Pferdeheilkunde15 (1999)6 (November/Dezember)
608-610
Uterineoxytocin responsivenessand maternal
recognitionof pregnancyin the mare
LÄ.E Stoutand W.R.Allen
Universty of Cambridge,Department
of ClinicalVeterinary
lvledicine,
Cambridge,
L.J.
K.
Summary
Establishmentof pregnancyin the mare,as wth the other largedomesticanimalspecies,dependson the conceptus orchestratedsuppression of endometrialprostaglandinFr. (PGFr")secretionduring days 11-16 atter ovulation,the period when cyclicalluteolysiswould otherw se occur. lt is frustratng that, n the mare,the conceptussignalis)responsiblefor prolongingthe I fespanof the corpus luteum(CL)has nol
been identified.Nor is it understoodhow suppressiongf PGFr. re ease is ach eved. However,recent studieshave suggestedthat oxytocin
plays an importantrole in drivjngthe endometrialreleasesof PGF2,that cause uteolysisin the cycling mare and, with this in mind, the current paper reviewsthe evidencein favour of the hypothesisthat uteostass during early pregnancydepends on an inhibitionof endometrial
ox)4oclnresponsiveness,
as t does n ruminants.In addltion,we examinethe extentto which mechanlsmsother than the hypothesisedinhibition of endometrialoxytoc n receptorsare necessaryif the conceptus ls to realiseits goal of extendingthe lifespanof the pr mary CL
beyondthe time of endometrialcup formationand thus secretionof equineChoronic Gonadotrophln(eCG).
Keywords:
mare,pregnancy,oxytocin,uterus,prostaglandin
Fr,
Uterine Ansprechbarkeit auf Oxldocin und maternale Erkennungder Gravidität bei der Stute
We bei den anderengroßenHaustieradenhängt die Etablierungder Trächtigkehbei der Stute ab von der durch den Konzeptusausgelösten
Unterdrückungder endometrialenPcF2"-Sekretionwährend des 11.-16. Tages post ovulationem,also der Zelt, in der sonst die zyklische
Luteolyseeingesetzthätte. Bedauerlicherweise
st das Sgnal des Konzeptus,das für das Persisterendes Corpus luteumverantworUichist,
beim Pferd nicht identifiziert.
Auch ist nicht klar,wie die Suppressionder PGFr"-Freisetzung
erreichtwird. Dagegenwurde in neuestenArbeiten vermutet,daß das Oxltoc n eine wichtige Ro le in der Regulationder endometrialenPGF2..Abgabe während der zyk ischen Luteolyse
spielt.N4itdiesernHintergrundwird in diesemArtikelversucht,den Nachweisder Hypothesezu führen,daß die Luteostasein der Frühträch
tigkeit bdm Pferd, wie be m Bind, von der Hemmungder endometrialenOxy,tocin-Ansprechbarkeit
abhängt.Zusätzlichw rd untersucht, n
welchem Ausmaß andere lvlechanismenals die hypothetisierteInhibitionder endometrialenOxytocinrezeptorennotwendig sind, falls der
Konzeptussein Ziel erreicht,die Persistenzdes primärenCorpus luteum uber die Zeit der Formationder endometria cups und damit der
Sekretionvon equinemChoriongonadotropin,
eCG, zu initileren.
Schlüsselwörter:
Stute,Trächtigkeit,Oxytocin,Uterus,PGF"-
Introduction
Maternal recognition of pregnancy in ruminants
Short (1969)coinedthe term ,,maternal
recognitionof pregnancy" to describe the process by which the dam determines biochemically
that a conceptusis presentin her uterus and makes the appropriatephysiologicalchanges to
ensurethat a suitableenvironmentis establishedfor the future growth and developmentof that conceptus. In polyoestrousspecies,the term has come to referspecifically
to
the conceptus-initiated
events which result in prolongation
of the lifespanof the CL, since progesteronesecretedby
this structurestimulatesmany of the changeswhich ensure
nutrientsfor, and otherwiseprotect,the growingembryo.In
the mare,the antiluteolytic
effectof the conceptusappears
to be manifestedas an absolutereductionin uterinePGF2"
synthesisand/or releaseduringthe luteolyticperiod (Sharp
et al., 19BB)and the remarkablylong period of intrauterine
mobilityof the conceptusuntilaroundday 16-17 afterovulation,is essentialif the conceptusis to deliverenoughof its
anti-luteolytic
messageto a sufficientproportionof the total
area of endometriumto inhibitPGF2*releasefrom the latter, lf the mobilityof the conceptus is restricted,luteolysis
will occur and pregnancy loss will follow (McDowellet al.,
1 9 8 5 ).
As in the mare, luteolysisin the domestic ruminantsis effected by pulses of PGF,. released by the endometrium.
