total absence of symptoms to a state of endotoxic or septic shock. Pyometra, CEH, mucometra, hydrometra and haematometra are associated with a considerable variety of anatomopathological findings.
The potentially life-threatening nature of pyometra, in contrast to mucometra, hydrometra and haematometra, makes it essential that the condition is identified promptly.
SIGNALMENT AND HISTORY
The prevalence of naturally occurring CEH/pyometra complex is 0.6%, but, considering its increase in sexually intact bitches with age, the prevalence may even reach 66% in animals over 9 years old. Although the real incidence of mucometra and hydrometra is unknown, the incidence in a study of 60 pathological uteri was 13%.
Pyometra typically affects mature animals (mean age, 7.25 years). However, the age at onset of pyometra in some studies was reported to range between 4 months and 16 years, and in another investigation, carried out on 192 bitches with pyometra, the mean age of development of the condition was 2.4 years. Pyometra normally appears between 4 weeks and 4 months after the end of oestrus (on average, 5.7 weeks) or following treatment with oestrogens or progestins. Iatrogenic pyometra can occur in any phase of the oestrous cycle, and even in pregnancy, and is related to the dose and duration of the hormone treatment.
Nulliparous bitches are more susceptible (accounting for 75% of all animals with pyometra), although the exact mechanism by which pregnancy is able to provide a protective effect is unknown. Subjects affected at a young age have often been given hormonal therapy to suppress (progestins) or induce oestrus or to interrupt pregnancy (oestrogens). Oestrogens increase the number of endometrial receptors for progesterone, amplifying this latter’s effect. The presence of anatomical anomalies, such as defects of the vulva, vagina or cervix (stenosis or septa, segmental aplasia, etc.), could be a predisposing factor in young subjects.
No correlation has been found between phantom pregnancy and the onset of pyometra.
Although it seems that some breeds may be predisposed to the development of pyometra, there is not complete agreement on this. Breeds thought to be more predisposed include the Rottweiler, St. Bernard, Chow Chow, Golden Retriever, Miniature Schnauzer, Irish Terrier, Airedale Terrier, Cavalier King Charles Spaniel, Collie and Bernese Mountain Dog, while breeds among which the risk is reported to be low include the German Shepherd, the Fox Terrier and the Basset Hound.
AETIOPATHOGENESIS
During dioestrus, the high levels of progesterone increase the secretory activity of the endometrial glands and proliferation of the endometrium, reduce the contractile activity of the myometrium and lead to closure of the cervix. Repeated stimulation by progesterone during the luteal phase of the cycle induces CEH, characterized by thickening of the endometrium with possible accumulation of fluid. This fluid, usually mucoid or serous (mucometra or hydrometra, respectively) is sterile, unlike the fluid of pyometra, which is contaminated by bacteria. The effects of the action of progesterone are cumulative, so this syndrome is more likely to be observed in middle-aged or elderly animals.
Oestrogen stimulation also plays an important role in the pathogenesis, since it enhances the sensitivity of the uterus to progesterone, even if oestrogen stimulation alone is not able to induce the pathology. Oestrogens act on the uterus by promoting growth, vascularisation and oedema of the endometrium, opening of the cervix and intraluminal migration of polymorphonuclear leukocytes. Oestrogens also increase the number of endometrial receptors for progesterone, amplifying this latter’s effects. The possible lack or defective down-regulation of endometrial oestrogen receptors, induced by the increase in the concentrations of progesterone, and not by the absolute concentrations of circulating progesterone or oestrogens, could be the cause of the development of CEH.
Progesterone also has a local immunosuppressive effect, particularly in the first phase of dioestrus, which, associated with favourable uterine conditions such as increased glandular secretions and reduced myometrial activity, make this phase of the cycle ideal for bacterial colonisation and the consequent appearance of pyometra.
