Mucometra, cystic endometrial hyperplasia, and pyometra in the bitch: advances in treatment and assessment of future reproductive success.
ABSTRACT Pyometra is a common reproductive disorder which affects nearly one fourth of all female dogs before they reach 10 y of age. An association between pyometra and the most common uterine disease of the bitch, cystic endometrial hyperplasia, has been established, as the latter allows commensal bacteria originating from the vagina to proliferate in the uterus at the end of estrus. The progressive degenerative process in the development of cystic endometrial hyperplasia is usually proposed as the initiating lesion for pyometra in bitches; this is mediated by progesterone and potentially aggravated by estrogens. However, a separate process caused by local uterine irritation to trophoblastic reaction and bacterial proliferation has been recently proposed as an alternate mechanism leading to the development of pyometra. Pyometra is clinically distinct in pathogenesis, signs, treatment and prognosis from postpartum metritis or mucometra. Treatment of pyometra has historically involved ovariohysterectomy, however, during the last 10 y, numerous effective treatments have been proposed to treat both open and closed cervix pyometra with good success and future fertility. Among the treatments available, the use of repeated low doses of prostaglandins alone or in association with either dopamine agonists or progesterone-receptor antagonists has been demonstrated to be a viable alternative for valuable breeding dogs.
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ABSTRACT: Pyometra is a serious, life-threatening disease of both domestic and non-domestic species often requiring ovariohysterectomy to preserve the life of the animal. Medical management of pyometra has been successful in domestic and non-domestic species, and the consideration of such treatment is of marked importance in a critically endangered species. Of the canids, the red wolf (Canis rufus) is second only to African hunting dogs (Lycaon pictus) in terms of the prevalence of both cystic endometrial hyperplasia and pyometra. In this report, three red wolves were medically managed for pyometra. Aside from vaginal discharge, none of the wolves exhibited clinical signs, nor were there reflective inflammatory changes in the laboratory findings. All wolves received standard treatment for pyometra, including prostaglandin F2alpha and antibiotic therapy, while one wolf was more aggressively managed with uterine lavage. Pyometra recurred in two of the treated wolves, while the most aggressively managed wolf continues to show ultrasonographic resolution 2 yr posttreatment. Aggressive medical management of pyometra should be considered a treatment option in certain red wolf females, as it may preserve the animal's reproductive potential.Journal of Zoo and Wildlife Medicine 12/2013; 44(4):1010-7. · 0.43 Impact Factor
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ABSTRACT: The ability to safely and effectively manage reproduction is central to the success of AZA captive-breeding programs. Although the AZA Wildlife Contraception Center routinely monitors contraceptive safety, there have been no studies that compare the effects of contraceptive use to separation of males from females, the other option for preventing reproduction. We used retrospective medical records and pathology reports submitted by AZA and related facilities for the seven AZA-managed canid species to assess rates of uterine pathology relative to female reproductive life histories. Our results showed that the prevalence of both pyometra and endometrial hyperplasia (EH) was associated not only with treatment with the two most common contraceptives (Suprelorin® and MGA implants) but also with the number of years barren (i.e., not producing a litter and not contracepted). Rates of pyometra and EH were especially high in African painted dogs and red wolves, but lowest in swift and fennec foxes. The number of years producing a litter had a low association, suggesting it could be protective against uterine pathology. A more recently developed Suprelorin® protocol using Ovaban® to prevent the initial stimulation phase, followed by implant removal when reversal is desired, may be a safer contraceptive option. These results concerning the relationship between reproductive management and uterine health have important implications for AZA-managed programs, since the unsustainability of many captive populations may be due at least in part to infertility. Managing a female's reproductive lifespan to optimize or maintain fertility will require a reconsideration of how breeding recommendations are formulated. Zoo Biol. XX:XX-XX, 2013. (c) 2013 Wiley Periodicals Inc.Zoo Biology 02/2014; 33(1):8. · 1.14 Impact Factor
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ABSTRACT: Objective-To determine the prevalence of various lesion types detected by histologic evaluation of uterine biopsy samples collected from subfertile bitches. Design-Retrospective case series. Animals-399 sexually intact bitches. Procedures-Results of histologic evaluation of canine uterine biopsy samples submitted by a single veterinary practice and clinical histories of dogs from which samples were obtained were reviewed. Clinical data including age, reason for biopsy, and histopathologic findings were recorded. The prevalence of specific lesions was determined, categorized by severity and age, and statistically analyzed. Results-Endometritis (170/399 [42.6%] cases) and cystic endometrial changes, including cystic endometrial hyperplasia (133/399 [33.3%]) were the most prevalent lesions in the study population. Eighty-nine of 170 (52.4%) cases of endometritis were characterized as chronic with predominantly lymphocytic or lymphoplasmacytic inflammatory infiltrates, 51 (30.0%) included mixed inflammatory reactions, and 30 (17.6%) were characterized as having acute inflammation with neutrophils, eosinophils, or both. Fibrosis was common (101/399 [25.3%] cases). Eosinophilic endometritis was significantly associated with a history of fetal loss during the same breeding cycle. No significant difference was found in prevalence of lesions among age groups. Conclusions and Clinical Relevance-The high prevalence of endometritis in this population of dogs suggested that acute and chronic endometritis may be related to subfertility in bitches. The association of eosinophilic endometrial infiltrates with a history of fetal loss may be an important diagnostic finding in dogs with endometritis.Journal of the American Veterinary Medical Association 01/2014; 244(2):180-6. · 1.72 Impact Factor
