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Endometritis: A review

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 Endometritis: A Review
I M Sheldon BVSc PhD DCHP DBR MRCVS

Department of Veterinary Clinical Science, Royal Veterinary College, London, UK

First published in the Journal of Animal Breeding (1999) 3, 2-19

INTRODUCTION
Endometritis is defined as an inflammation of the endometrium. It is normally characterised by the
presence of a mucopurulent vaginal discharge, 21 days or more after calving and associated with
delayed uterine involution.

The reported incidence of endometritis in cattle varies widely: 11% (Tennant & Peddicord, 1968),
10% (Bouters & Vandeplassche, 1977), 38% (Oltenacu and others, 1983), 37% (Markusfeld, 1984)
and 20% (Whitmore and Anderson, 1986). In a literature review (Morris 1989) the average incidence
of endometritis was 16% and Arthur and others (1989) estimated the United Kingdom incidence was
10% and this variation may be due to differences in definition of the term "endometritis" and the time
postpartum when cows were examined. In a number of papers, the term "metritis" is used to include
cases of endometritis (Martinez and Thibier, 1984). For example, Etherington and others (1988)
found the incidence of metritis before day 26 postpartum was 9.9% and the incidence of endometritis
more than 40 days postpartum was 4.8%. The incidence of endometritis in the U.K. was recently
reported to be 10.1% in 5 dairy herds studied by Borsberry & Dobson (1989) and 11.4% in 27 herds
following analysis of computer records (Eddy, 1991).

AETIOLOGY AND PATHOGENESIS

It is assumed that the uterus and its contents are sterile during a normal pregnancy and prior to
parturition, and that at the time of parturition or just afterwards the uterine lumen becomes
contaminated by micro-organisms from the animal's environment, skin and faeces. The changes in
the normal puerperium involve: the elimination of bacterial contamination of the uterus, uterine
involution, endometrial regeneration and repair and return of normal ovarian cyclical activity, in
preparation for the next pregnancy. The presence and persistence of pathogenic organisms causing
endometritis is assumed to preclude the establishment of pregnancy. Griffin and others (1974b) found
48% of postpartum cows harboured a uterine microflora in the two weeks preceding the first service,
and the presence or the composition of the uterine flora did not affect the pregnancy rate.
Furthermore, after first service 24% of cows yielded a positive culture from uterine swabs, although
the majority of bacteria were classified as non-pathogens. Britton and others (1988) examined a
blastocyst from a cow with subclinical purulent endometritis and concluded, that although the
embryo was resistant to the bystander effect of the suppurative inflammation, the altered uterine
microenvironment may have caused sublethal blastocyst injury. Experimentally, intrauterine
inoculation of Actinomyces pyogenes in early pregnancy caused embryo mortality and delayed the
subsequent return of ovarian cyclicity (Semambo and others, 1991).

The source of infection of the uterus is the environment. Micro-organisms ascend the genital tract at
parturition and during the puerperium through the relaxed perineum, vulva and dilated cervix.
Within 15 days of calving, 93% of the uteri obtained from one abattoir yielded bacteria following
aerobic and anaerobic culture of lumenal swabs and endometrial tissue (Elliot and others, 1968); 33

1
different bacterial species were isolated. The proportion of uteri from which bacteria were later
isolated had declined to 78% by 16-30 days and 9% by 46-60 days postpartum. Similarly, Johanns
and others (1967) found 85% of uteri had bacterial contamination immediately postpartum, falling to
5% by day 55 after calving. In the live animal, using aerobic culture of swabs collected by the
transcervical route, Griffin and others (1974a) found 92% of uteri contained bacteria at 1-7 days
postpartum, 96% on 8-14 days, and 30% by 29-42 days.

There are a number of predisposing factors for uterine infection and endometritis (Andriamanga and
others, 1984; Markusfeld, 1984, 1985; Arthur and others, 1989; Noakes, 1991):
• Bacterial flora
• Rate of uterine involution
• Uterine defence mechanisms
• Retained foetal membranes
• Dystocia
• Calving environment and hygiene
• Gestation length
• Twins
• Induced parturition
• Early or late return of ovarian cyclicity
• Stillbirth or abortion
• Milk yield at last lactation
• Extended dry period
• Ketosis and milk fever
• Overfeeding when dry
• Season of year
• Protein deficient diet
• Breed
• Stress
• Selenium or Vitamin E deficiency

The bacterial flora of the uterine lumen constantly fluctuates during the first 7 weeks postpartum due
to spontaneous contamination, clearance and recontamination (Griffin and others, 1974a; Hussain
and others, 1990). Although a wide range of micro-organisms have been isolated, cows with a
uterine infection associated with A. pyogenes more than 21 days postpartum develop a severe
endometritis and are almost invariably subfertile to the first service. Fertility to subsequent services
may not necessarily be impaired in those cows which have eliminated A. pyogenes sufficiently early
to allow complete uterine involution by day 50 postpartum. A. pyogenes was the most severe
pathogen of the genital tract (Studer and Morrow 1978) and the most common isolate in field cases of
endometritis (Miller and others, 1980; Dobson and Noakes, 1990); its presence was directly
correlated with the histological inflammatory changes in endometrial biopsies (Miller and others,
1980; Farin and others, 1989). During the healing process of an endometritis the micro-organisms
disappear first, and later the inflammatory changes regress (de Bois, 1986).

