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Abstract
Uterine health is often compromised in cattle because postpartum contamination of the uterine
lumen by bacteria is ubiquitous, and pathogenic bacteria frequently persist causing clinical dis-
ease. The subfertility associated with uterine infection involves perturbation of the hypothalamus,
pituitary and ovary, in addition to the direct effects on the uterus, and appears to persist even after
clinical resolution of the disease. Absorption of bacterial components from the uterus can prevent
the follicular phase LH surge and ovulation. In addition, the first postpartum dominant follicle has a
slower growth rate and secretes less estradiol at the end of the growth phase. There are also localised
ovarian effects of high uterine bacterial growth density, because fewer first dominant follicles are
selected in the ovary ipsilateral than contralateral to the previously gravid uterine horn. Thus, it is
important to diagnose and treat uterine disease promptly and effectively. Examination of the con-
tents of the vagina for the presence of pus is the most useful method for diagnosis of endometritis.
The character and odor of the vaginal mucus can be scored and this endometritis score is corre-
lated with the growth density of pathogenic bacteria in the uterus, and is prognostic for the likely
success of treatment. The challenge for the future is to design prevention and control programs
to reduce the incidence of disease, and understand how the immune and endocrine systems are
integrated.
2004 Elsevier B.V. All rights reserved.
Keywords: Bovine; Postpartum; Uterus; Disease; Ovary
1. Introduction
Postpartum uterine health is more likely to be compromised and clinical disease more
common in cattle than other ruminants, such as sheep (Borsberry and Dobson, 1989;
Regassa and Noakes, 1999; Sheldon et al., 2002c). The risk factors for uterine infections
Corresponding author. Tel.: +44-1707-666282; fax: +44-1707-666239.
0378-4320/$ see front matter 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.anireprosci.2004.04.006
296 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306
Table 1
Risk factors for the establishment of uterine bacterial disease in cattle (Markusfeld, 1987; Hussain et al., 1990;
Noakes et al., 1991; Peeler et al., 1994; LeBlanc et al., 2002)
Uterine damage
Stillbirth, twins, dystocia, caesarean section operation
Retained placenta
Delayed uterine involution
Metabolic conditions
Milk fever, ketosis and left displaced abomasum
Balance between pathogenicity and immunity
Disruption of neutrophil function
Type of bacterial flora in the uterine lumen
Progesterone or glucocorticoid administration; early formation of a corpus luteum
Level of hygiene of the environment, cows or calving boxes may be less important
are well established (Table 1), but programs for disease prevention are not. The likelihood
of dystocia or caesarean section may be reduced by careful sire selection, and metabolic
diseases controlled by appropriate nutrition during the dry period and early lactation. How-
ever, the incidence of uterine infection has not changed appreciably over the last 30 years
(Griffin et al., 1974; Sheldon et al., 2002c).
Uterine bacterial infections are important because they disrupt not only the function of
the uterus, but also the ovary and the overarching higher control centres in the hypothala-
mus and pituitary. The inflammatory and immune response to uterine bacterial infection
compromises animal welfare as well as causing subfertility and infertility. Thus, for vet-
erinarians, the diagnosis and treatment of uterine disease is a key component of fertility
control programs. Understanding the mechanisms underlying the effect of uterine bac-
terial contamination and the associated immune response on bovine reproduction is an
important challenge for reproductive biologists in the 21st century (Sheldon and Dobson,
2003).
Before parturition the uterine lumen is sterile and if bacterial invasion occurs, there is
usually resorption of the fetus or abortion (Semambo et al., 1991). During parturition, the
physical barriers of the cervix, vagina and vulva are compromised providing the opportunity
for bacteria to ascend the genital tract from the environment as well as the animals skin and
feces. Indeed, bacterial contamination of the uterine lumen is almost ubiquitous in cattle
(Fig. 1) and notably greater than in other mammals including ruminants such as sheep
(Elliot et al., 1968; Gier and Marion, 1968; Regassa and Noakes, 1999; Sheldon et al.,
2002c). The reasons for the species differences are not clear, as sheep and cattle inhabit
similar environments and the progress of uterine involution is similar (Regassa et al., 2002;
Sheldon et al., 2003). Surprisingly, the level of hygiene of the environment during and
immediately after parturition appears to have little effect on the qualitative or quantitative
uterine bacterial flora (Noakes et al., 1991).