However,it is now well establishedin these speciesthat
oxytocin secreted by the CL plays a pivotal role in the
luteolyticprocessbecauseit stimulatesthe endometriumto
secrete its PGFr,.(Flintand Sheldrick, 1986). Fudhermore,
the criticalstep in the initiationof this luteolyticpathwayis a
dramatic upregulationof oxytocin receptors(OTRs)within
the endometriumand the resultingdevelopmentof 'oxytocin
sensitivity'(VVathes
et al., 1996).Once this has occurred,
and becausePGFro,in turn, stimulatesoxytocinsecretion,
lutealoxytocinand endometrialPGF2"engage in a positive
feedback loop which generatesthe large pulses of PGFr.,
neededto effect luteolysis(Silviaet al., 1991).
The discoverythat oxytocinand its endometrialreceptorare
centralto luteolysishas helpedconsiderablyto explainhow
a developingruminantconceptuspreventsthe destruction
of its mother'sCL. lt secretesdirectlyonto the endometrium
protein,interJeron
an uniqueantiluteolytic
tau (lFN-r'.Bazer,
1992),which acts primarilyto preventthe cyclicalupregulation of OTRs and, in so doing, disarmsthe oxytocin-PGFr,
positive feedback loop (McCrackenet al., 1984). This, in
608
Pferdeheilkunde
15
T.A.E.StoutundW.R.Allen
turn, disruptsthe patternof PGF,* secretionand prevents
the generationof the largepulsesof hormonerequiredto effect lutealdestruction(Payneand Lamming,7994).
late that some other mechanism(s),which is probably
beyond oxytocinreceptorsuppression,must completethe
inhibitionof PGFr"releaseduringearlypregnancy.
The role of oxytocin in cyclical luteolysis in the mare
Other'control points' in equine pregnancy recognition
Giventhe importanceof the dam's recognitionof her pregnancy state to embryonicsurvival,it would not be surprising if more than one pathwaywas employedto ensureCL
survival.Indeed,cattle embryos appear to use more than
one mechanismto inhibituterinePGF2.releaseand pregnant bovine endometriumsecretesup to 50% less PGF2"
than cyclicalendometriumwhen incubatedin vitro due to
the existence in the tissue of an intrinsic endometrial
prostaglandinsynthesis inhibitor (EPSI',Thatcher et al,
1995),the expressionand activityof which is enhancedby
the IFN-t secreted by the elongatingbovine trophoblast.
However,althoughFranklrnet al. (1989)reportedsignificantly
lower levelsof PGFr. secretionin vitro by endometriumrecoveredfrom pregnantmares versus cycling mares, other
studieshave not supporledthis finding(Sharpet al., 19BB;
Sfouf, 1998).Thus, if the antiluteolytic
actionsof the equine
conceptusare not sustainedconstitutivelyin endometrium
removedfrom a pregnantmare, it seems most unlikelythat
an equineanalogousEPSIexists.lf it does, its action must
be extremelyshort-lived.
Finally,while recent experimentshave demonstratedthat
the uterus of the mare is a major potentialsource of oxytocin duringcyclicalluteolysis,they may have also unearthed
an additionalcontributionto a reduced oxytocin-PGFr*
drive during pregnancy.Namely,Behrendtet al. (1997)noted that the expressionof mRNA for oxytocinin the endometriumof the mare is lowerduringearlypregnancythan at
an equivalentstage of the oestrouscycle and Sfout (1998)
Oxytocin receptors and maternal recognition of pregnancy in the mare
found a similarreductionin uterinelumenaloxytocin concentrationsduring days 14-18 of gestation.On the other
lf it is accepted that the developmentof uterinesensitivity hand, Watson et al. (1997) reporled an increasein the conto oxytocinis the criticalstep in the onset of luteolysisin the
centrationsof oxytocinpeptidewithin endometrialepithelial
non-pregnantmare, it becomeseasierto conceivehow the
cells during early pregnancy,compared to late dioestrus,
conceptus might act to suppress PGF2, secretionduring
and thereforeit appears that both oxytocin production and
the period of maternalrecognitionof pregnancy.Between releaseare reducedduring early pregnancy,thereby reducing the hormonaldriveto luteolysis.
days 1 1 and '16after ovulation,pregnantmares do not develop the abilityto secrete PGF2"in responseto oxytocin
challengein the way that non-pregnantmares do so dramatically(Goffet al., 1987; Starbucket al., 1998).Therefore, Uterine lumenal concentrations of PGFr"
it is likely that the antiluteolyticsignal(s)secreted by the
Recently,we measuredconcentrationsof PGFr. within the
equineblastocystacts eitherto preventthe developmentof
oxytocinsensitivityin the endometriumor it uncouplesthe
uterine lumen of day 18-30 pregnant mares and found
interactionbetween the oxytocin-OTRcomplex and the
these to be of the same order as the levelsrecordedin the
prostaglandinsynthesispathway.In this respect,OTRs are
uteri of mares undergoingcyclical luteolysis(Sfouf and
reduced, both in number and in their affinityfor oxytocin, Allen, 1998).This observationcomplimentedthe findingby
during days 12-14 of pregnancy (Sharp et al., 1997; SfarStarbucket al. (7997)IhaI, althoughthe abilityof the uterus
buck et al., 1998).However,the levelof suppressionis not
to respondto oxytocinchallengeis inhibitedbetweendays
as completeas that seen in ruminantsduringthe equivalent 1Oand 14 of gestation,its responsiveness
beginsto recover
period and it is thereforeunlikelythat inhibitionof OTR acby day 18. Takentogether,these findingsseem to suggest
tivity alone accounts for the almost total suppressionof
that the antiluteolytic
strategyof the equineblastocystis not
PGF2*releasethat occurs. Hence,it is necessaryto specuto induce a total abolitionof the luteolvticmechanismbut,
Initially,it was thought that control of PGFr, releaseduring
luteolysisin the mare differedfundamentallyfrom the mechanismsemployedby ruminantsand earlyauthorssuggested that oxytocin was not involved at all in the process
(Neelyet al., 1979). However, Betteridgeet al. (7985) discovered that administrationof oxytocin to mares in late
dioestrus provoked an immediate increase in peripheral
p l a sm a c onc ent r at i o n so f 1 3 , 1 4 -d i h y d ro1 S -k e to P GF2.