Ruder and others (1981) first suggested bacterial synergism existed between A. pyogenes and
Fusobacterium necrophorum because cows presented more severe clinical signs of infection when
both organisms were isolated compared with similar cows where either organism was isolated alone.

2
Olson and others (1984) also found synergism between A. pyogenes, F. necrophorum and
Bacteroides melaninogenicus. Furthermore, El-Azab and others (1988) and Farin and others (1989)
created experimental models for endometritis using uterine inoculations of A. pyogenes together with
either B. melaninogenicus or F. necrophorum. The synergistic role of Gram negative anaerobic
bacteria with A. pyogenes in field cases has also been confirmed by Noakes and others (1989; 1990).

Uterine involution is the return of the genital tract after calving to its normal non-pregnant size,
which involves: physical shrinkage, necrosis and sloughing of the caruncles, and regeneration of the
endometrium. Evaluation of the physical state of the uterus by palpation per rectum would indicate
uterine involution to be complete by 21-28 days postpartum (Tennant and Peddicord, 1968; Johanns
and others, 1967). However, Gier and Marion (1968) found uterine involution was not complete until
day 50 postpartum, involution being on a decreasing logarithmic scale with the greatest changes
occurring in the first few days postpartum; this was in agreement with other workers who found the
majority of change in physical dimensions had occurred by day 30 postpartum. The epithelium of the
endometrium had regenerated and covered the caruncular surface by day 25 - 30 postpartum (Gier
and Marion, 1968; Wagner and Hansel, 1969).

The rate of uterine involution may be affected by a number of factors:

• Postpartum disease
• Parity
• Season
• Suckling and milk yield

Involution of the cervix and uterus was delayed in Holsteins cows that presented abnormalities
peripartum such as retained foetal membranes and uterine infection, compared with normal cows
(Gier and Marion, 1968; Fonseca and others, 1983). Similarly, cervical involution occurred sooner
for cows with a normal uterine discharge compared with those with an abnormal discharge (Oltenacu
and others, 1983). Uterine involution occurred more rapidly in primipara than pluripara (Fonseca and
others, 1983; Oltenacu and others, 1983), and in Springtime. Fonseca and others (1983) found
involution occurred sooner in cows with a higher milk yield although Wagner and Hansel (1969)
found no similar effect.

Uterine defence mechanisms are important in eliminating bacterial contamination postpartum.

Uterine contractions and involution physically expel the lochia, which together with the degeneration
and sloughing of the caruncles expel any adherent bacteria. The resident bacterial flora of the vagina
may prevent ascending colonisation. Non-specific humoral defence mechanisms, secretory
immunoglobulins and cell mediated immunity also have an antibacterial role. However, the main
defence mechanism of the uterine lumen is by phagocytosis (Frank and others, 1983); 80% of the
cells in uterine exudate are neutrophils. Peripheral lymphocyte function may be depressed in cows
with chronic endometritis (McEvoy and Pollock, 1994).

Markusfeld (1984) investigated the factors responsible for retained foetal membranes and metritis in
dairy cattle; together with Hussain and others (1990), Grohn and others (1990) and Peeler and others
(1994) he reported that retained foetal membranes were a predisposing factor for endometritis and
retained foetal membranes were associated with an increase in severity of endometritis (Sheldon
1996).

3
Dystocia and assistance at calving often leads to faecal contamination of the genital tract. Bretzlaff
and others (1983a) induced acute metritis in cows when a small handful of faeces and bedding was
placed in the uterus within 24 hours of calving. Andriamanga and others (1984) and Peeler and others
(1994) reported that dystocia was a risk factor for endometritis. Following caesarean section or
induced parturition, an increased proportion of bacterial uterine isolates and delayed involution was
found compared to cows after a normal calving (Hussain and others, 1990). There is also an
increased incidence of vulval discharge after calving twins (Eddy and others, 1991) or a dead calf
(Peeler and others, 1994).

A dirty calving environment may increase the risk of endometritis. Noakes and others (1991)
described two hygienically contrasting farms; on one with a relatively clean environment the
incidence of endometritis was 2-3%, compared with an incidence of 15% for one with a dirty
environment. However, there was no difference in the quantitative or qualitative uterine bacterial
flora in cows calved on either farm.

Uterine infection has a seasonal incidence, being highest in Winter (Markusfeld, 1984), Spring
(Andriamanga and others, 1984), October to March (Anderson, 1984) and September to February
(Grohn and others, 1990). This may be linked to the calving environment during the housed period.