Mucometra, cystic endometrial hyperplasia, and pyometra in
the bitch: Advances in treatment and assessment of
future reproductive success
J. Verstegen*, G. Dhaliwal, K. Verstegen-Onclin
Large Animal Clinical Sciences, Small Animal Reproduction Center, College of Veterinary Medicine, University of Florida,
PO Box 100136, 2015 SW 16th Avenue, Gainesville, FL 32610-0136, United States
association between pyometra and the most common uterine disease of the bitch, cystic endometrial hyperplasia, has been
established, as the latter allows commensal bacteria originating from the vagina to proliferate in the uterus at the end of estrus. The
progressive degenerative process in the development of cystic endometrial hyperplasia is usually proposed as the initiating lesion
for pyometra in bitches; this is mediated by progesterone and potentially aggravated by estrogens. However, a separate process
caused by local uterine irritation to trophoblastic reaction and bacterial proliferation has been recently proposed as an alternate
mechanism leading to the development of pyometra. Pyometra is clinically distinct in pathogenesis, signs, treatment and prognosis
from postpartum metritis or mucometra. Treatment of pyometra has historically involved ovariohysterectomy, however, during the
last 10 y, numerous effective treatments have been proposed to treat both open and closed cervix pyometra with good success and
future fertility. Among the treatments available, the use of repeated low doses of prostaglandins alone or in association with either
# 2008 Elsevier Inc. All rights reserved.
Keywords: Mucometra; Cystic endometrial hyperplasia; Pyometra; Treatment; Dog
Pyometra is a common reproductive disorder which
affects nearly one fourth of all female dogs before they
reach 10 y of age . In a beagle colony followed over
several years, the incidence of pyometra was 15.2% in
female dogs >4 y old . Pyometra is a clinical entity,
distinct in pathogenesis, signs, treatment and prognosis
from postpartum metritis or mucometra. An association
between pyometra and themost common uterinedisease
of the bitch, cystic endometrial hyperplasia (CEH), has
been established; the latter allows commensal bacteria
originating from the vagina to proliferate in the uterus at
proposed as the initiating lesion for pyometra in bitches;
this is mediated by progesterone and potentially
aggravated by estrogens .
Pyometra is considered a disease diestrus, although
some anestrous bitches can be diagnosed with pyometra
Available online at www.sciencedirect.com
Theriogenology 70 (2008) 364–374
* Corresponding author. Tel.: +1 352 392 2212x5157;
fax: +1 352 392 8289.
E-mail address: email@example.com (J. Verstegen).
0093-691X/$ – see front matter # 2008 Elsevier Inc. All rights reserved.
. In the anestrous cases (approximately one-third of
the total pyometra cases), it is uncertain whether the
animals described were observed after the end of a
normal luteal phase or whether there had been, at least
in some of the animals, a premature shortening of the
luteal phase. This premature shortening of the luteal
phase may be induced by production of endogenous
prostaglandin in response to the uterine inflammation,
as observed in other species. The relevance of the
association between pyometra and diestrus was
demonstrated by Lesboyries and Berthelon in 1936
; they reported that ovariectomy without hyster-
ectomy in bitches with pyometra was followed by
clinical cure in 5–7 d. Similarly, in a retrospective study
of >10 y, Janssens and Janssens  confirmed the
evidence of the role of ovarian steroids in the
pathogenesis of the disease, as bilaterally ovariecto-
mized dogs never developed pyometra. The importance
of progesterone in the pathogenesis of the spontaneous
disease is attributed to its suppression of immune
responses, stimulation of endometrial gland secretions
which provide a suitable environment for bacterial
growth, functional closure of the cervix which inhibits
drainage of uterine exudates, and mediation of cystic
endometrial hyperplasia [7,8]. Considering the role of
progesterone, it is interesting to observe that some dogs
with pyometra present with basal plasma progesterone
concentrations and one would typically expect the
pyometra to resolve in such conditions. Failure to
resolve may be due to either the inability of the
degenerated uterus to contract or failure of the cervix to
relax. Another possibility is that although plasma
progesterone concentrations are below the sensitivity of
standard progesterone assays, there is enough proges-
terone produced to inhibit uterine contraction and
Although the association between pyometra and
diestrus has been well-established, the precise mechan-
ism is still not clear . Early reports suggested that
excessive or prolonged exposure to progesterone was
responsible for the susceptibility to pyometra and,
indeed, the disease can be induced experimentally by
the administration of exogenous progesterone to
ovariectomized bitches . However, more recent
studies have not been able to substantiate that either
higher concentrations or more prolonged periods of
progesterone secretion in bitches resulted in develop-
risk-enhancing effect of progestin treatment was
detected and it was concluded that, if present, such
risk is probably low. Likewise, the importance of
potential predisposing factors such as nulliparity,
irregular estrous cycles, or pseudopregnancy has not
been determined . In the same Finnish case-control
study, pyometra was reported in animals ranging from 9
m to 18 y of age, with diagnosis at a median age of 9 y.
