Proceedings of the 5th International Symposium on EQUINE ...

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Havemeyer Foundation Monograph Series No. 3ADMINISTERED OESTROGENS ARE LUTEOLYTICDURING EARLY PREGNANCY IN MAREST. A. E Stout and W. R. Allen*Department <strong>of</strong> Equine Sciences, Utrecht University, Section <strong>of</strong> Reproduction, Yalelaan 12, 3584 CMUtrecht, The Ne<strong>the</strong>rlands; *Equine Fertility Unit, Mertoun Paddocks, Woodditton Road, Newmarket,Suffolk CB8 9BH, UKINTRODUCTIONRecent surveys have reported early pregnancy loss(EPL) rates <strong>of</strong> between 5 and 24% in young,healthy mares and up to 70% in aged, subfertilemares (see Ball 1993 for review), <strong>the</strong>rebyconfirming that EPL is a significant cause <strong>of</strong>economic loss to <strong>the</strong> horsebreeding industry. In <strong>the</strong>present monograph, Carnevale et al. report similarrates <strong>of</strong> EPL for pregnancies established byembryo transfer (12–25%) and <strong>the</strong>y discuss some<strong>of</strong> <strong>the</strong> factors that may have contributed to <strong>the</strong>selosses. In general, while it is clear that <strong>the</strong> majority<strong>of</strong> EPL occurs within <strong>the</strong> first 35 days <strong>of</strong> gestation,when maintenance <strong>of</strong> <strong>the</strong> primary corpus luteum isessential to conceptus survival, <strong>the</strong> conditionsunder which <strong>the</strong> CL might undergo luteolysis in<strong>the</strong> presence <strong>of</strong> a normal conceptus are not wellunderstood. On <strong>the</strong> o<strong>the</strong>r hand, it has been widelyspeculated that oestrogens secreted by <strong>the</strong>developing horse conceptus may effect maternalrecognition <strong>of</strong> pregnancy and luteostasis, as <strong>the</strong>ydo in pigs (Bazer and Thatcher 1977). However,this hypo<strong>the</strong>sis has remained unproven, primarilybecause administration <strong>of</strong> exogenous oestrogensdoes not reliably prolong luteal activity in cyclingmares. Indeed, G<strong>of</strong>f et al. (1993) reported that <strong>the</strong>administration <strong>of</strong> oestrogens to mares in latedioestrus stimulates, ra<strong>the</strong>r than inhibits,luteolysis, <strong>the</strong>reby mirroring <strong>the</strong> situation in <strong>the</strong>domestic ruminants in which oestrogens promoteluteolysis by enhancing endometrial oxytocinreceptor development and, <strong>the</strong>reby, oxytocininducedPGF 2α release (McCracken et al. 1984).Moreover, in cattle, hormonal treatments given toprotect against failure <strong>of</strong> maternal recognition <strong>of</strong>pregnancy and loss <strong>of</strong> <strong>the</strong> primary CL, namely,exogenous progesterone or a mid-dioestrousinjection <strong>of</strong> a GnRH analogue, have been proposedto do so by reducing circulating oestradiolconcentrations and <strong>the</strong>reby weakening <strong>the</strong>luteolytic drive (Mann and Lamming 1995).Similar treatments are being used increasingly inmares in an attempt to minimise early pregnancyloss, despite a lack <strong>of</strong> evidence to support <strong>the</strong>irefficacy. Fur<strong>the</strong>rmore, <strong>the</strong>re is no rationale forsuch treatments unless it can be established thatoestrogens are pro-luteolytic during earlypregnancy in equids; such an effect is bothunproven and contrary to <strong>the</strong> existing dogma. Theaim <strong>of</strong> this study was to determine if administeredoestrogens might be luteolytic during earlypregnancy in <strong>the</strong> mare and, if so, whe<strong>the</strong>r <strong>the</strong>y actby stimulating PGF 2α release directly or byenhancing endometrial oxytocin-sensitivity.MATERIALS AND METHODSOn Days 14 and 22 <strong>of</strong> pregnancy and Day 14 <strong>of</strong> <strong>the</strong>oestrous cycle, Welsh pony mares (n = 3 in each <strong>of</strong>6 groups) were given ei<strong>the</strong>r an iv injection <strong>of</strong> 0.01mg/kg oestradiol-ß alone, or an im injection <strong>of</strong>0.03 mg/kg oestradiol-ß followed 6 h later by an ivinjection <strong>of</strong> 20 iu/500 kg oxytocin. Jugular veinplasma samples were collected at 10 min intervalsfrom 1 h before to 1 h after oestradiol-ß oroxytocin injection and assayed for <strong>the</strong>irconcentrations <strong>of</strong> 13,14-dihydro,15-keto PGF 2α(PGFM). Additional blood samples were collectedtwice daily to monitor post treatment peripheralprogesterone concentrations and pregnancy wasmonitored by palpation and ultrasound scanning <strong>of</strong><strong>the</strong> reproductive tract on alternate days.RESULTSOestradiol benzoate followed by oxytocin, but notoestradiol-ß alone, caused a rapid decline in93