Martinez and Thibier (1984) found ovarian inactivity predisposed to endometritis. The return of
ovarian cyclicity by day 37 postpartum significantly reduced the incidence of endometritis to 34%
compared with 49% for acyclic cows (Andriamanga and others, 1984). However, if the interval from
calving to first ovulation is too short, Olson and others (1984) suggested that pyometra occurred
because A. pyogenes and Gram negative anaerobic bacteria remained within the uterus after
ovulation, so that bacterial growth continued following corpus luteum formation. An upsurge in the
numbers of Gram negative anaerobes isolated following the first ovulation and subsequent luteal
phase was confirmed by Noakes and others (1991).

Fonseca and others (1983) reported a breed influence on the incidence of endometritis, 6.25% and
10.3% occurring in Jersey and Holstein cattle respectively.

Milk yield, diet and metabolic disease may influence postpartum uterine infection. Markusfeld
(1984) reported low milk yield before drying off was associated with metritis. Feeding amino acid-
chelated minerals to heifers reduced postpartum endometritis (Manspeaker and others, 1988). Higher
herd milk yield in the previous lactation was a risk factor for endometritis, metritis and retained foetal
membranes (Grohn and others, 1990). Ketonuria (Markusfeld, 1985) and milk fever (Grohn and
others, 1990) were also associated with postpartum uterine infection.

EFFECT ON FERTILITY
Endometritis has a detrimental effect on fertility. Tennant and Peddicord (1968), Bretzlaff and others
(1982a) and Borsberry and Dobson (1989) found that endometritis extended the calving to conception
interval by 12, 10 and 32 days, respectively, compared to normal cows and increased the number of
services per conception by 0.33, 0.42 and 0.64, respectively. Similar findings were reported by
Nakao and others (1992). Johanns and others (1967) and Studer and Morrow (1978) found the
calving to conception interval was related to the degree of genital tract involution postpartum.
Uterine infection has been reported to be associated with an increased incidence of cystic ovarian

4
disease (Erb and others, 1981; Bosu and Peter, 1987). Tennant and Peddicord (1968) and Bretzlaff
and others (1982a) also found culls were increased from 6.2% to 13.6%, and from 5% to 20.6%,
respectively.

ECONOMIC COST
The economic cost of endometritis depends on the detrimental effect on fertility, increased culling
rate, and, to a lesser extent, the cost of treatment. Bartlett and others (1986) reported that the cost
associated with each cow treated for metritis was $106. Morris (1989), in a review of the literature,
found there was a 16% annual incidence of endometritis, that resulted in a 39 day extension of the
calving - conception interval and a 7% increase in culling rate compared with normal cows, at a total
estimated cost of £279 per case. Esslemont and Spincer (1993) found that cows treated for
endometritis had an increased calving interval of 18 days, an increase of 0.3 services per conception
and a 300 litre reduction in milk yield, compared with untreated normal cows; the estimated cost to
the farmer was £160.

DIAGNOSIS, CLINICAL SIGNS AND ASSESSMENT

Clinically, endometritis is characterised by the presence of a mucopurulent discharge in the vagina,
21 days or more after calving and associated with delayed uterine involution. The definitive
diagnosis of endometritis is made on the basis of histological examination of endometrial biopsies.
Bacteriological examination of uterine cultures, vaginal examination, and palpation per rectum of the
genital tract are the ususal aids to diagnosis.

Griffin and others (1974a) concluded that the bacteriological information derived from in vivo
sampling of the uterus during the first seven weeks postpartum was of little value in predicting
subsequent fertility; both the number of bacterial isolates and their identification are practical
problems to overcome (Elliott and others, 1968; Hussain and others, 1990). Indeed, Noakes and
others (1990) found that the bacterial flora varied with time, even in a case of pyometra with a closed
cervix. Etherington and others (1988) reported that taking a uterine biopsy had a detrimental effect
on subsequent reproductive performance. Bacterial and histological examination of uterine biopsies
require specialist equipment, facilities and skills (Bonnett and others, 1991). However, Bonnett and
others (1993) found the presence of A. pyogenes or anaerobic bacteria together with specific
histological features in endometrial biopsies were predictive for reproductive performance. One
alternative to bacterial culture may be the Latex Agglutination test, for identifying Streptococcus
agalactiae (Hussain and Daniel, 1992).

Under field condtions, Studer and Morrow (1981) and Roberts (1986) concluded that vaginal
examination and palpation of the genital tract per rectum were the most useful techniques for the
diagnosis of endometritis, because routine use of special equipment for endometrial biopsy and
culture was not practical. However, endometritis could not be consistently diagnosed solely by
palpation per rectum of an enlarged cervix or uterus (Tennant & Peddicord, 1968). Visual or manual
examination of the vagina for an abnormal uterine discharge is essential for the diagnosis of
endometritis (Miller and others, 1980; Bretzlaff, 1987), although the contents of the vagina do not
always reflect the contents of the uterus.