Nulliparous bitches had a moderately higher risk of
developing pyometra and prior administration of
estrogen increased the risk for pyometra. Seventeen
breeds had an increased risk, whereas the Wire-Haired
Dachshund and mongrels had a decreased risk of
developing the condition. Other studies suggested that
an exaggerated response to progesterone, rather than
progesterone concentrations, may be present in bitches
evaluation of steroid receptors in normal and patholo-
gical tissues have not been able to clearly demonstrate
any significant differences in receptor expression .
In the common dogma, CEH-associated degenera-
tive changes within the uterine tissues (cystic distention
of glands, fibrosis, etc.) are suggested to provide
opportune conditions for establishment of uterine
infections. The already compromised uterus is invaded
by opportunistic pathogens (primarily Escherichia coli)
from the vagina which, particularly when it possesses
optimal adhesion factors, will proliferate and establish
infection within the uterus. It is inferred that infection is
established because of excessive amounts of secretory
fluids accumulated within the lumen, the presence of
numerous crypts and cysts where bacteria can
proliferate, and reduced local immunity, either asso-
ciated with or resulting from local tissue degeneration.
This association is reflected in the naming of the
condition ‘‘Cystic Endometrium-Pyometra Complex’’
However, while common dogma dictates that CEH
usually precedes pyometra development, it is also
obvious that CEH does not inevitably progress to
pyometra in all bitches. This is evident, as all dogs
develop CEH with age, whereas only some of them will
develop a pyometra. Similarly, pyometra can develop in
young animals which do not have prior clinical or
pathological evidence of CEH.
Recent work by Nomura and co-workers [16–22]
and the clinical observations of Koguchi et al.  have
suggested that the classical sequence of progesterone
leading to CEH and subsequently, CEH to pyometra
may not be correct, and that the sequence may in fact be
reversed with bacteria being the initiating factor. A
subtle (sub-clinical) uterine infection or endometrial
irritation by foreign bodies may first occur at the end of
estrus or during the first half of diestrus, providing the
stimulus for an excessive endometrial hypertrophy and
hyperplasia, similar to what is observed at the time of
J. Verstegen et al./Theriogenology 70 (2008) 364–374 365
implantation (‘‘trophoblastic or decidual reaction’’).
The resulting increase in endometrial glandular pro-
liferation and luminal epithelial cellular secretions can
initiate the development of a pyometra or a mucometra,
or not, respectively. This hypothesis is supported by
results of experiments done in dogs which have shown
that, at specific periods during the luteal phase of the
cycle, a variety of physical, biological, and chemical
substances will cause the endometrium to proliferate.
This hypothesis, however questioned by De Bosschere
et al. , can also be supported by clinical
observations of pyometra in young animals where
CEH is obviously not present.
Thebacteriamostfrequently isolated fromthe uterus
in case of pyometra include E. coli, Staphylococcus
aureus, Streptococcus spp., Pseudomonas spp., and
Proteus spp. These organisms are also those most
commonly isolated from the vagina of normal bitches
[24–27]. E. coli, the most predominant organism,
adheres specifically tobinding sites inthe progesterone-
stimulated endometrium through its uropathogenic
virulence factor (UVF) genes such as pap, sfa, hlyA,
cnF1 and fim. These genes have been shown in humans
to enhance the pathogenicity of E. coli by facilitating
attachment to the epithelium. Recently, Chen et al. 
and Arora  demonstrated that small numbers of
UVF genes bearing E. coli were associated with
enhanced severity of pyometra as a result of increased
binding to the uterine epithelium.
In conclusion, pyometra is currently believed to
result from an interaction between potentially patho-
genic bacteria and the progesterone primed (altered or
not) endometrium, in a sequence which still needs to be
A variety of signs may be detected by the owners.
The most obvious one is vaginal discharge, which may
vary from serosanguinous to mucopurulent. In some
bitches, the amount of discharge is minimal and
fastidious grooming by the bitch makes that discharge
difficult to detect. In other cases, signs of vaginal
discharge may not be externally apparent, but vaginal
smears and vaginoscopic examination reveal the
presence of uterine exudate in the cranial vagina. The
amount of vaginal discharge is also partially dependent
on the degree of cervical patency. Many bitches with a
‘‘closed’’ pyometra and apparently less obvious
discharge are presented in a more advanced stage of
the disease and in a more serious clinical condition.
Fortunately, some degree of discharge is evident most
Usually the onset of clinical signs is gradual and
insidious. Common signs include lethargy, depression,
and inappetance. Vomiting may be present and is more
common in the more severely affected patients.
Polyuria and polydipsia are often cited as signs of
pyometra, and renal impairment is a feature of the
disease, butthese clinical signs are not consistent, being
recorded in ?50% of bitches with confirmed pyometra.
In one reported case, uveitis was the presenting clinical
sign. Fever is not a common feature of pyometra.
Dehydration may be present in more advanced cases.
