Clinical evaluation of the use of aglepristone, with or without ...
Clinical evaluation of the use of aglepristone, with or without ...
Clinical evaluation of the use of aglepristone, with or without ...
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1552F. Fieni / Theriogenology 66 (2006) 1550–15562.3. Statistical <strong>evaluation</strong>Qualitative results, such as <strong>the</strong> success <strong>of</strong> <strong>the</strong>treatment, were rep<strong>or</strong>ted <strong>with</strong> a confidence interval <strong>of</strong>95%. Quantitative results were rep<strong>or</strong>ted as means S.D. Data were analyzed by Statview (SAS InstituteInc., Cary, NC, USA). Treatment efficacy and <strong>the</strong>clinical response <strong>of</strong> metritis/pyometra were comparedusing a Chi-square test. A Student-Fisher test was <strong>use</strong>dto compare <strong>the</strong> mean decrease in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong>uterine lumen, <strong>the</strong> mean leucocyte count and <strong>the</strong> meanperipheral plasma progesterone concentration betweentreatments at various times during <strong>the</strong> experiment.Values were considered statistically significant whenP < 0.05.3. ResultsWhen measuring efficacy at day 90, 54/67 bitcheswere cured (i.e. 80.6%, <strong>with</strong> a confidence interval range<strong>of</strong> 71.1–90.1%). The overall recovery rate was lower(P < 0.001) at day 14 (24/68, 35.3%) than at day 28 (46/67, 68.6%) and day 90 (54/67, 80.6%). The effectiveness<strong>of</strong> <strong>the</strong> treatment was not dependent on <strong>the</strong> clinicalf<strong>or</strong>m <strong>of</strong> uterine disease (Table 1).In bitches <strong>with</strong> metritis, treatment <strong>with</strong> <strong>aglepristone</strong>alone gave a high cure rate, <strong>with</strong> clinical resolution inover half <strong>of</strong> <strong>the</strong> bitches (9/15) <strong>with</strong>in 2 weeks and <strong>with</strong>in4 weeks f<strong>or</strong> <strong>the</strong> remainder <strong>with</strong>, one exception. Thebitch cured at day 90 had only a slight serous dischargeon day 28. This was visible by <strong>the</strong> clinician during <strong>the</strong>genital exam but not by <strong>the</strong> owner.<strong>Clinical</strong>ly, <strong>the</strong> administration <strong>of</strong> <strong>aglepristone</strong> incases <strong>of</strong> pyometra led to changes in <strong>the</strong> nature <strong>of</strong> <strong>the</strong>vaginal discharge, which changed from purulent, tomucous-like, bef<strong>or</strong>e finally becoming serous, <strong>with</strong> aconcurrent decrease in volume. The last clinical signrec<strong>or</strong>ded was self-cleaning <strong>of</strong> <strong>the</strong> vulval area by <strong>the</strong>bitch. F<strong>or</strong> all bitches <strong>with</strong> closed pyometra, cervicalopening was induced following <strong>the</strong> first two <strong>aglepristone</strong>treatments (18/18). The mean time to cervicalopening was 25.8 12.2 h. The sh<strong>or</strong>test time was 4 hafter <strong>the</strong> first administration <strong>of</strong> <strong>aglepristone</strong>; however,Table 1Number <strong>of</strong> bitches cured, at various stages in <strong>the</strong> trial, based on <strong>the</strong>f<strong>or</strong>m <strong>of</strong> uterine diseaseDay 14 Day 28 Day 90Metritis (%) 9/15 (60.0) 14/15 (93.3) 15/15 (100)Open pyometra (%) 13/35 (37.1) 20/35 (57.1) 26/35 (74.3)Closed pyometra (%) 2/18 (11.1) 12/17 (70.6) 13/17 (76.5)cervical opening was complete <strong>with</strong>in 48 h in all <strong>of</strong> <strong>the</strong>bitches. Cervical opening induced enabled <strong>the</strong> evacuation<strong>of</strong> large volumes <strong>of</strong> purulent discharge, which wasassociated <strong>with</strong> an immediate improvement in generalcondition and, in most cases, <strong>with</strong> increased appetite.F<strong>or</strong> bitches <strong>with</strong> open <strong>or</strong> closed pyometra, additionaltreatment <strong>with</strong> cloprostenol from days 3 to 7 improved<strong>the</strong> overall success rate at day 90 (P < 0.05); 27/32(84.4%) <strong>with</strong> cloprostenol versus 12/20 (60.0%) <strong>with</strong>outcloprostenol (Table 2). Recovery was accompanied by agradual decrease in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong> uterine lumen,which became non-detectable ultrasonographically. Themean decrease in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong> uterine lumen overtime depended on <strong>the</strong> treatment <strong>use</strong>d (Fig. 1) and wassignificantly greater between days 8 and 14 in bitchesreceiving <strong>the</strong> combined <strong>aglepristone</strong>–cloprostenol treatmentthan in those treated <strong>with</strong> <strong>aglepristone</strong> alone(84.8 20.7% versus 64.6 41.0%).The general condition <strong>of</strong> bitches suffering frommetritis was not altered; it remained good throughout <strong>the</strong>trial. Bitches suffering from open <strong>or</strong> closed pyometrapresented were depressed and an<strong>or</strong>exic in 41/53 (77.3%)and 34/53 (64.1%) cases, respectively. In all animalstreated, <strong>the</strong>re was a marked improvement in this criterionby <strong>the</strong> second day <strong>of</strong> treatment. On day 8, moderatelethargy was observed in 9 bitches (17.3%) and 14bitches (26.9%) showed loss <strong>of</strong> appetite. On day 15, allbitches still receiving treatment were in good generalcondition, <strong>with</strong> only one showing any loss <strong>of</strong> appetite. Noside effects were observed after treatment <strong>with</strong> cloprostenolin 15/33 bitches (45.5%). In <strong>the</strong> remainder, na<strong>use</strong>awas <strong>the</strong> most commonly observed side effect (12/33), andvomiting occurred in six bitches.None <strong>of</strong> <strong>the</strong> bitches had a noticeable change in redblood cell count. The mean white blood cell counts inbitches suffering from metritis were n<strong>or</strong>mal and,remained lower (P < 0.05) than <strong>the</strong> counts in bitches<strong>with</strong> open <strong>or</strong> closed pyometra (Fig. 2) throughout <strong>the</strong>trial. In bitches recovering from pyometra, a markeddecrease in leucocytosis was observed over <strong>the</strong> course<strong>of</strong> treatment. This mean decrease was significant on dayTable 2Number <strong>of</strong> bitches <strong>with</strong> open <strong>or</strong> closed pyometra (Group 1 + Group 2)cured by <strong>the</strong> administration <strong>of</strong> <strong>aglepristone</strong> alone compared to <strong>the</strong>combined administration <strong>of</strong> <strong>aglepristone</strong> + cloprostenolTreatment Day 14 Day 28 Day 90Aglepristone (%) 3/20 (15.0) 9/20 (45.3) 12/20 (60.0)Aglepristone +cloprostenol (%)12/33 (36.4) 23/32 (71.9) 27/32 (84.4)Difference in cure rate between <strong>the</strong> two treatments on day 90(P < 0.05).
F. Fieni / Theriogenology 66 (2006) 1550–1556 1553Fig. 1. Mean (S.E.M.) rates <strong>of</strong> decreases in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong> uterine lumen at various stages in <strong>the</strong> trial, in bitches <strong>with</strong> open <strong>or</strong> closed pyometra(Group 1 + Group 2) cured by <strong>the</strong> administration <strong>of</strong> <strong>aglepristone</strong> alone (n = 12), in comparison <strong>with</strong> those receiving a combination <strong>of</strong><strong>aglepristone</strong> + cloprostenol (n = 27). (*) Differences (P < 0.05).Fig. 2. Mean (S.E.M.) concentration <strong>of</strong> leucocytes at various stages in <strong>the</strong> trial, in bitches <strong>with</strong> metritis (n = 15), open pyometra (n = 26) <strong>or</strong> closedpyometra (n = 13) cured by treatment <strong>with</strong> <strong>aglepristone</strong> <strong>or</strong> <strong>aglepristone</strong> + cloprostenol. F<strong>or</strong> each day, <strong>the</strong> mean white blood cell count wassignificantly lower in cases <strong>of</strong> metritis than in cases <strong>of</strong> open <strong>or</strong> closed pyometra. In bitches <strong>with</strong> closed pyometra, <strong>the</strong> white blood cell count waslower at day 14 (P < 0.01) and at day 28 (P < 0.001) than at day 0.