One problem in the assessment of endometritis is quantifying the response to treatment, and to
determine when the genital tract is normal. Studer and Morrow (1978) concluded that cows with
clear mucus did not need treatment for endometritis, whether the cervix was enlarged or not; in

5
contrast, cows with a purulent vaginal discharge should be treated even if the cervical and uterine
diameters were normal. Roberts (1986) noted that flakes of pus in the vagina could come from the
uterus, cervix or vagina and slightly cloudy mucus may be normal; if there was a normal, involuted
uterus and clear vaginal mucus, then the degree of endometritis would not affect fertility.

A number of scoring systems have been used to assess the degree of uterine and cervical involution,
and the nature of the vaginal discharge. Johanns and others (1967) classified the uterine and cervical
diameter into three diameter categories similar to that used by Studer and Morrow (1978) to score the
severity of vaginal inflammation, cervical and uterine diameter and the amount of pus in the vagina.
Oltenacu and others (1983) found the optimum time to score the cervical diameter was 3 weeks
postpartum, and classified the diameter as being small, medium or large based on values of: <4.0cm,
4.0-5.5cm, and >5.5cm, for primiparous, and <4.5cm, 4.5-6.0cm, and >6.0cm for multiparous cows,
respectively. Concern that palpation and manipulation of the genital tract during diagnosis and
treatment may affect the response to treatment by altering uterine activity has been shown to be
unfounded (Cooper and Foote, 1986). Murray and others (1990) and Sheldon (1996) designed
scoring systems based on the clinical signs of endometritis and proposed that success or failure
should be assessed on the change in clinical score.

TREATMENT
There are a wide variety of treatments for endometritis including: antimicrobial agents, hormones
and various antiseptics. The choice of treatment for endometritis has caused considerable debate and
has been reviewed extensively in the literature (Gustafsson & Ott, 1981; Bretzlaff, 1987; Noakes,
1991). Gustaffson (1984) has suggested that records should be kept for each herd to allow periodic
evaluation of the best treatment for endometritis. Treatment success rates were greater for mild cases
of endometritis compared with severe cases (Sheldon 1996) and the success rate was reduced if the
vaginal discharge had a foul odour.

Antimicrobials
A wide variety of antimicrobials have been used for the treatment of endometritis, either alone or in
combination with hormones and administered by intrauterine infusion or other parenteral routes. In
selecting a suitable antimicrobial agent, Noakes (1991) recommended that the following factors
should be considered:
• Efficacy against the causal organism.
• Efficacy within the uterine environment.
• Must not inhibit natural uterine defence mechanisms.
• Must not traumatize the endometrium or other tissues.
• There must be an effective concentration at the site of infection.
• Data concerning absorption from the uterus, and excretion in the milk should be known.
• Must maintain or enhance fertility.
• Must be cost effective.
• Be free of danger to human health.

The chosen antimicrobial must be effective against the causal organisms of endometritis. Ideally, the
choice should be made on the basis of sensitivity testing of the organisms isolated from each case of
endometritis. However, this is impractical in normal clinical practice and so the veterinary surgeon
has to rely upon the known sensitivity of the most common and important organisms isolated from

6
cases of endometritis, such as A. pyogenes and the anaerobic bacteria. The large variety of species of
bacteria isolated from cases of endometritis suggests that a broad-spectrum antibiotic may be
preferred. Miller and others (1980) found all uterine organisms isolated from cases of endometritis
were sensitive in vitro to penicillin and oxytetracycline, but not to nitrofurazone and
dihydrostreptomycin. Chloramphenicol has been recommended for treatment of endometritis on the
basis of sensitivity testing (Steffan and others, 1984; Mohanty and others, 1992); ampicillin and
penicillin were the least sensitive. In vitro studies also allow the Minimum Inhibitory Concentration
(MIC) of the antimicrobial to be determined, for example the MIC of oxytetracycline for A. pyogenes
in one study was 20.4µg/ml (Miller and others, 1980). However, the MIC for each antimicrobial
agent and bacteria varies from herd to herd and within a herd over time (Gustaffson, 1984).
Furthermore, the in vivo clinical response was less effective than suggested by in vitro sensitivity of
bacteria from cases of metritis (Bretzlaff and others, 1982a). An alternative method of selecting the
most suitable antimicrobial is the clinical trial. Intrauterine treatment of cows with oxytetracycline
significantly reduced the incidence of A. pyogenes metritis (Callahan and Horstman, 1993), and
prevented sepsis developing postpartum in cows with retained foetal membranes (Cairoli and others,
1993).

The chosen antimicrobial should be effective within the uterine environment. Fluid and tissue debris
reduce the effect of sulphonamides, aminoglycosides and nitrofurazones. Aminoglycosides are
ineffective in an anaerobic environment, such as the uterine lumen (El-Azab and others, 1988). At
less than 30 days postpartum, mixed bacterial infections may render intrauterine infusion of penicillin
ineffective, due to penicillinase produced by non-pathogenic bacteria (Whitacre, 1992).
Oxytetracycline is broad spectrum and is effective in the presence of pus and reduced oxygen tension
(Bretzlaff, 1987).