Becausethe signsare notdefinitive,pyometrashould
be suspected in any post-estrus bitch with any of the
following: vaginal discharge, depression and lethargy,
polyuria or polydipsia, vomiting, and/or fever. Classi-
cally, pyometra cases are regarded as being accom-
panied by marked leukocytosis characterized by
neutrophilia with a left shift and toxic degeneration
of neutrophils, as well as a monocytosis. However, this
cases may have leukograms within the normal range.
Many affected bitches have a mild to moderate
normocytic, normochromic anemia (PCV 30–35%).
This is believed to reflect the chronic nature of the
disease and the toxic suppression of the bone marrow.
Evaluation of the anemia is often complicated by
concomitant dehydration. Hysterectomy leads to rapid
improvement of hematologic and immunologic para-
meters in bitches with pyometra . However, similar
results are observed after medical treatments .
due to pyometra is still approximately 4% .
Myocardial injury secondary to endotoxemia, inflam-
mation, disseminated bacterial infection,orinfarctionis
suspected to be a contributing factor in unexpected
The most consistent clinical blood chemistry finding
is elevated serum alkaline phosphatase, present in
approximately 50–75% of cases; occasionally serum
alanine aminotransferase concentrations may also be
mildly elevated. These changes reflect hepato-cellular
damage in response to toxemia, or diminished hepatic
circulation due to dehydration. Hyperproteinemia may
develop in response to dehydration, and hyperglobu-
linemia reflects the chronic antigenic stimulation
present with this disease.
canine pyometra. Serum blood urea nitrogen and
creatinine concentrations are not usually elevated,
unless pre-renal azotemia develops as a consequence
J. Verstegen et al./Theriogenology 70 (2008) 364–374366
of dehydration. In surgically treated animals, azotemia
resolves promptly after fluid therapy, anesthesia, and
surgery, confirming the pre-renal nature of the
azotemia. Azotemia is generally associated with more
severe clinical signs. Even in non-azotemic rehydrated
patients, glomerular filtration is usually decreased,
indicating that some factors associated with the disease
affect renal perfusion either in the presence or absence
In a few cases, a urinary tract infection with the same
organism infecting the uterus (usually E. coli) is found.
However, cystocentesis is not recommended in bitches
suspectedofhavinga pyometra, asthereisahighriskof
perforating the distended uterus. Urine specific gravity
is variable and is frequently within normal limits in the
early stages of the disease. Bacterial endotoxins impair
the ability of the loop of Henle to reabsorb sodium and
chloride. E. coli endotoxins seem to have a specific
ability to cause tubular insensitivity to anti-diuretic
hormone (causing development of a secondary nephro-
genic diabetes insipidus), resulting in further loss of
urinary concentrating ability; this leads to polyuria and
a compensatory polydipsia. Functional glomerular
impairment is an early development, preceding tubular
damage, and indicated by elevated urinary gamma-
glutamyl transferase. Renal protein loss is uncommon,
however,protein may be elevated on dipstick evaluation
of free-catch samples of urine, due to contamination
with utero-vaginal discharge.
On histological evaluation with light microscopy,
pyometra, but glomerular damage beyond age-related
changes, could not be demonstrated as being more
significant in dogs with pyometra compared with a
normal population of dogs. Lympho-plasmacytic inter-
stitial infiltrates, often seen in a peri-glomerular
location, were accompanied by a higher prevalence
of interstitial fibrosis and tubular atrophy in dogs with
pyometra, confirming previous reports of renal lesions
in those dogs . Severe proteinuria after surgery may
predispose to development of renal failure. Blood
pressure control andACEinhibitionhasbecomeroutine
in canine nephrology and should certainly be followed
carefully in dogs with pyometra. One recent study in
humans demonstrated that proteinuria is a strong
independent predictor of end-stage renal disease in a
mass-screening context . Some dogs with pyometra
and severe proteinuria progress to renal failure. This
finding illustrates the importance of proteinuria as a
valuable prognostic indicator and post-surgical follow-
up of urinary protein excretion patterns in dogs with
pyometra. Heiene et al.  reported progression to
renal failure in one proteinuric dog, out of six dogs with
pyometra, despite close follow-up and treatment .
These data are not consistent with the commonly
accepted notion that pyometra leads to an immune-
mediated glomerulonephritis. Current literature is
equivocal on that point. The two studies investigating
immune-mediated glomerulonephritis did not include
an age-matched control group  or just a control
group . Immune deposits in glomeruli of healthy
individuals are documented in pigs  and in humans
. Glomerular immune deposits are documented in
dogs without any known kidney disease and more
predominantly in old dogs . In one controlled study
, pyometra-related changes in the kidneys were
similar in severity to age-related changes in healthy
dogs, as evaluated by light microscopy, electron
microscopy, and immunohistochemistry.
Uterine enlargement may sometimes be palpable but
may be demonstrated more safely and reliably with
pyometra much easier. The thickness of the uterine
walls and the characteristics of the fluid may be
determined, allowing differentiation between preg-
nancy, CEH, pyometra and mucometra. In pyometra,
the uterine wall is usually thickened and the uterus is
distended to a variable extent with serous to viscid
heterogenic fluid often presenting flocculation, whereas
mucometra will be characterized by thin uterine walls
and hypoechoic fluid.