I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306 297
Elliot et al (1968)
100 Griffin et al (1974)
Sheldon et al (2002)
Williams et al (unpublished data)
Percent animals with uterine bacteria
80
60
40
20
0
0 10 20 30 40 50 60
Day postpartum
Fig. 1. Proportion of uteri contaminated with bacteria during the first 60 days postpartum drawn from the data of
Elliot et al. (1968), Griffin et al. (1974) Sheldon et al. (2002b) and Williams, Dobson and Sheldon (unpublished
data).
The innate immune system is principally responsible for combating bacterial contami-
nation of the uterus by a range of anatomic, physiological, phagocytic and inflammatory
defences. The vulva, vestibule, vagina and cervix act as physical barriers to bacteria as-
cending the genital tract. Physiological barriers include the copious amounts of mucus
secreted by the vagina and cervix, particularly during estrus. The main phagocytic barrier is
provided by the invasion of neutrophils in response to bacterial challenge, and the inflam-
matory barriers include the non-specific defence molecules such as lactoferrin, defensins
and acute phase proteins. Neutrophils are the earliest and most important phagocytic cell
to be recruited from the peripheral circulation to the uterine lumen, killing internalised
bacteria and contributing to the formation of pus when the phagocytes die. However, the
functional capacity of neutrophils is reduced after parturition in many cattle (Zerbe et al.,
2000); and this may predispose to the establishment of uterine disease. Later, macrophages
are likely to be important in the uterine immune response. Immune cells detect bacterial
components such as endotoxin and peptidoglycan via toll-like receptors, which activate
down-stream signalling to stimulate the release of cytokines including tumour necrosis
factor-alpha (TNF ), and interleukins (IL-1, IL-6, IL-8) (Beutler et al., 2003). These cy-
tokines cause pyrexia, and provide a positive feedback loop to further increase immune
cell mobilization. Pro-inflammatory cytokines released in response to bacterial infection or
tissue turnover, also stimulate hepatic secretion of acute phase proteins. Thus, peripheral
plasma acute phase protein concentrations increase around parturition and then decrease
with the concomitant elimination of bacterial contamination and uterine involution (Sheldon
et al., 2001).
The postpartum return of ovarian cyclic activity impinges on the uterine immune response.
In particular, luteal phase concentrations of progesterone suppress the immune response
making the uterus mores susceptible to bacterial infection (Lewis, 2003). Early ovulation
after parturition and establishment of a progesterone phase before elimination of uterine
bacterial contamination predisposes to the establishment of pyometra (Olson et al., 1984).
Similarly, in postpartum beef cows, intrauterine infusions of A. pyogenes and E. coli when
progesterone concentrations were basal did not cause uterine infections, whereas all cows
developed infections when the bacteria were infused after the onset of luteal function and
progesterone concentrations had begun to increase (Del Vecchio et al., 1994). In addition,
an early ovulation and formation of a corpus luteum after calving (<19 days versus >32
days) increased the risk for prolonged luteal cycles before service in dairy cattle (Opsomer
et al., 2000). Conversely, it is difficult to establish experimental uterine infections when
estrogens dominate the uterus (Seals et al., 2003). However, the mechanisms underlying
these observations are not clear. For example, peripheral blood or uterine neutrophil cell
function in cattle is not consistently upregulated by exogenous estradiol, nor suppressed by
progesterone (Subandrio et al., 2000).
It is important to differentiate between the contamination of the uterine lumen with a
range of bacteria and the persistence of pathogenic bacteria with the establishment of uter-
ine disease, which might be described as uterine infection. Metritis is a severe inflammatory
reaction involving all layers of the uterus: endometrium, submucosa, muscularis and serosa
(BonDurant, 1999). Clinically, metritis is characterised by pyrexia (39.5 C) up to 10
days postpartum with a fetid purulent vulval discharge, often associated with delayed in-
volution of the uterus. The incidence of metritis using this definition was 18.5% in dairy
I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306 299
cattle (Drillich et al., 2001). However, there is a wide variation between farms with the in-
cidence ranging up to 40% (Markusfeld, 1987). Endometritis is a superficial inflammation
of the endometrium, extending no deeper than the stratum spongiosum (BonDurant, 1999).