The chosen antimicrobial should not inhibit the normal uterine defence mechanisms. A wide variety
of concentrations of tetracyclines and penicillins, by intrauterine administration and other parenteral
routes, did not impair the chemotactic response of polymorphonuclear neutrophils (PMN's).
However, streptomycin and sulphamerazine produced a dose-dependant reduction in chemotactic
response of PMN's (Jayappa and Loken, 1983).

Neither the antimicrobial nor its vehicle must traumatize the tissues. Intrauterine infusion, of either
oxytetracycline in propylene glycol or aqueous solution, or Lugol's iodine (a mixture of Iodine and
Potassium Iodide in a 1:2 ratio) cause endometrial inflammation (Oxender and Seguin, 1976;
Bretzlaff, 1986). In addition, Seguin and others (1974) showed that intrauterine infusion of an
irritant solution could affect the oestrous cycle length by causing premature luteolysis, whereas saline
and other non-irritant antibiotics had no effect on cycle length.

The chosen antibiotic must reach appropriate concentrations at the site of infection and persist a
sufficient length of time to eliminate the infection. In endometritis the site of action for the
antimicrobial is the uterine lumen and the endometrium. The use of the intrauterine route of
administration has prevailed for many years and the pharmaceutical industry continues to develop
antibiotic products administered by this route, despite the widespread use of systemic antibiotics for
treatment of other bacterial infections in cattle. An antimicrobial agent administered by the
intrauterine route is distributed within the lumen of the uterus and a proportion will be absorbed by
the endometrium, where it will pass into the blood stream, and be distributed to other tissues. The

7
concentration of the antimicrobial agent in the tissues of the genital tract will depend on its
pharmacokinetics, which will be influenced by the formulation and the volume of infusion, tissue
binding, diffusion from the lumen to the tissues, and, absorption in blood. Smythe (1942) reported,
that to achieve an even distribution of a substance within the uterine lumen administered by uterine
irrigation, the fluid should be infused as soon as the tip of the catheter passed the last cervical ring.
The maximum infusion volumes suggested were 120ml and 160ml for heifers and cows, respectively;
excess volumes of fluid infused into the uterus caused rupture of the myometrium.

If the antimicrobial agent is administered systemically, it circulates in the blood and is distributed
throughout all tissues, including the endometrium, from where it may pass into the uterine lumen.
The plasma concentration depends on its rate of absorption, distribution, metabolism and excretion.
The genital tissue and uterine lumen concentration of an antimicrobial agent is dependant on many
factors, including: plasma protein and tissue binding, diffusion characteristics of the drug,
concentration gradients between blood, tissue and uterine lumen, lipid solubility, and, pH
differentials between blood, tissue and uterine lumen (Bretzlaff, 1986).

Unfortunately, relevant pharmacokinetic studies are sparse, although there is some information on
sulphamethazine, penicillin and oxytetracycline. Sulphamethazine was absorbed from the uterus of
normal cows in dioestrus and reached peak plasma levels 1-2 hours following intrauterine infusion
(Bierschwal and others, 1956) and remained in plasma for 24 hours (Righter and others, 1975).

The intramuscular administration of sodium benzyl penicillin gave higher concentrations in the
endometrium compared to plasma, but both declined within 180 minutes following injection (Ayliffe
and Noakes, 1978a). Absorption of the same antibiotic into the plasma after intrauterine
administration was greater during oestrus than the luteal phase (Ayliffe and Noakes, 1978b) and in
cows with endometritis (Ayliffe and Noakes, 1978a). However, the short persistence of sodium
benzyl penicillin would necessitate treatment at least twice daily.

Masera and others (1980) investigated the intrauterine and intramuscular administration of
oxytetracycline hydrochloride in propylene glycol. The intramuscular injection at a dose rate of 8
mg/kg body weight produced a higher concentration of oxytetracycline in the endometrium and
uterine secretion compared with plasma; the intrauterine infusion of 4 mg/kg produced a higher
concentration of oxytetracycline in the endometrium and uterine secretion than intramuscular
administration of 8 mg/kg body weight. However, only the intramuscular route produced
concentrations of oxytetracycline in all genital tissues, including the myometrium, serosa, cervix and
vagina.

When intrauterine administration of oxytetracycline was repeated in cows with severe endometritis
the plasma oxytetracycline concentration was less than for normal cows; a contradiction to previous
trials using sodium benzyl penicillin (Ayliffe and Noakes, 1978a). Bretzlaff and others (1983b)
found similar results after the intrauterine infusion of 5.5 mg/kg water soluble oxytetracycline
hydrochloride, with a concentration of 25-42 µg/g in the endometrium 24 hours after infusion, but
low concentrations in plasma, uterine wall and the ovaries; there was a reduction in absorption of
oxytetracycline from the uterus for cows with metritis compared to normal cows. Should infection be
restricted to the uterine cavity and endometrium, the intrauterine route of administration produced

8
higher concentrations of antibiotic at those sites; if inflammation in deeper tissues was present
parenteral routes for antibiotic administration were indicated.