Equine Embryo Transferperipheral serum progesterone concentrations. In<strong>the</strong> pregnant mares, however, progesteroneconcentrations plateaued and stabilised at around2–3 ng/ml so that <strong>the</strong> pregnancies weremaintained. Circulating PGFM concentrations didnot rise within <strong>the</strong> first h after oestradiol-ßinjection in any <strong>of</strong> <strong>the</strong> animals whereas oxytocinchallenge 6h after oestradiol-benzoate resulted in asignificant rise in plasma PGFM concentrations inone Day 14 dioestrous mare (<strong>of</strong> one analysed thusfar) and two <strong>of</strong> three Day 22 pregnant mares, butnot in ei<strong>the</strong>r <strong>of</strong> 2 Day 14 pregnant mares.CONCLUSIONSThese results indicate that a single oestrogenchallenge, given as an iv injection <strong>of</strong> oestradiol-ß,does not stimulate uterine PGF 2α release or reduceluteal activity in <strong>the</strong> mare when administeredei<strong>the</strong>r late in dioestrus or early in pregnancy. On<strong>the</strong> o<strong>the</strong>r hand, more prolonged oestrogen <strong>the</strong>rapy(im oestradiol benzoate) followed by oxytocinchallenge caused partial luteolysis in all pregnantmares treated on Day 14 or 22 after ovulation;although <strong>the</strong>re was no discernable rise in PGFMconcentrations in those treated on Day 14. Thisargues against <strong>the</strong> effect <strong>of</strong> oestradiol benzoatebeing mediated primarily by enhancement <strong>of</strong> <strong>the</strong>oxytocin-PGF 2α pathway and, since oxytocininjection alone does not influence peripheralserum progesterone concentrations in Day 22pregnant mares (authors, unpublishedobservations), <strong>the</strong> luteolysis seen in <strong>the</strong> presentstudy was unlikely to have been caused by <strong>the</strong>administered oxytocin per se. On <strong>the</strong> o<strong>the</strong>r hand,an earlier experiment recorded a similar fall incirculating progesterone concentrations in Day 23pregnant mares to which oestradiol benzoate wasadministered once daily for 10 days (Gerstenberg1998), which also supports <strong>the</strong> proposal thatoestradiol benzoate has a luteolytic action which isindependent <strong>of</strong> exogenous oxytocin and whichrarely results in complete CL lysis.In summary, we present preliminary evidencethat <strong>the</strong> administration <strong>of</strong> longer-acting oestrogensto mares during early pregnancy may compromiseluteal survival. Although <strong>the</strong>se findings need to beconfirmed and extended, <strong>the</strong>y none<strong>the</strong>less lendsupport to <strong>the</strong> hypo<strong>the</strong>sis that high systemicoestrogen concentrations may be detrimental topregnancy in <strong>the</strong> mare.REFERENCESBall, B.A. (1993) Embryonic death in mares. In: EquineReproduction Eds. A.O. McKinnon and J.L. Voss,Lea and Febiger, Pennsylvania, USA. pp 517-531.Bazer, F.W. and Thatcher, W.W. (1977) Theory <strong>of</strong>maternal recognition <strong>of</strong> pregnancy in swine based onoestrogen controlled endocrine versus exocrinesecretion <strong>of</strong> prostaglandin F 2α by <strong>the</strong> uterineendometrium. Prostagla. 14, 397-401.Carnevale, E.M., Ramirez, R.J., Squires, E.L.,Alvarenga, M.A. and McCue, P.M. (2000) Factorsaffecting pregnancy rates and early embryonic deathafter embryo transfer. Proc. <strong>5th</strong> Int. Symp. on EquineEmbryo Transfer.G<strong>of</strong>f, A.K., Sirois, J. and Pontbriand, D. (1993) Effect <strong>of</strong>oestradiol on oxytocin-stimulated prostaglandin F 2αrelease in mares. J. reprod. Fert. 98, 107-112.Gerstenberg, C. (1999) Factors controlling epi<strong>the</strong>liochorialplacentation in <strong>the</strong> mare. University <strong>of</strong> CambridgePhD Thesis.McCracken, J.A., Schramm, W. and Okulicz, W.C.(1984) Hormone receptor control <strong>of</strong> pulsatilesecretion <strong>of</strong> PGF 2α from <strong>the</strong> ovine uterus d.uringluteolysis and its abrogation in early pregnancyAnim. reprod. Sci. 7, 31-55Mann, G.E. and Lamming, G.E. (1995) Effect <strong>of</strong> <strong>the</strong>level <strong>of</strong> oestradiol on oxytocin-inducedprostaglandin F 2α release in <strong>the</strong> cow. J. Endocrinol.145, 175-180.94
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