Histologically, there is some disruption of the surface epithelium, infiltration of inflamma-
tory cells and vascular congestion. However, clinically endometritis is characterised by the
presence of pus in the vagina, 21 days or more postpartum, and often associated with de-
layed uterine involution (Sheldon and Noakes, 1998). Using this definition of the presence
of purulent vaginal mucus, the incidence of endometritis is about 1020% in dairy cattle
(Borsberry and Dobson, 1989; LeBlanc et al., 2002).
Infection causes damage to the uterine tissues and features of endometrial damage such
as increased inflammation in the stratum compactum are associated with poor reproductive
performance (Bonnett et al., 1993). Similarly, the presence of A. pyogenes or anaerobic
bacteria is a risk factor for reduced fertility. Endometritis causes infertility at the time the
uterine infection is present and subfertility even after successful resolution of the disease.
In typical studies the conception rate is about 20% lower for cows with endometritis, the
median calving to conception interval 30 days longer and there are 3% more animals culled
for failure to conceive (Borsberry and Dobson, 1989; LeBlanc et al., 2002). Furthermore,
cows with a purulent cervical discharge have lower submission rates (McDougall, 2001).
As well as the effects on fertility, uterine infection is associated with lower milk yields
particularly if associated with retained placenta (Esslemont and Kossaibati, 2002; Sheldon
et al., 2004). The financial losses associated with uterine infection are dependent on the cost
of treatment, reduced milk yield, and subfertility. In the UK, the direct costs of treatment and
reduced milk yield of a cow with uterine disease were 62, and the indirect costs of a longer
calving interval, increased culling rate, extra inseminations and lower estrus expression
were 69 per cow (Esslemont and Kossaibati, 2002). The direct costs of uterine disease
were estimated at 725 per 100 cows per annum for 21 dairy herds where data was recorded
intensively between 1989 and 1999 (Esslemont and Kossaibati, 2002). There are 2.2 106
dairy cows in the UK (http://statistics.defra.gov.uk/esg/publications/auk/2002/default.asp),
and projecting the direct costs of uterine disease on a national basis would represent a cost
of 16 million.
The subfertility associated with uterine infection involves disruption of ovarian function
as well as the effects of uterine damage, and appears to persist even after clinical resolu-
tion of the disease. Presumably uterine damage disrupts the luteolytic mechanism to cause
the prolonged postpartum luteal phases, as determined by progesterone profiles, associated
with retained placenta (odds ratio (OR) 3.5), metritis (OR 11.0) or endometritis (OR 4.4)
(Opsomer et al., 2000). However, these epidemiological studies also indicate that uterine
infection is a risk factor for delayed ovulation (OR 4.5) (Opsomer et al., 2000). Similarly,
300 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306
Table 2
Endometritis clinical score
Description Score
Mucus character
Clear or translucent mucus 0
Clear or translucent mucus containing flecks of white pus 1
<50 ml exudate containing <50% white or cream pus 2
>50 ml exudate containing 50% white, cream or bloody pus 3
Mucus odor
No unpleasant odor 0
Fetid odor 3
The vaginal mucus is scored for character and odor using the given descriptions. The two scores are summed to
give the endometritis score.
when endometritis was monitored by clinical evaluation (see later and Table 2) and ovarian
function by transrectal ultrasonography, fewer cows with endometritis score 6 compared
with scores <3 ovulated the first postpartum dominant follicle (8% versus 40%, n = 113,
P < 0.05). Furthermore, ovarian function is perturbed in cattle with greater uterine bacterial
contamination after parturition (Sheldon et al., 2002c). The first postpartum dominant folli-
cle has a slower growth rate and secretes less estradiol at the end of the growth phase (Fig. 2).
The mechanisms underlying these observations are multi-level, affecting the hypothalamus,
pituitary and ovary.