Oxytetracycline has a greater persistence in the uterus than penicillin. The half life of
benzylpenicillin is 0.7 hours and oxytetracycline is 4.1 - 6.5 hours (Ziv, 1980; Bretzlaff and others,
1982b). A single uterine infusion of oxytetracycline at a dose rate of 4 mg/kg gave endometrial
concentrations of > 4 µg/g for over 72 hours following infusion (Masera and others 1980, Miller and
others 1980). However, using the intravenous route to achieve a uterine concentration of 5 µg/g
would need a twice daily injection of 11 mg/kg of oxytetracycline (Bretzlaff and others, 1983a) . In
addition, during the early postpartum period the ratio of the blood plasma to uterine tissue
concentration is 30% greater, so the intravenous dose would need to be increased to 15 mg/kg twice
daily.

Furthermore, formulation of the antimicrobial agent can significantly affect its pharmacokinetics.
For example, Al-Guedawy and others (1983) found a 30% absorption rate of gentamycin saline
solution from the uterine lumen 6 hours after infusion, compared with 83% for an aqueous solution.

The milk withdrawal period must be known and observed for each antimicrobial agent. Righter and
others (1975) found high concentrations of sulphamethazine in milk for 48 hours after intrauterine
infusion, but only traces of oxytetracycline, penicillin and streptomycin. Oxytetracycline was
detected in milk for only 24 hours after intrauterine infusion (Miller and Bergt, 1976), and
intrauterine infusion of oxytetracycline produced a lower concentration in milk and for a shorter
period compared with an intramuscular injection (Masera and others, 1980). The oxytetracycline
solution licensed for intrauterine infusion in the U.K. (Metrijet 1500, Intervet UK Ltd) has a nil milk
withdrawal period. Any milk withdrawal period would make a treatment for endometritis
unattractive under practice conditions; for example, parenteral tylosin gave effective concentrations
in genital tract tissues and the uterine lumen, but has a milk withdrawal period of 96 hours (Cester
and others, 1993). Metronidazole and cholramphenicol are prohibited in food producing animals in
the U.K.

On the basis of the evidence presented above, the antimicrobial agent usually recommended for
treatment of endometritis in cattle is 2 - 5 g oxytetracycline by intrauterine infusion (Noakes, 1991).

Hormones
The hormonal treatment of endometritis is based upon observations that the genital tract is more
susceptible to infection when under progesterone dominance and more resistant under the influence
of oestrogens.

Oestrogens
Rowson and Spriggs (1942) first reported the beneficial efficacy of induced luteal regression or
exogenous oestrogen for treating pyometra. Furthermore, Rowson and others (1953) demonstrated
that the bovine uterus was more resistant to infection with A. pyogenes when either endogenous or
exogenous oestrogen was present compared to dioestrus, and suggested that exogenous oestrogen
may be used therapeutically. These conclusions were supported by Hawk and others (1964) who
reported that the uterine leucocytic response to an inoculum of Escherichia coli was delayed in the
luteal phase, and stimulated during oestrus.

9
Bouters and Vandeplassche (1977) suggested that periparturient problems could delay the onset of
phagocytosis in the uterus. Roth and others (1983) found PMN function was depressed in the luteal
phase by progesterone but stimulated in the follicular phase; oestrus potentiated cellular defence
mechanisms (Frank and others, 1983). Furthermore, the opsonising ability of uterine flushings was
reduced in the luteal phase of the oestrous cycle (Watson, 1985).

In addition to effects on the natural defence mechanisms of the uterus, raised concentrations of
oestrogens during oestrus may help the physical expulsion of detritus from the uterus. Al-Eknah and
Noakes (1989) reported greatest frequency (35.0 vs. 1.2 per hour) and amplitude (9.5 vs. 0.1 kPa) of
uterine contractions at oestrus rather than mid-dioestrus. In ovariectomised cattle an infusion of
oestradiol benzoate initially inhibited spontaneous uterine activity before stimulating contractions,
with some evidence of a dose response effect.

Endogenous follicular-derived oestrogens are also pivotal in the ovarian cycle in controlling
endometrial and myometrial oxytocin receptors, the production of Prostaglandin F2α (PGF2α ), and
hence the timing of luteolysis (McCracken and others, 1984). Exogenous oestrogens can influence
the luteolytic cascade and disrupt folliculogenesis (Bo and others, 1994) and this may be beneficial
for the treatment of endometritis.