Historically, pyometra has been most commonly
treated by ovariohysterectomy (OHE), once the bitch
has been adequately stabilized. This remains the
recommended treatment in all cases for bitches without
strong desire to breed the bitch. Due to the insidious
nature of the disease and its sometimes equivocal
clinical signs, patients are often presented in poor
condition for anesthesia and surgery. Although treat-
ment should not be unduly delayed, patients should be
stabilized prior to surgery, by administration of
intravenous fluids and broad-spectrum antibiotics.
Kidney function and liver enzymes should be evaluated
and treated accordingly. Supportive measures should be
continued during and after surgery; antibacterial
therapy should be continued for at least 1 wk following
surgical treatment. Despite these precautions, some
complications may still be observed. The main
advantage of OHE is the exclusion of any risk of
recurrence. However, surgical treatment has its limits
J. Verstegen et al./Theriogenology 70 (2008) 364–374367
when the risks of anesthesia and surgery are life
threatening. During the last 10–15 y, other conservative
strategies have been developed.
The earliest proposed medical therapy employed
simply the use of systemic and local single antibiotics
[42,43]. However, this generally leads to either a
worsening or a delay in the worsening of the disease,
with need for additional treatment at a later date.
More recent and successful medical treatments have
involved the repeated administration of prostaglandin
F2a(PGF), which causes luteolysis and thus reduces
plasma progesterone concentrations [44,45]. Reduction
in progesterone concentrations induces cervical relaxa-
tion, a decrease in uterine secretions and, since
prostaglandins also have a uterine spasmogenic action,
the expulsion of uterine fluid. However, when high
doses are used, prostaglandins have also been asso-
ciated with substantialrisk of uterine rupture,especially
in cases of closed-cervix pyometra . Furthermore,
higher doses of prostaglandins are associated with
substantial adverse effects, including salivation, vomit-
ing, straining, diarrhea, pyrexia, some occasional
respiratory distress , as well as cases of shock
and death .
Historically, estrogen administration was proposed
to relax and open the cervix, as well as to increase
uterine contractility. However, the initial induced
vasodilatation and the increased blood flow at the level
of the uterus was associated with an abrupt increase in
toxin resorption and this increased toxemia dramati-
cally worsened the clinical picture. The therapeutic
success was thus mediocre and the use of estrogens was
During the last 10 y, new approaches have been
proposed and numerous successful results of medical
treatment for canine pyometra have been reported.
Although these approaches have involved different
protocols, they all essentially have the same goals
(only the uterine aspects of the treatment are covered
(1) Preventing progesterone effects by either inducing
luteolysis or preventing progesterone binding to its
receptors. New protocols for the use of PGF have
been proposed, either alone or in association with
either dopamine-agonists or progesterone-receptor
(2) Promotion of cervical relaxation in closed pyometra
to allow for the expulsion of the uterine contents.
This is generally achieved by the administration of
(3) Induction of uterine contractions and emptying,
either directly through the use of PGF, or indirectly
via progesterone-receptor antagonists.
(4) Inhibition of bacterial growth and development
through the use of broad-spectrum or specific-
(5) Facilitating uterine regeneration in animals with
clear signs of uterine degeneration. This is
accomplished by prolonging anestrus. Prolongation
of anestrus allows for further apoptosis and
regeneration of the endometrium, preparing the
animal for a new pregnancy. The androgen-receptor
agonist, mibolerone, is used for this goal.
4.1. Luteolysis, cervical opening and uterine
When treating pyometra, the first objective after
initially stabilizing the patient, is to remove the effects
of progesterone either directly (luteolysis) or indirectly
(progesterone receptor blockade). Inhibiting progester-
one secretion or its effects should obviously be the first
goal of any treatment; in that regard, progesterone
inhibits uterine contractions, is responsible for the
cervical closure, has negative effects on uterine
immunity and protection against infections, and
facilitates uterine secretion, and cystic endometrial
development. Preventing these effects can be achieved
by attacking the CL directly with prostaglandins, or
indirectly by using a dopamine-agonist which, through
prolactin inhibition, will induce functional arrest and
preventing progesterone binding to its receptors by
using a progesterone-receptor antagonist such as
The use of PGF to treat pyometra in dogs has been
reported by several authors and the results have
generally been positive, except when high doses were
used [54–57]. Treatment with PGF, apart from its
luteolytic effects, mediates functional opening of the
cervix, which permits drainage of exudate, and
promotes myometrial contractions, facilitating uterine
drainage. Prostaglandin therapy is not approved for use
in the dog in many countries, and, even if considered
safe at new recommended dosages, the client’s consent
must be secured for this extra-label drug use.