Examination of the effect of uterine infection on hypothalamic and pituitary function
has focussed on the role of endotoxin, which is a component of Gram-negative bacterial
cell walls. Indeed, endotoxin can be absorbed from the postpartum uterine lumen into the
peripheral circulation and plasma endotoxin concentrations are increased in cows with spon-
taneous postpartum uterine infections (Peter et al., 1990; Mateus et al., 2003). Spontaneous
uterine infection does not appear to alter the first postpartum transient increase in FSH con-
centration and follicle wave emergence (Sheldon et al., 2002c). However, infusion of E. coli
endotoxin into the uterine lumen of heifers prevents the expected pre-ovulatory LH surge
and ovulation, causing persistence of follicular cysts (Peter et al., 1989). Indeed, high doses
of endotoxin perturb the follicular phase rise in peripheral plasma estradiol concentration
and the LH surge in a range of species, and the sheep has been used as a model to study
the underlying mechanisms (Karsch et al., 2002). Endotoxin inhibits pulsatile LH secretion
from the pituitary, suppressing hypothalamic GnRH secretion and reducing the pituitary
responsiveness to endogenous or exogenous GnRH pulses. However, in some animals, en-
dotoxin blocks the pre-ovulatory increase in peripheral plasma estradiol concentration even
in the face of normal LH pulsatility (Battaglia et al., 2000). This observation suggests that
there may also be direct effects of endotoxin on the ovary.
A further indication that there may be direct effects of uterine infection on the ovary is the
unequal distribution of postpartum follicular growth in cattle. There are fewer animals with
a follicle >8 mm diameter in the ovary ipsilateral to the previously gravid uterine horn than
the contralateral ovary (26.1% versus 49.6%, n = 284, P < 0.001), between 14 and 28 days
postpartum (Sheldon et al., 2000). This could be a carry over effect of pregnancy, but at least it
is not due to the regressing corpus luteum of pregnancy (Sheldon et al., 2002a). Furthermore,
I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306 301
Fig. 2. Mean S.E.M. (a) first dominant follicle diameter, and (b) plasma estradiol concentrations between day
7 and 16 postpartum for cows in which there was a standard (, n = 50) or high (, n = 20) uterine bacterial
contamination on day 7 as determined by collection of uterine lumen swabs for aerobic and anaerobic culture
and semi-quantitative evaluation of the number of bacterial colonies. Within a day, values differ between bacterial
contamination category P < 0.05, P < 0.01, P < 0.001. Graphs redrawn from Sheldon et al. (2002b,c).
these ovarian differences decline with increasing interval postpartum, in parallel with uterine
involution and elimination of bacterial contamination. These observations are of interest
because although less frequent, the presence of a dominant follicle in the ovary ipsilateral to
the previously gravid uterine horn is a marker of subsequent fertility (Bonnett et al., 1993;
Sheldon et al., 2000). It is likely that this improved fertility associated with the presence of a
dominant follicle in the ovary ipsilateral to the previously gravid uterine horn reflects uterine
health. When uterine bacterial growth density is high at 7 or 21 days postpartum, fewer first
or second dominant follicles are selected in the ipsilateral than the contralateral ovary,
respectively, compared with animals that have a lower uterine bacterial growth density
(Sheldon et al., 2002c). We hypothesise, therefore, that the immune response to uterine
infection has a localised effect on ovarian function. It may be that the larger previously gravid
uterine horn can contain more bacteria or that the greater uterine venous vasculature delivers
302 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306
Fig. 3. Higher endometritis clinical score is associated with greater mean S.E.M. bacterial growth density of
recognised pathogenic (), but not potential pathogenic ( ) or opportunist contaminant () bacteria in the uterine
lumen. Endometritis score based on evaluation of vaginal mucus character and odor (see Table 2). Uterine bacterial
growth density determined by collection of uterine lumen swabs for aerobic and anaerobic culture, identification
of bacterial colonies and semi-quantitative evaluation of the number of colonies on the plate as follows: 0: no
growth; 1: <10 colonies; 2: 10100 colonies; 3: 101500 colonies; and 4: >500 colonies (Noakes et al., 1991).
