30 Jan 2012
Jon Hall
Job TitleJon Hall provides an overview of pyometra in bitches, including its diagnosis and management, and discusses techniques for treating the disease
Pyometra is a common disease of the reproductive system, with up to 25 per cent of all entire female dogs developing the disorder before they reach the age of 10.
Although surgical ovariohysterectomy definitively prevents future occurrence of pyometra and neoplasia of the female reproductive tract, medical management is an alternative treatment that preserves future breeding potential.
Recurrence of pyometra ranges from 10 per cent to 40 per cent in 12 months and up to 77 per cent in 27 months. Conception rates in the subsequent season may be as high as 75 per cent in younger animals. Medical management involves the use of natural or synthetic prostaglandins, preferentially in combination with medications such as dopamine agonists or progesterone receptor antagonists. Stabilisation of a patient in shock should not be overlooked, whether medical management or surgical management is to be pursued.
Antimicrobial selection should ideally be made based on culture and sensitivity, but empirical selection of broad spectrum drugs should be made in consideration of the bacterial species commonly encountered in pyometra. This article summarises several approaches to the medical management of pyometra in the bitch.
pyometra, medical management, cystic endometrial hyperplasia
PYOMETRA is a common reproductive disease with up to 25 per cent of all entire female dogs developing the disorder before they reach 10 years of age (Verstegen et al, 2008).
Pyometra is most commonly treated by ovariohysterectomy following stabilisation of the patient using IV fluid therapy and broad-spectrum antibiosis. However, numerous medical treatments have been proposed for both open and closed cervix pyometra with good success and preservation of future fertility. Since ovariohysterectomy offers a definitive, rapid resolution of clinical symptoms, prevention of the condition’s recurrence and of future neoplasia of the female reproductive tract, medical management is likely to be reserved for the treatment of bitches with high breeding value.
Traditionally, pyometra has been considered the end stage of cystic endometrial hyperplasia (CEH), whereby optimal conditions within the uterus allow opportunistic ascending pathogens to establish infection (Figure 1). However, it has been suggested that CEH and pyometra may be separate disease entities since all dogs develop CEH with age, but not necessarily pyometra. Similarly, pyometra may occur without evidence of CEH in younger animals. It has been suggested that bacteria may be the initiating factor, stimulating uterine wall hypertrophy and hyperplasia towards the end of oestrus in a similar manner to trophoblastic implantation and subsequently proliferating, leading to infection.
Irrespective of the aetiopathogenesis of the disease, dioestrus is characterised by elevated progesterone levels, which lead to:
• suppression of immune responses;
• stimulation of endometrial gland secretions (providing a suitable environment for bacterial growth);
• functional closure of the cervix with decreased myometrial contractility (preventing drainage of uterine exudates); and
• cystic endometrial development.
Clinical signs are variable and generally seen within eight weeks of oestrus in bitches. Table 1 summarises the clinical signs, examination and pathological laboratory results most commonly seen in cases of pyometra (Figure 2). Endotoxins produced by Escherichia coli infection have been implicated in the pathogenesis of the polyuria and polydipsia (PU/PD) often seen in animals with pyometra. The PU/PD and azotaemia are likely to be due to a decreased response to anti-diuretic hormone, glomerular dysfunction and renal tubular cell damage caused by the deposition of immune complexes within the kidneys (Fransson and Ragle, 2003).
Abdominal radiographs and ultrasonography may demonstrate an enlarged, fluid-distended uterus. Around 30 per cent of dogs with pyometra have concurrent urinary tract infections (UTI). A urine sample should be obtained for culture and sensitivity testing in animals with evidence of UTIs or those that are systemically unwell. If a decision to perform surgery is made, preoperative stabilisation is vital, especially in very sick animals (Figure 3).
Anti-progesterone drugs are an important component of medical management of pyometra. They promote cervical relaxation and induce uterine contraction and emptying.
Anti-progesterone effects may be achieved by inducing luteolysis or by preventing progesterone binding to receptors. Luteolysis may be accomplished directly through the use of prostaglandins (Prostaglandin F2α [PGF]) or indirectly by inhibiting prolactin through the use of dopamine agonists. Progesterone receptor antagonists mimic the effects of luteolysis.
Therapy is also targeted towards inhibition of antimicrobial proliferation, through the rational use of limited or broadspectrum antimicrobials, and also possibly towards encouraging endometrial regeneration by prolonging anoestrus using androgen receptor agonists.
• Prostaglandins
Prostaglandins have been used with good results (Verstegen, 2008). Effects include luteolysis, opening of the cervix and myometrial contraction. Natural prostaglandin (such as dinoprost tromethamine) leads to more substantial uterine contraction than synthetic prostaglandin analogues (such as cloprostenol), but may result in more severe side effects (particularly emesis). Side effects are dose dependent and include vomiting, diarrhoea and panting (20 minutes to 30 minutes after injection).