Treatment with PGF at doses of 10–50 mg/kg,
administered three to five times daily for 3–7 d, have
been used successfully for treatment of canine
pyometra, either solely or in combination with other
J. Verstegen et al./Theriogenology 70 (2008) 364–374368
drugs. These dosages apply only to the natural forms of
prostaglandin (i.e. dinoprost tromethamine). Natural
it not only induces substantial luteolysis, but also results
in more substantial uterine contractions. Extreme care
should be exercised in calculating the dose, as the
therapeutic index is relatively small (LD50 in dogs is
approximately 5 mg/kg) andside effects are quite severe
is recommended that one start with the lowest dosage to
avoid the classic side effect of vomiting, and then to
slowlyincrease the dosageto reach higher doses (50 mg/
kg) after 2–3 d. We generally administer 10 mg/kg five
daythe secondday, andreach 50 mg/kg on Day 3. Doses
of 50 mg/kg are then administered three to five times
daily for the rest of the treatment. Side effects are
uncommon with this regimen (<15% show signs). They
are rarely observed after the first two or three injections,
and may consist of vomiting, diarrhea, panting of
moderate to mild intensity beginning 20–30 min after
administration and never lasting for >30 min. Synthetic
prostaglandins such as cloprostenol can be used instead
of natural prostaglandins. Although their use is
associated with reduced side effects (essentially emesis)
and prolonged activity, they have a reduced ability to
induce uterine contractions, resulting in slower evacua-
tion of the uterus.
Intravaginal infusion of natural prostaglandins once
or twice daily has also been tried with apparently good
results and with the advantage of no side effects .
This approach needs further validation before being
recommended, but opens new therapeutic possibilities
for pyometra treatment.
4.1.2. Dopamine agonists
The most important luteotropic hormone in the bitch
is prolactin and repeated administration of prolactin
inhibitors from 25 d after ovulation onward results in a
rapid and permanent reduction of plasma progesterone
concentration , an effect that has been used to
inhibitors have been combined with low-dose prosta-
glandin regimens to treat pyometra in an attempt to
hasten luteolysis, as demonstrated in studies of induced
line, with substantial anti-prolactin activities, have been
used in combination with either natural or synthetic
prostaglandins. Cabergoline is the authors’ first choice,
only once a day versus twice or thrice daily for
bromocriptine. The combination of dopamine-agonist
and prostaglandin potentiates the luteolytic effects of
each drug and results in more rapid luteolysis [60,61].
When the combination is used, serum progesterone
of prostaglandins alone will exert their effects only after
at most 2 d), with the combination protocol, versus
several days when PGF is used alone.
4.1.3. Combination of PGF and dopamine agonists
Recently, England et al.  presented results for the
treatment of 22 bitches with closed or open pyometra
using the combination of cabergoline 5 mg/kg/d and
day. There was a rapid clinical improvement associated
with a reduction in plasma progesterone concentration,
an increase in vulvar discharge and a reduction in the
diameter of the uterus, in an average of 10 d. The
hematologicalprofiles of21 ofthe 22 bitchesreturnedto
normal within 6 d of treatment, and their biochemical
profiles returned to normal within 9 d. Nineteen of the
bitches were managed successfully with 10 d of
treatment, whereas two of the bitches required a further
3 d treatment, and in one bitch with a partial uterine
torsion, treatment was not successful. Adverse effects of
the treatment were limited to the 60 min immediately
after the administration of prostaglandins, and included
retching, vomiting, mild abdominal straining, diarrhea,
and panting. The incidence of adverse effects was
reduced after each successive dose of prostaglandins.
Side effects may have been reduced by decreasing the
cloprostenol dose to 1 or 2.5 mg/kg with the same
luteolytic activity, but this would probably require more
frequent administration. This treatment appears easier
than the classical one, characterized by numerous
repeated administrations of low doses of natural
prostaglandins; however, side effects are more signifi-
observed with natural prostaglandins.
When dopamine-agonists are used in a combined
protocol with natural prostaglandins, similar doses and
regimes are used with either cabergoline at 5 mg/kg
once a day orally for 7 d, or bromocriptine at 25 mg/kg
thrice daily orally for 7 d.
4.1.4. Progesterone-receptor antagonists
use of progesterone-receptor antagonists has been
J. Verstegen et al./Theriogenology 70 (2008) 364–374369
proposed with sometimes controversial results. Pro-
gesterone-receptor antagonists, such as mifepristone
 or aglepristone [63–66], bind to the progesterone-
receptor which they completely block, preventing any
biological activity. Progesterone-receptor antagonists
competitively prevent progesterone from binding to its
receptor to induce transcription and exert all its
biological effects at the cellular level. Consequently,
the absence of receptor stimulation and activation
mimics the effects observed when luteolysis is induced
and thereby causes relaxation of the cervix.
Controversy still exists regarding the ability of this
treatment to induce uterine contractions if used alone.
Unlike the action of PGF, progesterone antagonists are
not expected to induce myometrial contractions. How-
ever, some studies hypothesize that uterine contractions
are indirectly induced by the local uterine release of
endogenous prostaglandins as a consequence of the
endometrial inflammatory process associated with the
pyometra. In the authors’ experience, uterine contrac-
tions associated with the use of progesterone-receptor
antagonists have neverbeen obvious enoughto allow for
prostaglandins. The use of this combination of medica-
luteolysis, which in turn prevents all the effects of
progesterone on the uterus and on the immune system.