1554F. Fieni / Theriogenology 66 (2006) 1550–1556Table 3Means (S.D.) plasma progesterone concentrations (nmol/L) in bitches <strong>with</strong> open <strong>or</strong> closed pyometra (Group 1 + Group 2) treated <strong>with</strong> <strong>aglepristone</strong>alone, compared to those treated <strong>with</strong> a combination <strong>of</strong> <strong>aglepristone</strong> + cloprostenolTreatment Day 1 Day 8 Day 14 Day 28Aglepristone (n = 20) 12.8 14.4 a 5.6 6.6 bx 4.8 5.1 b 3.3 4.2 bAglepristone + cloprostenol (n = 32) 19.3 11.6 a 15.08 10.5 ay 4.7 1.1 b 3.96 2.8 bWithin a row, values <strong>with</strong> different superscript letters (a and b) differ (P < 0.05); <strong>with</strong>in a column, values <strong>with</strong> different superscript letters (x and y)differ (P < 0.05).15 f<strong>or</strong> bitches <strong>with</strong> closed pyometra (Fig. 2). Among <strong>the</strong>67 treated bitches, on day 1, 15 had plasma progesteroneconcentrations below 3.18 nmol/L. Treatment wassuccessful in all <strong>of</strong> <strong>the</strong>m, except f<strong>or</strong> two bitches <strong>with</strong>open pyometra. F<strong>or</strong> bitches <strong>with</strong> open <strong>or</strong> closedpyometra treated <strong>with</strong> cloprostenol (n = 32), <strong>the</strong>rewas a significant decrease in mean peripheral plasmaprogesterone concentration at day 8 (12.8 14.4 nmol/L versus 5.6 6.6 nmol/L on days 1 versus 8,respectively). However, in bitches treated <strong>with</strong>outcloprostenol (n = 20), no significant decrease in meanplasma progesterone concentration was observed untilday 14 (19.3 11.6 nmol/L versus 4.7 1.1 nmol/Lon days 1 versus 14; Table 3).Among <strong>the</strong> 13 failures using this treatment, onebitch did not present f<strong>or</strong> follow-up and recovery couldnot be confirmed. One bitch <strong>with</strong> open pyometratreated <strong>with</strong> <strong>aglepristone</strong> died on day 5 in <strong>the</strong> owner’sho<strong>use</strong>, and ano<strong>the</strong>r treated <strong>with</strong> <strong>aglepristone</strong> andcloprostenol was euthanized in a private clinic on day15 due to declining health. Ten bitches underwent anovariohysterectomy. In this last group, six had ovariancysts. After recovery, 23 bitches underwent follow-upvisits over <strong>the</strong> 24 months following <strong>the</strong> beginning <strong>of</strong>treatment. Three <strong>of</strong> <strong>the</strong>m developed pyometra between7 and 12 months later (3/23, 13.0%) and ano<strong>the</strong>rdeveloped it at 19 months (4/21, 19.0%). Two <strong>of</strong> <strong>the</strong>mreceived an additional, successful course <strong>of</strong> treatment(<strong>aglepristone</strong> + cloprostenol) and no pyometra wasobserved at <strong>the</strong> next cycle. We have kept in contact<strong>with</strong> <strong>the</strong> owners <strong>of</strong> three <strong>of</strong> <strong>the</strong> bitches <strong>use</strong>d in <strong>the</strong> trialf<strong>or</strong> some considerable time. They were treated m<strong>or</strong>ethan 6 years ago and have come into estrus n<strong>or</strong>mally,<strong>with</strong> no recurrence <strong>of</strong> uterine disease. Five bitcheswere mated at <strong>the</strong> first estrus after recovery; fourbecame pregnant.4. DiscussionThe <strong>use</strong> <strong>of</strong> <strong>aglepristone</strong> alone cured 27/35 (77.1%)bitches in 90 days. These results are equivalent tothoserep<strong>or</strong>tedbyH<strong>of</strong>fmannetal.[11] (25/31, 80.6%at day 30) and by Trasch et al. [12] (44/52, 84.6% atday 90). The number <strong>of</strong> animals treated is insufficientto show any difference in efficacy depending onclinical type (metritis, open pyometra and closedpyometra). This study, however, demonstrated <strong>the</strong>satisfact<strong>or</strong>y results obtained from<strong>the</strong><strong>use</strong><strong>of</strong><strong>aglepristone</strong>in bitches suffering from metritis (recovery rate,15/15). The <strong>use</strong> <strong>of</strong> <strong>aglepristone</strong> is also <strong>of</strong> particularinterest in <strong>the</strong> treatment <strong>of</strong> closed pyometra, since itinduces cervical opening, and <strong>the</strong> subsequent evacuation<strong>of</strong> purulent discharge <strong>with</strong> a marked improvementin <strong>the</strong> animal’s general condition. These resultsdemonstrated that surgery is no longer <strong>the</strong> onlytreatment f<strong>or</strong> closed pyometra. M<strong>or</strong>eover, even ifsurgery has been planned, it is possible to recommendmedication as a first-line treatment (<strong>aglepristone</strong> andrehydration) to improve <strong>the</strong> general health <strong>of</strong> <strong>the</strong> bitchand minimize surgical risk. In this study, <strong>the</strong> cervix <strong>of</strong>all <strong>the</strong> bitches <strong>with</strong> closed pyometra opened <strong>with</strong>in48 h. In a study <strong>of</strong> nine bitches <strong>with</strong> closed pyometra,Wehrend et al. [14] observed cervical opening <strong>with</strong>in72 h and <strong>the</strong> same marked improvement in <strong>the</strong>animal’s general condition.In bitches <strong>with</strong> open <strong>or</strong> closed pyometra, <strong>the</strong> repeatedadministration <strong>of</strong> low dose cloprostenol significantlyincreased <strong>the</strong> success rate at day 90 (27/32, 84.4%). Theuterotonic action <strong>of</strong> cloprostenol lead to a significantlyfaster decrease in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong> uterine lumen andits luteolytic action ca<strong>use</strong>d a faster drop in mean plasmaprogesterone concentration. This decline in progesteronewas commonly observed in bitches treated f<strong>or</strong>pyometra <strong>with</strong> cloprostenol alone [15], <strong>or</strong> <strong>with</strong>cloprostenol associated <strong>with</strong> <strong>aglepristone</strong> [13]. In <strong>the</strong>present study, a decrease in progesterone concentrationswas also observed in bitches treated <strong>with</strong> <strong>aglepristone</strong>only, but at a later stage. Beca<strong>use</strong> <strong>of</strong> <strong>the</strong> antiprogesteroneproperties <strong>of</strong> <strong>aglepristone</strong>, this luteolysisdoes not seem to modify sh<strong>or</strong>t-term effectiveness.Between 30 and 90 days, we did not note any c<strong>or</strong>relationbetween blood progesterone concentration and successrate. The low dose <strong>of</strong> cloprostenol given (1 mg/kg) doesnot usually ca<strong>use</strong> any adverse reactions [16–18].Contrary to <strong>the</strong> results <strong>of</strong> a similar study [13], 56%<strong>of</strong> bitches treated had side effects, usually vomiting.