Bacterial contamination, mainly caused by opportunistic microbes, probably becomes established during oestrus, when the cervix is open; the persistence of bacteria in the uterine lumen, if not resolved before the luteal phase, associated with the possible presence of fluid, favours colonisation and proliferation of germs. Bacterial contamination, with Escherichia coli being the most commonly found bacterium (90%), usually occurs by the ascending route from faeces, from a subclinical urinary infection or from normal vaginal microbial flora. The pathogenicity of E coli, which is particularly marked for some strains, is due to a capsule that makes it resistant to phagocytosis, to the production of haemolysin, necrotising cytotoxic factors and other cytotoxins, to the presence of the K antigen which facilitates its colonisation and adhesiveness, and to the presence of membrane lipopolysaccharides that act as endotoxins following the destruction or death of the bacteria. The endotoxins are responsible for the more severe clinical pictures, characterized by endotoxic shock. Other bacteria that can be found are Streptococcus spp., Staphylococcus spp., Klebsiella, Proteus, Pseudomonas, Enterococcus, Pasteurella, Serratia, Haemophilus andBacillus.
SIGNS
The clinical signs in bitches with pyometra can vary greatly and depend mainly on whether the cervix is open or closed and on the duration of the pathology. In the cases in which the cervix is open, the most obvious sign is the malodorous vulvar discharge, which varies from muco-purulent to frankly bloody (Fig. 1). Bitches affected by this form do not usually have other signs of systemic involvement, especially at the onset of the condition. Other signs, when present, include lethargy, depression, lack of appetite/anorexia, polyuria, polydipsia, vomiting and diarrhoea.
In contrast, bitches with pyometra and a closed cervix have general malaise, with marked clinical signs of depression, lethargy, polyuria, polydipsia, vomiting, diarrhoea and possible abdominal distension; they are often dehydrated, with septicaemia and toxaemia and in a state of shock. Some animals may develop hyperthermia, although, in the case of toxaemia, hypothermia is found more frequently. Renal dysfunction is common in bitches with pyometra caused by E coli. In this case the renal damage is due to various factors, such as dehydration or septic shock with diminished renal perfusion and consequent pre-renal azotaemia, and damage to the glomeruli with a reduction in the glomerular filtration and of the capacity of the tubules to concentrate urine because of endotoxaemia. Since the cervix is closed, there is no vulvar discharge, the uterus increases in size and there may be abdominal distension. Abdominal distension may also be observed in bitches with hydrometra or mucometra with large intrauterine fluid collections. In these cases, systemic signs are not present although there may be some signs due to the increased size of the uterus and compression of other intra-abdominal viscera. In pyometra the uterine enlargement, which is inversely proportional to the degree of opening of the cervix, can be detected by a simple clinical examination: transabdominal palpation of the uterus. This palpation must, however, be carried out with particular care in the case of pyometra with a closed cervix in order not to cause rupture of the uterus.
DIAGNOSIS
Pyometra must always be considered in the differential diagnosis of sexually intact bitches with general malaise, in part because of the potential danger of the disorder, which can rapidly evolve into septicaemia and toxaemia and threaten the animal’s life in the cases with a closed cervix.
Signalment and the clinical history can provide some useful indications in suspected pyometra: the age of the bitch, the date of the last oestrus, any hormone treatments and observation of vaginal discharges with characteristics and timing not compatible with the typical discharge of oestrus. The typical reasons why a consultation with a veterinarian is requested for bitches with pyometra are changes in dietary and water intake and altered gastrointestinal function, sometimes associated with general malaise or sensorial changes.
At a general clinical examination, the nutritional status of an animal with pyometra is usually good; it is poor in only 7-10% of patients. More than 50% of affected animals have sensorial depression and up to 70% of cases have pale mucosae. Dehydration is present, to a variable extent, in over 50% of cases. Body temperature is usually normal; hyperthermia is less common and hypothermia is rare (4-10% of patients). As far as concerns major bodily functions, anorexia and vomiting can be seen in 50-90% and 15-70% of cases, respectively, diarrhoea in over 70%, polydipsia in 5-65% and polyuria in 5-40% of subjects.
Specific clinical examination is aimed at determining the presence, origin and characteristics of any vulvar discharge. In 65-98% of cases of pyometra the cervix is open and there is a vulvar discharge which must be distinguished from that of normal oestrous flow, vaginitis or other systemic disorders (e.g. immune-mediated thrombocytopenia).
Transabdominal palpation of the uterus, carried out with great care to avoid rupturing it, reveals enlargement of the organ, in inverse proportion to the openness of the cervix, and allows an evaluation of the softness of the uterus and any pain. However, the differential diagnosis of an enlarged uterus includes pregnancy and tumours. Cytological examination of the genital discharge, even if it demonstrates the presence of a high number of degenerated neutrophils and intra- and extracellular bacteria, is not sufficient to make a diagnosis of pyometra. In fact, polymorphonuclear neutrophils are present in the uterus of bitches during normal dioestrus, so their finding does not necessarily indicate a pathological process. Samples of uterine discharge for cultures should be taken from the most cranial part of the vagina to avoid contamination by normal vaginal flora. The significance of the culture studies depends on the characteristics of the bacterial growth (extent and degree of purity).