Aglepristone, not available in United States, sup-
pressed the biological actions of progesterone during
pregnancy, interrupting gestation [67–69], causing
cervical relaxation, and inducing parturition . This
product has been effectively used in the treatment of
uterine infections associated with elevated plasma
progesterone concentrations [64,71,72]. Some recent
work has described the use of aglepristone, in
combination with cloprostenol, to treat bitches with
pyometra . Treatment with aglepristone alonewas a
safe and effective treatment for pyometra, and was an
effective means of inducing cervical opening in some
cases of closed pyometra. Furthermore, the combina-
tion of aglepristone with cloprostenol was more
effective in the medical treatment of open and closed
pyometra than aglepristone alone [73,74].
4.1.5. Prostaglandin E
In many species, normal relaxation of the cervix at
the time of estrus and ovulation is probably the result of
the peri-ovulatory changes in reproductive hormones
that occur at this time. The increases in estradiol (and
possibly oxytocin) receptor concentrations  during
the peri-ovulatory period are thought to increase
prostaglandin E2 synthesis and receptors , leading
to remodeling of cervical extracellular matrix [77,78]
which allows relaxation of the cervix. In ewes,
misoprostol has been demonstrated to improve cervical
patency and penetrability at the end of estrus . This
effect appears to be related to misoprostol-induced
increased expression of the mRNA for FSH-R in all
cervical layers . Anecdotcal results concerning the
successful use of misoprostol intravaginally to promote
cervical relaxation have been presented in dogs, but
without scientific evidence of its efficacy.
4.2. Antimicrobial treatment
Concomitant broad-spectrum antimicrobial therapy
should be administered during any treatment protocol.
Ideally, identification and sensitivity should be deter-
mined from vaginal discharges as soon as possible and
before initiating any antimicrobial treatment. Some
bitches with pyometra are bacteremic and it is
reasonable to propose that the increased uterine
contractility associated with medical treatment may
predispose bitches to further increases in bacteremia, or
to potentially induce septicemia. Many antimicrobials
have been used successfully, but in vitro sensitivity
studies and clinical evidence suggest that amoxicillin,
amoxicillin plus clavulanic acid, cephalosporins, or
potentiated sulfonamides are good initial choices. The
final choice should always be based on the culture,
identification and sensitivity of the bacteria involved.
If drugs are administered orally, provision must be
made for the possibility of vomiting which may follow
PGF injections. It is recommended that the antimicro-
bial therapy be continued for 10–14 d after complete
resolution of the pyometra, as assessed by ultrasono-
should be re-evaluated 2 wk after completion of the
prostaglandins (with or without dopamine agonist or
progesterone-receptor antagonist treatment) by ultra-
sonographicexamination and ifvaginaldischarge, fever
or neutrophilia are still present, a prolonged course of
antibiotic therapy is recommended.
4.3. Uterine regeneration
To avoid recurrence of the pyometra, particularly in
animals with clear signs of uterine degenerative
processes age-related (CEH), it is essential to facilitate
uterine regeneration during the post-treatment anestrus.
Prolongation of anestrus (and postponement of the next
estrus), allows for further apoptosis and regeneration of
the endometrium; this can be achieved with adminis-
tration of an androgen-receptor agonist such as
J. Verstegen et al./Theriogenology 70 (2008) 364–374370
months (?2 mo, to a maximum 3 mo) will prolong the
healing period and facilitate regeneration of the uterus,
with a reduction of the major CEH lesions. Mibolerone
can be administered following the manufacturer’s
recommendations, starting approximately 1 mo after
the end of medical pyometra treatment. Estrus will be
observed from a few weeks to months after cessation of
mibolerone treatment. Uterine lavage, culture and/or
uterine biopsies may be indicated in refractory cases. If
performed, biopsies should be obtained in anestrus to
reduce the risk of trophoblastic reaction induction (see
4.4. Disease evolution
The condition of dogs under treatment should be
monitored closely. In some animals, due to the increase
contractility of the uterus, resorption of toxins may
increase and the overall condition of the animal may
eventually deteriorate. Supportive treatments are abso-
lutely required and should minimally include perfusion
with IV fluids at 1.5–2 times the maintenance rate, and
eventually renal and hepatic as well as cardiovascular
authors when prostaglandins are used at low doses (see
above), but described by others when prostaglandins
were used at doses >100 mg/kg, spontaneously or
during treatment, may be observed by temporary
improvement of the clinical status of the dog before
a severe bacterial peritonitis supervenes and an acute-
abdomen syndrome develops.
When prostaglandins alone, or in association with a
dopamine agonist or a progesterone-receptor antago-
nist, are used, the condition of the animals usually
improves within the first 48 h after the onset of
treatment. This is accompanied with a noticeable
increase in the amount of discharge 24 h after initiation
of treatment. This increase in the amount of the exudate
is associated with the decrease in plasma progesterone
concentrations or progesterone inhibition. The dis-
charge changes from purulent or serosanguineous to
serous, and its cessation occurs in most cases, in 4–7 d.