Despite the potential of oestrogens for the treatment of endometritis, only a small number of workers
have reported on their use. Wilson (1953) suggested that intrauterine oestrogen therapy for
endometritis was more successful than using other routes of administration, but Dawson (1960) noted
that parenteral stillbenes caused an increased incidence of cystic ovarian disease following treatment.
For treatment of endometritis, Oxenreider (1982) used 10mg oestradiol valerate intramuscularly
followed 2-4 days later by a variety of 600ml intrauterine infusions, and reported 90-100 % clinical
recovery. Hemeida and others (1986) recommended an intramuscular injection of 3-10 mg oestradiol
benzoate, oestradiol valerate or oestradiol cypionaterepeated after 3 days. Pepper and Dobson
(1987) used a single intramuscular injection of 10mg oestradiol benzoate, which was as effective as
prostaglandin for treating endometritis. However, the treatment to conception interval was longer for
cases of endometritis treated with a single intramuscular injection of 3mg oestradiol benzoate per
500kg estimated body weight compared with those treated using prostaglandin or intrauterine
oxytetracycline (Sheldon 1996).

Prostaglandins
The effect of PGF2α and its analogues in the treatment of pyometra is widely accepted (Ott and
Gustafsson, 1981). Exogenous prostaglandins can be used to treat endometritis, since increased
oestrogen and reduced progesterone concentrations following luteolysis, follicular growth and the
subsequent oestrus increase the uterine resistance to bacteria.

In contrast to oestrogens, the parenteral use of PGF2, or its analogues, have been widely reported for
the treatment of endometritis. For example, Jackson (1977) used 500µg cloprostenol for the
treatment of endometritis and confirmed that in each case luteolysis had occurred; whilst none of
three cases treated in the absence of a corpus luteum (CL) responded, 51 out of 56 cases with a CL
did. Similarly, Coulson (1978) reported a 76% recovery rate, of which 88% did so within 15 days.
Chaffaux and others (1991) described prostaglandin as the treatment of choice for endometritis, with

10
a 69% recovery rate by 30 days after treatment, compared with 56% for control cows given a placebo.
Roberts (1993) found that intrauterine infusion of prostaglandin was a less effective treatment
compared with the intramuscular route.

A number of studies have compared the use of prostaglandin F2 in the treatment of endometritis
with other forms of therapy. Anderson (1984) found subsequent reproductive performance was
similar in cows treated for endometritis with dinaprost or an intrauterine infusion of
sulphachlorpyridazine, sulphapyrazole, clioquinol and ethinyloestradiol (Ostrilan, Ciba Geigy).
These conclusions were similar to those of Steffan and others (1984) who compared two injections of
PGF2 given 14 days apart with 3 doses of antibiotic intrauterine infusions given 1 week apart and
found the calving to conception interval was reduced for the prostaglandin-treated cows. In a study
comparing the treatment of endometritis using “Ostrilan”, oestrogen or prostaglandin there was no
difference in response (Pepper and Dobson, 1987). Similarly, Murray and others (1990) and Sheldon
(1996) reported no significant difference in the success of parenteral prostaglandin or intrauterine
antibiotic infusions for treatment of endometritis. However, in contrast to previous studies,
Vujosevic and others (1984) found that cows treated on day 18-19 postpartum with cloprostenol had
improved first service pregnancy rates (34.6 vs. 16.2 %), fewer days open (89.5 vs. 105.9) and a
greater proportion conceived within 85 days postpartum (60.9 vs. 38.2 %) compared with cows
treated with an intrauterine antibacterial infusion.

The majority of authors report that the presence of an active corpus luteum is required for optimal
results using prostaglandin to treat endometritis, which supports the hypothesis that the subsequent
induced oestrus increases the uterine resistance to bacteria. Conversely, Pepper and Dobson (1987)
found that the efficacy of prostaglandin therapy for endometritis did not depend on the presence of an
active CL, determined by measuring milk progesterone concentrations. In a study by Bonnett and
others (1990) cows examined 40 days postpartum following prostaglandin treatment on day 26 had
less vaginal discharge, smaller diameter uterine horns, less inflammation and fibrosis in endometrial
biopsies and were less likely to yield isolates of A. pyogenes, compared with untreated cows; these
results were independent of the peripheral blood progesterone concentration at the time of treatment.

An alternative hypothesis for the mechanism of action of prostaglandin as a treatment for

endometritis is a direct myometrial effect with physical expulsion of uterine detritus. Cooper and
Foote (1986) found that a single injection of PGF2 given on day 17 of the oestrous cycle, but not at
oestrus, increased intrauterine pressure. Lindell and Kindahl (1983) found that when PGF2 was
administered twice daily on days 3 to 13 postpartum in three cows it promoted uterine involution, and
concluded that there was a positive effect on uterine muscular tone. Additionally, Garcia-Villa and
others (1985) reported the ecbolic activity of different prostaglandin analogues; fenprostalene had a
more prolonged oxytocic effect on the myometrium than both cloprostenol and dinaprost.