Bacterial growth density differs significantly from endometritis score 0, within pathogenicity group P < 0.01,
P < 0.001 (Williams, Fischer, England, Noakes, Dobson and Sheldon, unpublished observations).
ment of choice for cases of endometritis in which a corpus luteum is present. Whereas, in
the absence of a corpus luteum, a range of intrauterine treatments have been administered
including antiseptics and antibiotics. Estradiol at doses of 510 mg per animal has been used
therapeutically for postpartum endometritis and is as effective as prostaglandin F2 (Pepper
and Dobson, 1987; Sheldon and Noakes, 1998); both are superior to the spontaneous re-
covery rate of untreated animals. However, the interval from treatment to conception was
longer with estradiol treatment than prostaglandin F2 or intrauterine antibiotic (Sheldon
and Noakes, 1998).
6. Conclusions
but also suppress hypothalamic GnRH and pituitary LH secretion, and have localised effects
on ovarian function. The mechanisms underlying the effects of infection on the reproductive
tract involve the immune or inflammatory response. Conversely, the reproductive endocrine
environment can modulate the immune response and understanding the integration of the
immune and endocrine systems is an important emerging discipline.
Acknowledgements
The authors work is supported by the Wellcome Trust (Project Grant No. 064155), the
Biotechnology and Biological Sciences Research Council (BBSRC, Grant No. S19795),
the Royal College of Veterinary Surgeons Trust, and a Royal Veterinary College Internal
Grant.
References
Battaglia, D.F., Krasa, H.B., Padmanabhan, V., Viguie, C., Karsch, F.J., 2000. Endocrine alterations that underlie
endotoxin-induced disruption of the follicular phase in ewes. Biol. Reprod. 62, 4553.
Beutler, B., Hoebe, K., Du, X., Ulevitch, R.J., 2003. How we detect microbes and respond to them: the Toll-like
receptors and their transducers. J. Leukoc. Biol. 74, 479485.
BonDurant, R.H., 1999. Inflammation in the bovine reproductive tract. J. Dairy Sci. 82 (Suppl. 2), 101110.
Bonnett, B.N., Martin, S.W., Gannon, V.P., Miller, R.B., Etherington, W.G., 1991. Endometrial biopsy in
Holstein-Friesian dairy cows. III. Bacteriological analysis and correlations with histological findings. Can.
J. Vet. Res. 55, 168173.
Bonnett, B.N., Martin, S.W., Meek, A.H., 1993. Associations of clinical findings, bacteriological and histological
results of endometrial biopsy with reproductive performance of postpartum dairy cows. Prev. Vet. Med. 15,
205220.
Borsberry, S., Dobson, H., 1989. Periparturient diseases and their effect on reproductive performance in five dairy
herds. Vet. Rec. 124, 217219.
Bretzlaff, K., 1987. Rationale for treatment of endometritis in the dairy cow. Vet. Clin. N. Am. Food Anim. Pract.
3, 593607.
Del Vecchio, R.P., Matsas, D.J., Fortin, S., Sponenberg, D.P., Lewis, G.S., 1994. Spontaneous uterine infections
are associated with elevated prostaglandin F2 metabolite concentrations in postpartum dairy cows.
Theriogenology 41, 413421.
Drillich, M., Beetz, O., Pfutzner, A., Sabin, M., Sabin, H.J., Kutzer, P., Nattermann, H., Heuwieser, W., 2001.
Evaluation of a systemic antibiotic treatment of toxic puerperal metritis in dairy cows. J. Dairy Sci. 84, 2010
2017.
Elliot, L., McMahon, K.J., Gier, H.T., Marion, G.B., 1968. Uterus of the cow after parturition: bacterial content.
Am. J. Vet. Res. 29, 7781.
Esslemont, D., Kossaibati, M.A., 2002. The cost of poor fertility and disease in UK dairy herds. Intervet UK Ltd.,
Milton Keynes.
Gier, H.T., Marion, G.B., 1968. Uterus of the cow after parturition: involutional changes. Am. J. Vet. Res. 29,
8396.
Griffin, J.F.T., Hartigan, P.J., Nunn, W.R., 1974. Non-specific uterine infection and bovine fertility. I. Infection
patterns and endometritis during the first 7 weeks post-partum. Theriogenology 1, 91106.