The most obvious abnormality of blood tests is peripheral leukocytosis, which is more marked in the closed form of pyometra and often with a leftward shift in the Arneth count (70-75% of cases), although neutropenia can be seen during endotoxaemia. The average white blood cell count is about 37,000 cells/mm3, although the leukocytosis can exceed 196,000 cells/mm3. The number of immature leukocytes varies between 0 and 4,300 cells/mm3; signs of toxicity of polymorphonuclear neutrophils depend on the severity of the condition.
The haematocrit varies between 21 and 48% and in about 25% of cases there is a mild normocytic and normochromic anaemia. Biochemical examinations may show azotaemia, hypergammaglobulinaemia, hypoalbuminaemia and metabolic acidosis. The azotaemia can be caused by renal dysfunction as a result of glomerular deposition of immune complexes or damage to the renal tubules induced by the endotoxins; however, pre-renal azotaemia can also be found in dehydrated subjects. The blood urea-nitrogen can range from 21 to 119 mg/dl, with a mean of 33 mg/dl. Hypergammaglobulinaemia, usually more marked in the cases of pyometra with a closed cervix, can be seen in about 27% of cases and hypoalbuminaemia in 23% of cases.
Urinalysis is not particularly useful for the diagnosis of pyometra, even if the specific gravity of the urine is reduced in about 20% of affected bitches (indicating a reduced capacity of the renal tubules to concentrate urine) and proteinuria may be found following endotoxaemia-related renal damage.
Ultrasound examination is, however, an essential diagnostic investigation in cases of suspected pyometra.
Ultrasonography can show not only the increased size of the uterus, but also the thickness and echostructure of its walls and the characteristics of its contents. The typical observations are an enlarged uterus containing anechoic or hypoechoic material, usually with a homogeneous appearance, although more echoic flocculations may be present. During CEH there may be thickening of the endometrium, which is sometimes oedematous, with cystic areas. Mucometra, hydrometra and haematometra also seem to be associated with the presence of CEH, but the ultrasound features of these intrauterine collections distinguish them from pyometra. X-rays, usually in a latero-lateral projection, can show the enlargement of the uterus, but do not enable pyometra to be differentiated from other conditions, such as mucometra, hydrometra, uterine torsion, uterine neoplasia or a pregnancy in an early stage before mineralisation of the foetal skeletons has occurred.
TREATMENT
The clinical picture of the patient with pyometra varies greatly and in some cases may require truly intensive therapy. The treatment of choice is ovariohysterectomy (Figs. 2, 3 and 4), particularly when the cervix is closed, in elderly subjects and those with systemic effects. Depending on the condition of the animal, pre-operative stabilisation may be necessary; intra-operative and post-operative support may also be required. It should be remembered that some precautions may be necessary when performing the ovariohysterectomy given the possible substantial increase in the volume of the uterus and its fragility.
In some cases, if reproductive capacity is to be preserved, conservative treatment can be used; this is usually pharmacological. The patients for this management must be carefully selected on the basis of their age, general condition, laboratory test results and ultrasound findings. Generally speaking, possible candidates for pharmacological treatment are young, have pyometra with an open cervix and do not have systemic symptoms.
Prostaglandin F2α (PGF2α) can be used to lower the levels of circulating progesterone and induce expulsion of the uterine contents. PGF2α must be used with care and in animals admitted to hospital, given its well-known side-effects in dogs. The most frequent side effects are tachycardia, restlessness, nausea, vomiting, diarrhoea and hypersalivation, generally observed 5-60 minutes after its administration, which tend to become less intense as treatment is continued. The protocols for the administration of PGF2α vary greatly, depending on the type of prostaglandin used: 50-250 µg/kg, subcutaneously, every 12 hours for 3-5 days in the case of “natural” PGF2α; 1-3 µg/kg every 12 to 24 hours for 7-10 days in the case of cloprostenol, a synthetic analogue of natural PGF2α. Although there are reports of the use of PGF2α in bitches with closed-cervix pyometra, its use in this situation is not recommended because of the risk of uterine rupture. The efficacy of PGF2α has been reported to range from 83 to 100%.