F. Fieni / Theriogenology 66 (2006) 1550–1556 1555This particular sensitivity to low doses <strong>of</strong> cloprostenolcan be explained by <strong>the</strong> po<strong>or</strong> general condition <strong>of</strong> <strong>the</strong>bitches. Never<strong>the</strong>less, <strong>the</strong> owners did not make anycomments.Among <strong>the</strong> treated bitches, 17 had basal progesteroneconcentrations. Cases <strong>of</strong> pyometra were observed atall stages <strong>of</strong> <strong>the</strong> reproductive cycle in a previous study[1]. The effects <strong>of</strong> <strong>aglepristone</strong> in pyometra have beenstudied in diestrus bitches selected <strong>with</strong> a progesteroneconcentration <strong>of</strong> m<strong>or</strong>e than 3.2 mm/L [1,10,11]. In <strong>the</strong>present study 15/17 bitches <strong>with</strong> a low progesteroneconcentration were cured after <strong>the</strong> administration <strong>of</strong><strong>aglepristone</strong>. Similar results were observed in ano<strong>the</strong>rrep<strong>or</strong>t [13]. This seems to confirm that, in <strong>the</strong>pathogenesis <strong>of</strong> pyometra in bitches, <strong>the</strong> action <strong>of</strong>progesterone on <strong>the</strong> uterus is dependent on <strong>the</strong> number<strong>of</strong> progesterone recept<strong>or</strong>s <strong>or</strong> <strong>the</strong>ir specific sensitivity,and not on <strong>the</strong> plasma progesterone concentration <strong>of</strong>this h<strong>or</strong>mone.The recurrence rate <strong>of</strong> pyometra after treatmentdiffered from results rep<strong>or</strong>ted in o<strong>the</strong>r studies. We didnot observe any recurrence between days 30 and 90,and <strong>the</strong> cure rate was higher, whereas Trasch et al.[12] rep<strong>or</strong>ted a recurrence rate <strong>of</strong> 9.8% (4/41) f<strong>or</strong> <strong>the</strong>same interval; this may be due to <strong>the</strong> length <strong>of</strong>treatment and <strong>the</strong> repeated administration <strong>of</strong> <strong>aglepristone</strong>until day 28 if needed (whereas Trasch onlyadministered <strong>aglepristone</strong> on days 1, 2 and 7). Therecurrence rate from 12 to 14 months after treatmentwas 18.9% (4/37) f<strong>or</strong> Trasch et al. [12], 9% (1/11) f<strong>or</strong>H<strong>of</strong>fmann et al. [11] and 21.4% (3/14) f<strong>or</strong> Gobelloet al. [13]. The mean age <strong>of</strong> <strong>the</strong> bitches (8 years) mayexplain <strong>the</strong> recurrence <strong>of</strong> pyometra in <strong>the</strong> 24 monthsfollowing <strong>the</strong> end <strong>of</strong> treatment, since age is a maj<strong>or</strong>epidemiological fact<strong>or</strong> in <strong>the</strong> onset <strong>of</strong> pyometra inbitches. However, treatment failure <strong>or</strong> recurrence <strong>of</strong><strong>the</strong> disease is closely linked to <strong>the</strong> presence <strong>of</strong> ovariancysts, which maintain a permanent endocrine imbalance.Ovariancystswereobservedin6<strong>of</strong>10bitcheswho underwent ovariohysterectomy due to <strong>the</strong> failure<strong>of</strong> medical treatment.Conservative treatment <strong>with</strong> prostaglandins, which isrecommended f<strong>or</strong> bitches <strong>with</strong> metritis <strong>or</strong> pyometra<strong>with</strong> mild dilatation <strong>of</strong> <strong>the</strong> uterine