(PGFM),the majorcirculatingmetaboliteof PGFr., and Goff
et al. (1987) went on to demonstratethat a measurable
PGFr"-release
responseto oxytocinchallengefirst appears
on day 11 after ovulationin the cyclingmare and the response rises to peak during days 14-16, coincidentwith
functionalluteolysis,More recently,Sharp et al. (1997)and
Starbuck et al. (1998) have both reported that this late
dioestrousincreasein endometrialoxytocinsensitivitycorrelateswith a simultaneousincreasein endometrialoxytocin bindingcapacity,therebysupportingthe contentionthat
the developmentand functionof oxytocinreceptorsin the
endometriumof the mare change in a manner consistent
with oxytocinhavingan importantrole in luteolysis.
Additionally,a number of recentstudieshave indicatedthat, in the
mare, the endometriumitself is the primarysource of the
oxytocin involved in cyclical luteolysis (Behrendt et al.,
1997: Watsonet al., 1997: Sfouf et al., 1999).
Pferdeheilkunde
15
609
Uterineoxytocinresponsiveness
and maternalrecognitionof pregnancyin the mare
rather,a delay in the developmentof oxytocinsensitivity
so
as to protectthe CL untila stageof pregnancywhen a significant oxytocinchallengeis unlikelyto occur. From a practicalstandpoint,this leavesthe day 1B-30 conceptusin a remarkablyprecariouspositionbecause,at leastin theory,luteolysiscould be initiatedby any stimulusthat causedoxytocin release,includingmanipulation
of the uterus(Sharpet al.,
1997),such as mightoccur duringmanualpalpationper rectum to diagnosepregnancyor vigorousreductionof twinsto
a singletonpregnancy.This potentialfor a re-establishment
of the luteolyticmechanismafter day '18 to endangerthe
survivalof the pregnancywas demonstratedunintentionally
by Allen (1975) when he discoveredthat 3 injectionsof a
(hCG)given
normaldose of humanChorionicGonadotrophin
to mareson alternatedays between 1B and 33 days of gestationresultedin pregnancyfailureand a returnto oestrus.
Subsequenlly,Unuin (1985)demonstratedthat this resulted
from PGFr"-inducedluteolysiswhile Daelsand colleagues
(pers,comm.)have suggestedthat smallquantitiesof endotoxinsco-purifiedwith hCG in the extractionprocessare the
most likelycauseof the untowardPGF2*release.
C o n cl us ions
The conceptus factor(s)that inhibitendometrialreleaseof
PGF2, during early pregnancy in the mare continues to
elude identificaion.There remains considerablemerit in
determiningthe natureof this signal,and its mechanismof
action,since such informationmight well enablethe developmentof methodsto predictand/or limitearlypregnancy
losses.Establishing
a definiterolefor oxytocinin the control
of cyclical luteolysisin the mare has helped to identifya
number of potential,,control-points"
at which the conceptus might exert its luteostaticaction, In addition,it is anticipated that furtherinvestigations
into the expressionand regulationof the endometrialreceptorfor oxytocin may advance considerablyour understandingof how equineluteolysisis controlled,how the spherical,unattachedconceptus
interfereswith this processand what happenswhen one or
other of the mechanismsfails.
The likelihoodthat the luteolyticpathwayis re-activatedbetween days 1B-30 after ovulationis of both scientificinterest
and considerablepracticalimportanceas to how best to
managepregnantmaresto minimisethe potentialfor untoward diagnosticor therapeuticmanipulations
disturbingthe
statusquo duringthe ,,riskperiod"of equinepregnancy.
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610
Dr. T.A.E.Sfouf, (from 1.7.99)
ProfessorW.R.Allen
Departmentof EquineStudies
Facultyof VetennaryMedicine
Utrecht University
Utrecht
T.B.A. EqurneFertiiltyUnit
Mertoun Paddocks
Woodditton Road
Newmarket
Suffolk CBB gBH, U.K.
The Netherlands
Tel : ++31-30-2 531 057
Tel:++44-1638-662491
Fax:++44-1638-667
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