These diminish with repetition and a regime of gradually increasing dosage for the first few days may limit the incidence of adverse effects (Verstegen et al, 2008). Intravaginal infusion of natural prostaglandins has been used with good results and no side effects, although this method requires further validation before being recommended (Gabor et al, 1999). Prostaglandins can be used in conjunction with dopamine agonists (Table 3).
• Dopamine agonists
The use of dopamine agonists, such as cabergoline and bromocriptine, potentiates the luteolytic effects of PGF, leading to a much faster fall in serum progesterone concentrations and quicker cervical relaxation. Cabergoline acts directly at the anterior pituitary gland to prevent the secretion of prolactin. England et al treated 22 bitches ultrasonographically diagnosed with open and closed cervix pyometra using a combination of 5µg/kg cabergoline PO sid per day and 5 µg/kg cloprostenol IM every third day, plus potentiated sulphonamide PO twice a day (Table 4).
Treated animals showed a rapid clinical improvement, with haematological profiles of 21 bitches returning to normal within six days of treatment, and biochemical profiles returning to normal within nine days; 19 of the bitches were managed successfully by day 10 of treatment. Adverse effects were limited to 60 minutes immediately after prostaglandin administration. Eleven of the 21 successfully treated bitches were mated at the next oestrus, and seven became pregnant.
The pyometra recurred after the next oestrus in four of the bitches. A slightly longer treatment course may be required when compared with the use of natural prostaglandins alone. However, considerably less frequent administration of prostaglandins is a particular benefit.
• Progesterone receptor antagonists
Progesterone antagonists, such as aglepristone, mimic the effects of luteolysis, causing relaxation of the cervix. There is no direct action of the drug causing contraction of the uterus, although it has been suggested that inflammation of the myometrium associated with the pyometra causes endogenous prostaglandin release and uterine contraction.
Treatment using aglepristone alone has been shown to be safe and effective, and may lead to cervical opening in cases of closed pyometra. Combination treatment with cloprostenol may potentiate the action of aglepristone in cases of open and closed pyometra (Gobello et al, 2003; Fieni et al, 2006). Gobello et al used two different protocols combining cloprostenol and aglepristone (Table 5). Both treatments were shown to be effective and, although there were no significant differences in the results between the protocols, treatment one demonstrated a quicker resolution for more cases.
• Antimicrobials
E coli is the most commonly cultured pathogen, although Staphylococcus aureus, Streptococcus species, Pseudomonas species and Proteus species are also frequently isolated. Antimicrobials should be chosen based on culture and sensitivity results. In-vitro sensitivity studies suggest amoxicillin, amoxicillin clavulanate, cephalosporins and potentiated sulphonamides are good initial choices. Antibiosis should be continued for 10 to 14 days after complete resolution of pyometra and provision should be made to avoid oral dosing before giving medications that may induce emesis (such as prostaglandins).
• Additional drugs
Intravaginal misoprostol (prostaglandin E analogue) has been anecdotally used to promote cervical relaxation in dogs (Verstegen et al, 2008).
Promoting uterine regeneration using androgen receptor agonists, such as mibolerone, postpones the next cycle for approximately two months and reduces the recurrence of pyometra, particularly in cases of CEH. This can be used approximately one month after the end of medical treatment of pyometra (Verstegen at al, 2008).
Recurrence rates using natural prostaglandins range from 10 per cent to 40 per cent within 12 months to as high as 77 per cent in 27 months (Wallen and Flickinger, 1986; Johnston et al, 2001). Recurrence rates of 18.9 per cent with aglepristone alone (Trasch et al, 2003), 20 per cent with aglepristone and cloprostenol (Gobello et al, 2003) and 18 per cent with cloprostenol and cabergoline (England et al, 2007) have been reported.
Trasch et al suggested recurrence may have been lower if bitches with ovarian and endometrial cystic changes were not selected for medical treatment; these animals are most likely to demonstrate recurrence. However, it is difficult, and possibly impractical, to correctly identify these changes using ultrasound.
Estimated conception rates range from 50 per cent to 75 per cent at the subsequent oestrus, with younger animals generally demonstrating the highest conception rates (Nelson and Kelly, 1976; England et al, 2007). Some authors have also suggested reduced litter sizes (England et al, 2007).
Any evidence of vaginal discharge, pyrexia or neutrophilia may indicate further treatment is necessary. Ultrasonographic uterine examination should be performed two weeks after finishing medical treatment. Uterine lavage, culture and even biopsies may be indicated in refractory cases. Biopsies should be taken during anoestrus to avoid myometrial trophoblastic reaction.
If there is a poor response to success with five days of medical treatment, it may be advisable to recommend surgical management (Figure 4; Verstegen et al, 2008). Medical treatment is likely to stabilise the patient for general anaesthesia.
Jon Hall
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