lumen, produces acure rate <strong>of</strong> 83–100%, <strong>with</strong> recurrence rates varyingfrom 10 to 40%. The treatment, which requires severaladministrations, produces discomf<strong>or</strong>t and is <strong>of</strong>tenassociated <strong>with</strong> side effects such as hypersalivation,vomiting and diarrhea [3,4].In conclusion, treatment <strong>with</strong> <strong>aglepristone</strong> alone wasa safe and effective treatment f<strong>or</strong> metritis, and aneffective means <strong>of</strong> inducing cervical opening in cases <strong>of</strong>closed pyometra. The combination <strong>of</strong> <strong>aglepristone</strong> andcloprostenol was m<strong>or</strong>e effective in <strong>the</strong> medicaltreatment <strong>of</strong> open and closed pyometra than <strong>aglepristone</strong>alone. Never<strong>the</strong>less, in all cases, we onlyrecommend such treatment in bitches <strong>with</strong> no liver <strong>or</strong>kidney dysfunction, and advise close clinical monit<strong>or</strong>ingthroughout <strong>the</strong> entire course <strong>of</strong> treatment.References[1] Blendiger K, Bostedt H, H<strong>of</strong>fmann B. H<strong>or</strong>monal effects <strong>of</strong> <strong>the</strong><strong>use</strong> <strong>of</strong> an antiprogestin in <strong>the</strong> bitches <strong>with</strong> pyometra. J ReprodFertil 1997;(Suppl. 51):317–25.[2] Noakes DE, Dhaliwal GK, England GC. Cystic endometrialhyperplasic/pyometra in dogs: a review <strong>of</strong> <strong>the</strong> ca<strong>use</strong>s andpathogenesis. J Reprod Fertil 2001;(Suppl. 57):395–406.[3] Gilbert RO, Nöthling JO, Oettlé EE. 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Termination <strong>of</strong> mid-gestation pregnancy inbitches <strong>with</strong> <strong>aglepristone</strong>, a progesterone recept<strong>or</strong> antagonist.Theriogenology 2000;53:941–50.[8] Fieni F, Martal J, Marnet PG, Siliart B, Bernard F, Riou M, et al.H<strong>or</strong>monal variation after early <strong>or</strong> mid-pregnancy termination inbitches <strong>with</strong> <strong>aglepristone</strong> (RU534). J Reprod Fertil 2001;(Suppl.57):243–8.[9] Fieni F, Marnet PG, Martal J, Siliart B, Touzeau N, Bruyas JF,et al. Comparison <strong>of</strong> two protocols to induce parturition inbitches <strong>with</strong> a progesterone antagonist: <strong>aglepristone</strong> (RU534).J Reprod Fertil 2001;(Suppl. 57):237–42.[10] Breitkopf M, H<strong>of</strong>fmann B, Bostedt H. 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1556F. Fieni / Theriogenology 66 (2006) 1550–1556[15] Tainturier D, Treboz C. Traitement de la métrite chronique de lachienne par le cloprosténol, un analogue de la PgF2a. PMCAC1985;20:239–44.[16] Fieni F, Fuhrer M, Tainturier D, Bruyas JF, Dridi S, Siliart B,et al. Utilisation d’un analogue de synthèse des prostaglandines:le cloprosténol dans l’av<strong>or</strong>tement provoqué de la chienne.PMCAC 1989;24:557–72.[17] Fieni F, Fuhrer M, Tainturier D, Bruyas JF, Dridi S. Use <strong>of</strong> PGF2a analog, cloprostenol, f<strong>or</strong> pregnancy termination in dogs. JReprod Fertil 1989;(Suppl. 39):332–3.[18] Onclin K, Verstegen JP. Comparisons <strong>of</strong> different combinations<strong>of</strong> analogues <strong>of</strong> PGF2 alpha and dopamine agonistsf<strong>or</strong> <strong>the</strong> termination <strong>of</strong> pregnancy in dogs. Vet Rec 1999;144:416–9.