Hussain, A.M., Daniel, R.C.W., OBoyle, D., 1990. Postpartum uterine flora following normal and abnormal
puerperium in cows. Theriogenology 34, 291302.
Karsch, F.J., Battaglia, D.F., Breen, K.M., Debus, N., Harris, T.G., 2002. Mechanisms for ovarian cycle disruption
by immune/inflammatory stress. Stress 5, 101112.
I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306 305
Laven, R.A., Biggadike, H.J., Proven, M.J., Halfacre, S., Tickle, L.R., 2000. Changes in vaginal microbiology
associated with the use of progesterone-releasing intravaginal devices. Vet. Rec. 146, 760762.
LeBlanc, S.J., Duffield, T.F., Leslie, K.E., Bateman, K.G., Keefe, G.P., Walton, J.S., Johnson, W.H., 2002. Defining
and diagnosing postpartum clinical endometritis and its impact on reproductive performance in dairy cows. J.
Dairy Sci. 85, 22232236.
Lewis, G.S., 2003. Steroidal regulation of uterine resistance to bacterial infection in livestock. Reprod. Biol.
Endocrinol. 1, 117.
Markusfeld, O., 1987. Periparturient traits in seven high dairy herds. Incidence rates, association with parity, and
interrelationships among traits. J. Dairy Sci. 70, 158166.
Mateus, L., Lopes da Costa, L., Diniz, P., Ziecik, A.J., 2003. Relationship between endotoxin and prostaglandin
(PGE2 and PGFM) concentrations and ovarian function in dairy cows with puerperal endometritis. Anim.
Reprod. Sci. 76, 143154.
McDougall, S., 2001. Effect of intrauterine antibiotic treatment on reproductive performance of dairy cows
following periparturient disease. N. Z. Vet. J. 49, 150158.
Miller, A.J., Luheshi, G.N., Rothwell, N.J., Hopkins, S.J., 1997. Local cytokine induction by LPS in the rat air
pouch and its relationship to the febrile response. Am. J. Physiol. 272, R857861.
Noakes, D.E., Wallace, L., Smith, G.R., 1991. Bacterial flora of the uterus of cows after calving on two hygienically
contrasting farms. Vet. Rec. 128, 440442.
Olson, J.D., Ball, L., Mortimer, R.G., Farin, P.W., Adney, W.S., Huffman, E.M., 1984. Aspects of bacteriology
and endocrinology of cows with pyometra and retained foetal membranes. Am. J. Vet. Res. 45, 22512255.
Opsomer, G., Grohn, Y.T., Hertl, J., Coryn, M., Deluyker, H., de Kruif, A., 2000. Risk factors for post partum
ovarian dysfunction in high producing dairy cows in Belgium: a field study. Theriogenology 53, 841857.
Peeler, E.J., Otte, M.J., Esslemont, R.J., 1994. Inter-relationships of periparturient diseases in dairy cows. Vet.
Rec. 134, 129132.
Pepper, R.T., Dobson, H., 1987. Preliminary results of treatment and endocrinology of chronic endometritis in the
dairy cow. Vet. Rec. 120, 5356.
Peter, A.T., Bosu, W.T.K., DeDecker, R.J., 1989. Suppression of preovulatory luteinizing hormone surges in heifers
after intrauterine infusions of Escherichia coli endotoxin. Am. J. Vet. Res. 50, 368373.
Peter, A.T., Bosu, W.T.K., Gilbert, R.O., 1990. Absorption of Escherichia coli endotoxin (lipopolysaccharide)
from the uteri of postpartum dairy cows. Theriogenology 33, 10111014.
Regassa, F., Noakes, D.E., 1999. Acute phase protein response of ewes and the release of PGFM in relation to
uterine involution and the presence of intrauterine bacteria. Vet. Rec. 144, 502506.
Regassa, F., Sheldon, I., Noakes, D.E., 2002. Effect of experimentally induced metritis on uterine involution, acute
phase protein response and PGFM secretion in the postpartum ewe. Vet. Rec. 150, 605607.