The most commonly affected parameters include
changes in the blood profile (leukocytosis with
activity). It has been recently shown that following
hysterectomy for pyometra treatment, all affected
parameters return to normal within 7 d . In
medically treated dogs, the leukogram returns to normal
within 10–15 d, although leukocytosis may be initially
aggravated in some cases .
Evaluation of the efficacy of the treatment is
documented with ultrasonography and is demonstrated
3–5 d after the start of treatment. In cases where such a
reduction in the size of the uterus is not noted, the client
should be informed of the possibility of unsuccessful
medical treatment. The dog should be reassessed after
another 2–5 d of treatment and if the uterus is no longer
responding, either a complementary approach to the
should be considered.
Disseminated intravascular coagulation (DIC) has
been observed in some dogs when medical treatment is
initiated in very chronic cases and is not followed by a
significant improvement after 3–4 d. It is the authors’
routine to serially monitor fibrinogen, fibrinogen
degradation products, d-dimers, and platelet counts.
It was noteworthy that DIC was essentially detected
when dogs were treated with progesterone-receptor
antagonists without prostaglandins. Subcutaneous
administration of 100–500 IU/kg of heparin at the
start of the medical treatment may prevent intravas-
cular coagulation from developing. However, the
effectiveness of this treatment has never been
5. Recurrence of pyometra
The incidence of pyometra recurrence after medical
treatment is still controversial, with contradictory
results published. However, the percentage of recur-
rence is obviously decreasing over time with improve-
ments in therapeutic approaches and treatments.
Meyers-Wallen et al.  described therapeutic
success in 10 of 10 treated animals with recurrence in
40% of the bitches within 1 y, and 77% within 27 mo.
Johnston et al.  gave an overview of success and
recurrence rates after conservative treatment of pyome-
tra with prostaglandins and reported that recurrence
rates averaged 10%.
In a study published in 2003 by Trasch et al. ,
18.9% of the treated dogs relapsed after treatment with
aglepristone alone. In most cases of recurrence, there
were cystic changes in the ovaries and endometrium.
The authors concluded that the recurrence rate can be
minimized by the selection of bitches without ovarian
cysts and cystic endometrial hyperplasia. Although it
effects on pyometra as discussed above, the presence of
ovarian cysts is more difficult to assess, even with
ultrasonography. Furthermore, it is not possible to
differentiate some estrogen-producing ovarian cysts
J. Verstegen et al./Theriogenology 70 (2008) 364–374371
from non-pathologic para-ovarian cysts or corpora lutea
with a fluid-filled cavity [85,86].
In a case-based study comparing incidence of
pyometra in a population of previously treated
pyometra dogs (n = 57) and a control age-matched
group of dogs not having presented with pyometra
earlier (n = 256), we were not able to find any statistical
difference in the probability that a dog of any specific
age group either with or without prior disease would
develop a pyometra (unpublished). Therefore, when
treatment and uterine regeneration is successful, the
probability for the bitch to develop pyometra again is
the same as the probability for a naı ¨ve bitch of the same
age to develop a pyometra. These conclusions were the
same in terms of fertility, which is not affected. It
appears that a delayed response to treatment is
associated with the increased likelihood of recurrence
of symptoms, i.e. dogs that respond rapidly are more
likely to breed successfully in the future. Therefore, we
consider evaluation of success of treatment after 5 d and
usually recommend OHE to the client if the response is
As pyometra is often observed in older dogs,
breeding should be attempted at the first estrus
following treatment and at every subsequent estrus,
body and health condition permitting, until the desired
number of offspring have been obtained or until the
disease recurs. The main reason to breed at the ensuing
cycle is essentially not to lose one more cycle in an
animal that may already have age-related reductions in
Following treatment, fertility is generally considered
to be good. Nelson and Kelly  reported that 8 of 15
bitches treated with prostaglandins for (post-estrous)
pyometra whelped at least one healthy litter after
treatment. The same group reported clinical resolution
of uterine infections in 42 out of 44 dogs (93%); 38 of
those bitches subsequently whelped healthy pups.
Successful breeding was recorded in 9 of 20 treated
bitches followed for 1 y or longer after treatment.
Expected conception rates varied from 50 to 75%,
depending on the age of the animal considered, with
fertility generally being highest in younger animals.
6. Conclusions and perspectives
Substantial improvements in the treatment of
pyometra have been made over the last decade. Results
are good and continuously improving with the avail-
ability of better medications to achieve our goals:
luteolysis and prevention of progesterone effects,
uterine contraction and evacuation, uterine regenera-
tion, and inhibition of bacterial development. In
combination with good supportive and intensive care
during the period of treatment, which obviously
requires hospitalization of the animal, the old adage
that is unfortunately still taught, ‘‘never let the sun set
on a pyometra’’, is to be considered totally outdated.
Any patient with pyometra, valuable breeding stock or
not, may benefit from a medical approach to pyometra,
either to preserve reproductive capacity of the patient or
eventually to stabilize the patient and postpone the
surgery for a few days. Future developments can be
expected; for example, the authors have developed a
new transcervical endoscopic catheterization technique
(TECT) to treat pyometra (unpublished), allowing
resolution of the disease in 3–5 d versus 7–10 d. This
new approach should further improve our ability to
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