J. Vet. Med. A 50, 375–379 (2003)Ó 2003 Blackwell Verlag, BerlinISSN 0931–184XClinic f<strong>or</strong> Obstetrics, Gynaecology and Andrology <strong>of</strong> Large and Small Animals, Justus-Liebig University, Gießen, GermanyFollow-up Examinations <strong>of</strong> Bitches after Conservative Treatment <strong>of</strong> Pyometra<strong>with</strong> <strong>the</strong> Antigestagen AglepristoneK. Trasch 1 , A. Wehrend and H. BostedtAddress <strong>of</strong> auth<strong>or</strong>s:Clinic f<strong>or</strong> Obstetrics, Gynaecology and Andrology <strong>of</strong> Large and Small Animals, Justus-Liebig University,Germany, Frankfurter Str. 106, 35392 Gießen, Germany; 1 C<strong>or</strong>responding auth<strong>or</strong>:E-mail:katjatrasch@yahoo.deWith 2 figures and 2 tables Received f<strong>or</strong> publication:February 13, 2003SummaryThe aim <strong>of</strong> this study was to determine <strong>the</strong> <strong>the</strong>rapeutic success<strong>of</strong> <strong>the</strong> medical treatment <strong>of</strong> canine pyometra <strong>with</strong> <strong>the</strong> antigestagen<strong>aglepristone</strong> and to document <strong>the</strong> recurrence rate inrelation to <strong>the</strong> time interval after treatment <strong>with</strong> antigestagens.In 48 (92.8%) <strong>of</strong> <strong>the</strong> 52 treated bitches, healing could beachieved <strong>with</strong>in <strong>the</strong> first 3 weeks after <strong>the</strong> treatment had beenstarted. One bitch died as a result <strong>of</strong> renal insufficiency; inthree bitches <strong>the</strong>re was no emptying <strong>of</strong> <strong>the</strong> uterus, so ovariohysterectomybecame necessary. In <strong>the</strong>se three patients, ovarianand endometrial cysts were present. F<strong>or</strong>ty-one bitchescould be followed up f<strong>or</strong> 3 months. Four animals developed arecurrence (9.8%). In three bitches ovarian cysts and cysticendometrial hyperlasia could be found intra operationem. Thedevelopment <strong>of</strong> 37 bitches could be followed f<strong>or</strong> at least 1 year.Seven animals developed a pyometra again (18.9%). Tw<strong>or</strong>eceived a repeated treatment <strong>with</strong> <strong>aglepristone</strong> and have beenfree from recurrence f<strong>or</strong> over 12 months. In 37 animals data on<strong>the</strong> subsequent sex cycles are available. In 22 bitches next heatstarted at <strong>the</strong> expected time, in seven animals heat started tooearly. In eight bitches <strong>the</strong> period <strong>of</strong> anoestrus was prolonged.Five <strong>of</strong> <strong>the</strong> six bred bitches delivered at least one litter.Thepresented data show that treatment <strong>of</strong> pyometra by <strong>aglepristone</strong>results in a high healing rate. The recurrence rate can beminimized by <strong>the</strong> selection <strong>of</strong> bitches <strong>with</strong>out ovarian cysts andcystic endometrial hyperplasia.IntroductionPyometra has so far mostly been treated by ovariohysterectomy.The advantage <strong>of</strong> this treatment is <strong>the</strong> exclusion <strong>of</strong> <strong>the</strong> risk<strong>of</strong> recurrence. However, surgical treatment has its limits where<strong>the</strong> risk <strong>of</strong> surgery is increased <strong>or</strong> in case where <strong>the</strong> ownerref<strong>use</strong>s ovariohysterectomy. F<strong>or</strong> this reason, different strategies<strong>of</strong> conservative treatment have been developed. Theadvantages <strong>of</strong> a non-surgical intervention are that <strong>the</strong> ability tobreed can be maintained and that <strong>the</strong> risks <strong>of</strong> anaes<strong>the</strong>sia andsurgery are excluded.Different procedures <strong>of</strong> conservative pyometra treatmenthave been described. One <strong>of</strong> those is <strong>the</strong> single systemic andlocal <strong>use</strong> <strong>of</strong> antibiotics (Querol, 1981; Threlfall, 1995).A significant number <strong>of</strong> cases treated as above and transferredafterwards, show, however, that this treatment frequently didnot result in a healing but a protraction <strong>of</strong> <strong>the</strong> disease.Ano<strong>the</strong>r medical treatment is <strong>the</strong> parenteral application <strong>of</strong>prostaglandin F 2a . Even single cases <strong>of</strong> shock and death havebeen rep<strong>or</strong>ted (Berchtold, 1997). In <strong>or</strong>der to minimize <strong>the</strong>serisks, low concentrations are administered <strong>with</strong> a high applicationfrequency (Hubler et al., 1991; Nolte et al., 1993). Thisregime clearly restricts <strong>the</strong> practicability <strong>of</strong> <strong>the</strong> proposedtreatment protocols in practice, particularly in outpatients.Fieni et al. (2001a) treated bitches <strong>with</strong> <strong>the</strong> closed and openf<strong>or</strong>m <strong>of</strong> pyometra <strong>with</strong> a