Clinical trials have studied the possible direct myometrial effect of prostaglandin therapy, to reduce
the incidence of endometritis and improve subsequent fertility. A routine injection of 25mg dinaprost
14-28 days postpartum improved the first service pregnancy rate compared with untreated cows,
irrespective of the presence of a CL at the time of injection (Young and others, 1984; Young and
Anderson, 1986). Similarly, cloprostenol injected on day 24 postpartum (Etherington and others,
1984), or day 26 and/or day 40 postpartum (Etherington and others, 1988), shortened the calving to
conception interval in normal cows compared with control treatment. However, a number of

11
subsequent trials gave conflicting results. Meta-analysis of 24 trials where PGF2 was administered
to cattle within 40 days of calving (Burton and Lean, 1995) showed no beneficial effect on first
service pregnancy rate, although there was a small reduction in days open for treated cows. In
addition, a number of studies have found no evidence of an ecbolic effect of PGF2 or its analogues.
Eiler and others (1984) found no benefit using dinaprost when beef cows were injected 48-72 hours
postpartum; Burton and others (1987) found no effect when dairy cows were injected 1-4 days
postpartum with fenprostalene. Partial suppression of prostaglandin synthesis by flunixin meglumine
early postpartum failed to alter the rate of uterine involution (Guilbault and others, 1987) and no
effect was detected on the rate of involution after a single treatment with prostaglandin or oestrogen
48 hours postpartum (Tian and Noakes, 1991). It has been suggested that the use of prostaglandin
before day 21 postpartum may be detrimental, as pyometra is more likely to occur in cows that
ovulated early postpartum (Olson and others, 1984).

Gonadotrophin Releasing Hormone

Use of gonadotrophin releasing hormone (GnRH) or it's analogues in the early postpartum period has
been suggested for the treatment of uterine infections. Leslie and others (1984) reported that
administration of GnRH on day 8-14 postpartum to cows following retained fetal membranes reduced
both the number of days open and the serves per conception. These conclusions were not supported
by Oltenacu and others (1983) who found no effect of GnRH on calving to conception interval or
pregnancy rates when administered days 8-21 postpartum; furthermore, the induction of ovulation
and subsequent progesterone synthesis in cows with concurrent uterine infections may increase the
risk of pyometra (Etherington and others, 1984; Steffan and others, 1984).

Other treatments
A wide variety of antiseptics have been administered by intrauterine infusion for the treatment of
endometritis. Seguin and others (1974) used an intrauterine infusion of a 1-2% solution of Lugol's
Iodine. A necrotising endometritis developed within 24 hours of infusion, although the epithelium
regenerated by the next oestrus. Cycle length was similar to controls if the infusion was at oestrus,
but if the infusion was given on days 4 or 15 of the oestrous cycle, the cycle length was significantly
shorter (10.6 days) or longer (25.1 days). A 4% solution of Lugol's Iodine was used to treat repeat
breeders on day 4-5 of the oestrous cycle; oestrus occurred 5-7 days later, possibly due to release of
PGF2 following endometrial irritation (Hemeida and others, 1986). In an extensive study, Nakao
and others (1988) used a 2% polyvinyl pyrrolidine iodine intrauterine infusion and found that treated
cows, particularly for those with a purulent discharge, had an increased calving to conception interval
compared with controls. Further evidence that iodine treatment may be detrimental to fertility was
demonstrated by finding chronic inflammatory changes in the endometrium of mares given an
intrauterine infusion of a 1% povidone-iodine solution (Olsen and others, 1992).

Chlorhexidine is approved for intrauterine infusion in the USA (Roberts, 1986). De Bois (1982)
reported on the intrauterine infusion of carbamyl-Chinoxaline-det-N-Oxid and there are a number of
reports of the use of Metakresol Sulphonic acid. However, Vujosevic and others (1979) found that
cows treated for endometritis by intrauterine infusion of Metakresol Sulphonic acid had inferior
fertility in comparison with cows treated with a single injection of cloprostenol. Infusion of
Eucalypus compositus or the parenteral administration of a -antagonist combined with an immunity
modifier was described by Schnellbach (1991). Other intrauterine infusions have been investigated
by Strube and others (1991), including peroxiethanacid which increased phagocytosis in the uterus.

12
Intrauterine infusion of E. coli endotoxin also increased PMN counts in uterine fluid, and was an
effective treatment for endometritis induced experimentally with Streptococcus agalactiae (Hussain
and Daniel, 1991).

The selection of treatments for endometritis has been widely and frequently debated; they are based
partly on the published literature and on the individual preference and experience of various authors.
The three treatments most often used are parenteral prostaglandin F2α or its anologues, oestrogen
and intrauterine infusion of an oxytetracycline solution. However, Roberts (1986) noted that until
experiments are performed to compare the various treatments it is not possible to state which is
superior. In this context the appropriate experiments are controlled clinical trials, where a treatment
is compared with a nil treatment, or with another approved treatment (Sheldon 1996). Appropriate
supporting studies should be demanded by the veterinarian to validate the use of new and current
forms of therapy (Ott, 1986). Considering the number of cows treated for endometritis annually,
there is little published data on the efficacy of the different products available and further studies
should be encouraged.

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