Risco, C.A., Hernandez, J., 2003. Comparison of ceftiofur hydrochloride and estradiol cypionate for metritis
prevention and reproductive performance in dairy cows affected with retained fetal membranes. Theriogenology
60, 4758.
Ruder, C.A., Sasser, R.G., Williams, R.J., Ely, J.K., Bull, R.C., Butler, J.E., 1981. Uterine infections in the
postpartum cow. II. Possible synergistic effect of Fusobacterium necrophorum and Corynebacterium pyogenes.
Theriogenology 15, 573580.
Seals, R.C., Wulster-Radcliffe, M.C., Lewis, G.S., 2003. Uterine response to infectious bacteria in estrous cyclic
ewes. Am. J. Reprod. Immunol. 49, 269278.
Semambo, D.K., Ayliffe, T.R., Boyd, J.S., Taylor, D.J., 1991. Early abortion in cattle induced by experimental
intrauterine infection with pure cultures of actinomyces pyogenes. Vet. Rec. 129, 1216.
Sheldon, I.M., Noakes, D.E., 1998. Comparison of three treatments for bovine endometritis. Vet. Rec. 142, 575
579.
Sheldon, I.M., 1999. Bovine endometritis: a review. J. Anim. Breed. 2, 214.
Sheldon, I.M., Noakes, D.E., Dobson, H., 2000. The influence of ovarian activity and uterine involution determined
by ultrasonography on subsequent reproductive performance. Theriogenology 54, 409419.
Sheldon, I.M., Noakes, D.E., Rycroft, A., Dobson, H., 2001. Acute phase protein response to postpartum uterine
bacterial contamination in cattle. Vet. Rec. 148, 172175.
Sheldon, I.M., Noakes, D.E., Dobson, H., 2002a. Effect of the regressing corpus luteum of pregnancy on ovarian
folliculogenesis after parturition in cattle. Biol. Reprod. 66, 266271.
306 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306
Sheldon, I.M., Noakes, D.E., Rycroft, A.N., Dobson, H., 2002b. Effect of postpartum manual examination of the
vagina on uterine bacterial contamination in cows. Vet. Rec. 151, 531534.
Sheldon, I.M., Noakes, D.E., Rycroft, A.N., Pfeiffer, D.U., Dobson, H., 2002c. Influence of uterine bacterial
contamination after parturition on ovarian dominant follicle selection and follicle growth and function in cattle.
Reproduction 123, 837845.
Sheldon, I.M., Dobson, H., 2003. Reproductive challenges facing the cattle industry at the beginning of the 21st
century. Reprod. Suppl. 61, 113.
Sheldon, I.M., Noakes, D.E., Rycroft, A.N., Dobson, H., 2003. The effect of intrauterine administration of estradiol
on postpartum uterine involution in cattle. Theriogenology 59, 13571371.
Sheldon, I.M., Rycroft, A.N., Zhou, C., 2004. The association of postpartum pyrexia with uterine bacterial infection
in dairy cattle. Vet. Rec. 154, 289293.
Sheldon, I.M., Bushnell, M., Montgomery, J., Rycroft, A.N. Minimum inhibitory concentration of selected
antimicrobials against pathogenic bacteria causing uterine infection in cattle. Vet. Rec., in press.
Spicer, L.J., 1998. Tumor necrosis factor- (TNF-) inhibits steroidogenesis of bovine ovarian granulosa and
thecal cells in vitro. Involvement of TNF- receptors. Endocrine 8, 109115.
Subandrio, A.L., Sheldon, I.M., Noakes, D.E., 2000. Peripheral and intrauterine neutrophil function in the cow:
the influence of endogenous and exogenous sex steroid hormones. Theriogenology 53, 15911608.
Williams, E.J., Sheldon, I.M., 2003. Clinical evaluation of postpartum vaginal mucus reflects uterine bacterial
infection. Reprod. Abstr. Ser. 30, 91.
Zerbe, H., Schneider, N., Leibold, W., Wensing, T., Kruip, T.A., Schuberth, H.J., 2000. Altered functional and
immunophenotypical properties of neutrophilic granulocytes in postpartum cows associated with fatty liver.
Theriogenology 54, 771786.