An alternative (or complementary) pharmacological treatment to PGF2α is the use of antiprogestogens, including aglepristone, a steroid that antagonises the effect of progesterone by competing for this latter’s endometrial receptors. Among the various protocols proposed for the conservative treatment of pyometra in the bitch, one of the most widely used is a dose of aglepristone 10 mg/kg subcutaneously every 24 hours on days 1, 2 and 8. Within 12-48 hours this induces opening of the cervix, emptying of the uterine contents with improvement of the general condition of the animal and transformation of the vulvar discharge from purulent to mucoid and then to serous. The efficacy of the treatment must be monitored by ultrasound examinations to check that the pyometra does actually resolve; in the case of incomplete resolution, aglepristone must also be administered on days 14 and 28. The treatment success rate with aglepristone alone is about 60% but can reach 84% if the aglepristone is associated with cloprostenol. The administration of aglepristone may also be indicated in the view of planned ovariohysterectomy, because of its capacity to improve the animal’s general condition and, thereby, reduce the risk of surgery.
It is always advisable to give antibiotic therapy together with either PGF2α or aglepristone treatment. When the results from culture studies and the related antibiogram are not available, amoxicillin or amoxicillin in association with clavulanic acid or quinolones should be used.
Aglepristone has also been used successfully in the pharmacological treatment of pyometra in the cat at a dose of 10 mg/kg subcutaneously on days 1, 2, 7 and 14 (the last dose being given only if the previous ones were ineffective), administered in association with trimethoprim-sulphadoxine at a dose of 15 mg/kg/die subcutaneously for 7 days. The treatment, which did not have side effects, was effective in nine of ten queens treated and recurrences were not observed in 2 years of follow-up.
PROGNOSIS
The mortality rate in bitches affected by pyometra has fallen from 16 to 2-6%. However, given the wide range of the clinical pictures, the prognosis depends on a complete evaluation of the patient. Generally speaking the prognosis of bitches with closed-cervix pyometra is poor, because there are often multiple systemic complications that can compromise the patient’s recovery. The prognosis is more favourable in cases with an open cervix, although systemic involvement is also possible in these cases.
As far as concerns preservation of reproductive capacity, the main aim of conservative treatment, it has been reported that the incidence of recurrent pyometra is high, being 10-77% in the 2 years following treatment with PGF2α and 19% within 1 year of the administration of aglepristone. It is, therefore, advisable to plan mating in the first oestrus following the treatment which, in the case of PGF2α treatment, can occur at a shorter inter-oestrous interval. It should be noted that despite successful resolution of pyometra, there is a reported reduction in fertility, estimated to be in the order of 50-65% in the case of PGF2α treatment. As far as concerns aglepristone, it was recently demonstrated that 57% of treated bitches had a normal gestation, but that recovery of fertility depended on the age of the animal (no pregnancies were obtained in bitches over 5 years old, despite complete resolution of the pyometra). According to some authors, in order to maximise the possibility of conception, prior to mating the bitches should undergo vaginal culture during the first days of pro-oestrus, and be given the appropriate antibiotic therapy. The lack of conception during the oestrous cycle following treatment predisposes to recurrence.
Suggested readings
- Jurka P, Max A, Hawrynska K, Snochowski M (2010) Age-related pregnancy results and further examination of bitches after aglepristone treatment of pyometra. Reprod Domest Anim, 45: 525-529.
- Nak D, Nak Y, Tuna B (2009) Follow-up examination after medical treatment of pyometra in cats with the progesterone-antagonist aglepristone. J Feline Med Surg, 11: 499-502.
- PretzerSD(2008) Clinical presentation of canine pyometra and mucometra: A review. Theriogenology, 70: 359-363.
- Smith FO (2006) Canine Pyometra. Theriogenology, 66: 610-612.
- Fieni F (2006) Clinical evaluation of the use of aglepristone, with or without cloprostenol, to treat cystic endometrial hyperplasia-pyometra complex in bitches. Theriogenology, 66: 1550-1556.
- JohnstonSD, Kustritz MVR, Olson PNS (2001) Canine and Feline Theriogenology. Saunders 3rd edition.Philadelphia, 206-274.