combination <strong>of</strong> <strong>aglepristone</strong> andcloprostenol successfully, but 68% <strong>of</strong> <strong>the</strong> bitches showed sideeffectslike vomiting.The effects <strong>of</strong> oestrogen administration such as cervixrelaxation and opening, as well as <strong>the</strong> increase <strong>of</strong> uteruscontractility justify <strong>the</strong><strong>or</strong>etically <strong>the</strong> <strong>use</strong> <strong>of</strong> this h<strong>or</strong>mone in <strong>the</strong>treatment <strong>of</strong> pyometra. However, its mediocre <strong>the</strong>rapeuticsuccess and a high potential <strong>of</strong> undesired side-effects make its<strong>use</strong> ra<strong>the</strong>r questionable (Watson, 1942; Legendre, 1976; Kraftand Kuffer, 1995).The <strong>use</strong> <strong>of</strong> oxytocin and secale alkaloids was also discussed(Hardy and Osb<strong>or</strong>ne, 1974; Funkquist et al., 1983). The<strong>the</strong>rapeutic effect has not been proven to date. All f<strong>or</strong>ms <strong>of</strong>medical treatment presented so far show clear limitations in<strong>the</strong>ir usage and go along <strong>with</strong> undesired effects. Regarding <strong>the</strong>recurrence rates <strong>of</strong> <strong>the</strong> different <strong>the</strong>rapeutic regimens, <strong>the</strong>re areei<strong>the</strong>r no data available, <strong>or</strong>, <strong>with</strong> regard to prostaglandintreatment, <strong>the</strong> published data in literature vary strongly(Johnston et al., 2001).With <strong>the</strong> introduction <strong>of</strong> antigestagen-based drugs inveterinary medicine new <strong>the</strong>rapeutic agents f<strong>or</strong> <strong>the</strong> treatment<strong>of</strong> progesterone-dependent dis<strong>or</strong>ders have become available.After <strong>the</strong> demonstration <strong>of</strong> <strong>the</strong> antigestagenic effect <strong>of</strong> thisgroup <strong>of</strong> substances in <strong>the</strong> bitch (H<strong>of</strong>fmann and Gerres, 1989),<strong>the</strong> field <strong>of</strong> indication <strong>of</strong> this pharmaceutical agent in gynaecologyand obstetrics <strong>of</strong> small animals has been constantlyenlarged. The successful <strong>use</strong> <strong>of</strong> this medication could be shownnot only in <strong>the</strong> treatment <strong>of</strong> canine and feline pyometra(Blendinger et al., 1997; Breitkopf et al., 1997; Hecker et al.,2000; H<strong>of</strong>fmann et al., 2000; Fieni et al., 2001a), but also in<strong>the</strong> prevention <strong>of</strong> nidation (Hubler and Arnold, 2000), in <strong>the</strong>induction <strong>of</strong> ab<strong>or</strong>tion (Blendinger et al., 1994), in <strong>the</strong> treatment<strong>of</strong> fibroadenomatosis (Wehrend et al., 2001) and in <strong>the</strong>induction <strong>of</strong> labour (Riesenbeck et al., 1999; Fieni et al.,2001b).In <strong>or</strong>der to assess <strong>the</strong> <strong>use</strong> <strong>of</strong> antigestagens in <strong>the</strong> treatment <strong>of</strong>pyometra compared <strong>with</strong> o<strong>the</strong>r <strong>the</strong>rapeutic procedures, it isnecessary to know <strong>the</strong> healing and recurrence rate after <strong>the</strong> <strong>use</strong><strong>of</strong> antigestagens. So far, <strong>the</strong> only inf<strong>or</strong>mation available isbased only on a few number <strong>of</strong> animals and does not allow adifferentiated examination <strong>of</strong> <strong>the</strong> recurrence rate in differenttime intervals following successful treatment f<strong>or</strong> m<strong>or</strong>e thanU.S. Copyright Clearance Center Code Statement: 0931–184X/2003/5007–0375 $15.00/0www.blackwell.de/synergy
376 K. Trasch et al.1 year (H<strong>of</strong>fmann et al., 2000; Fieni et al., 2001a). Thepurpose <strong>of</strong> this study is to show <strong>the</strong> success <strong>of</strong> <strong>the</strong> treatment<strong>of</strong> pyometra <strong>with</strong> antigestagens as well as <strong>the</strong> recurrence rate inrelation to <strong>the</strong> time interval after treatment.Materials and MethodsThe data <strong>of</strong> 52 bitches <strong>of</strong> different breeds who suffered frompyometra and were treated <strong>with</strong> <strong>aglepristone</strong> were evaluated.All bitches underwent a general and gynaecological examinationincluding ultrasonography (5 MHz convex probe, KretzSA 9900 Ò ; Kretz, Zipf, Austria) and differential bloodcount (CELL - DYN 3500 Ò ; Abbott Diagnostika GmbH,Wiesbaden-Delkenheim, Germany). To determine ureaand creatinine concentrations a photometric procedure(Reflotron Ò ; Boehringer, Mannheim, Germany) was <strong>use</strong>d.The inclusion criteria f<strong>or</strong> this study were:1 Filled uterus detectable by ultrasonography (Fig. 1)2 Putrid vaginal discharge at <strong>the</strong> day <strong>of</strong> presentation (openpyometra) <strong>or</strong> onset <strong>of</strong> putrid vaginal discharge <strong>with</strong>in <strong>the</strong>first 24 h after first application (closed pyometra)Po<strong>or</strong> general condition, as well as increased renal parameters(n<strong>or</strong>mal values:urea >8.3 mmol/l, creatinine >106 lmol/l;Kraft and Du¨ rr, 1999) did not count as exclusion criterion.Only bitches <strong>with</strong> an uterus rupture were excluded fromconservative treatment.The antigestagenic agent <strong>aglepristone</strong> was licensed in Francein 1996 in f<strong>or</strong>m <strong>of</strong> <strong>the</strong> veterinary drug Alicine Ò (Virbac,Carros, France) f<strong>or</strong> <strong>the</strong> prevention <strong>of</strong> nidation and ab<strong>or</strong>tioninduction in <strong>the</strong> dog. The treatment protocol f<strong>or</strong> subcutaneousapplication <strong>of</strong> 10 mg/kg body weight on day 1, two and sevenwas applied (H<strong>of</strong>fmann et al., 2000). All animals receivedantibiotic treatment f<strong>or</strong> at least 7 days. Amoxicillin combined<strong>with</strong> clavulanic acid (Synulox Ò ; Pfizer, Karlsruhe, Germany)<strong>or</strong> enr<strong>of</strong>loxacin (Baytril Ò ; Bayer, Lever-k<strong>use</strong>n, Germany) indosages acc<strong>or</strong>ding to <strong>the</strong> manufacturer’s instructions were<strong>use</strong>d.The bitches underwent outpatient treatments, except f<strong>or</strong>three bitches. The reasons f<strong>or</strong> inpatient treatment were thattwo <strong>of</strong> <strong>the</strong>se had increased renal parameters and requiredinfusion <strong>the</strong>rapy, and <strong>the</strong> o<strong>the</strong>r one was in an extremely badcondition.The examination plan was fur<strong>the</strong>rm<strong>or</strong>e applied on day 2and 7 following <strong>the</strong> first presentation. Ano<strong>the</strong>r consultationtook place between day 14 and 21 after <strong>the</strong> first treatment. Thesh<strong>or</strong>t-term success <strong>of</strong> <strong>the</strong> treatment was defined up to day 21after <strong>the</strong> start <strong>of</strong> <strong>the</strong> treatment, <strong>the</strong> medium-term success up to3 months after <strong>the</strong> first application. The long-term successreflects <strong>the</strong> situation up to date, but at least up to <strong>the</strong> period <strong>of</strong>1 year. The necessary inf<strong>or</strong>mation regarding general andreproduction health were collected after <strong>the</strong> fourth consultationby questioning <strong>the</strong> owner by phone.ResultsData <strong>of</strong> anamnesisThe average age was 6.9 ± 4.5 years (1–17 years). Table 1shows <strong>the</strong> reasons f<strong>or</strong> consultation. The duration <strong>of</strong> <strong>the</strong>symptoms was between 2 days and 4 weeks.The main p<strong>or</strong>tion <strong>of</strong> patients was found to be in dioestrus(n ¼ 34, 65.4%), followed by those in anoestrus (n ¼ 8;15.3%). In seven bitches <strong>the</strong> heat was regularly suppressedby progestins (n ¼ 7, 13.5%). In three animals, nidation hadbeen prevented by oestrogens pri<strong>or</strong> to <strong>the</strong> date <strong>of</strong> <strong>the</strong>consultation (two times 2 weeks earlier, once 8 weeks earlier)beca<strong>use</strong> <strong>of</strong> unwanted breeding (n ¼ 3, 5.8%).Findings upon admittanceTwenty-two bitches were in good general condition, 25 animalsshowed slight impairments. Five <strong>of</strong> <strong>the</strong> bitches were in a po<strong>or</strong>general condition, three <strong>of</strong> <strong>the</strong>m were not able to get up. Therectally measured inner body temperature <strong>of</strong> 21 animals wasabove 39.0°C, that <strong>of</strong> <strong>the</strong> o<strong>the</strong>rs was <strong>with</strong>in <strong>the</strong> referencerange. In 44 animals an open f<strong>or</strong>m <strong>of</strong> pyometra was detected.In eight patients, a closed pyometra was diagnosed.The maximum total diameter <strong>of</strong> <strong>the</strong> filled uterus wasbetween 0.6 and 6.3 cm.The blood count <strong>of</strong> 27 bitches showed leucocytosis (leucocytes>12 g/l), in three animals leucopaenia could be noticed(leucocytes
Treatment <strong>of</strong> Canine Pyometra <strong>with</strong> Aglepristone 377treatment, despite immediate admission to a clinic and <strong>the</strong>start <strong>of</strong> infusion <strong>the</strong>rapy. In <strong>the</strong> second bitch, a lastingimprovement <strong>of</strong> <strong>the</strong> renal parameters under infusion <strong>the</strong>rapy<strong>with</strong> isotonic 0.9% sodium chl<strong>or</strong>ide solution (sodium chl<strong>or</strong>idesolution ad usum veterinarium, Selectavet, Weyau-Holzolling,Germany) could be rec<strong>or</strong>ded <strong>with</strong>in 3 days. Up to day 7 <strong>the</strong>inner body temperature returned to n<strong>or</strong>mal in all patients. Adecline <strong>of</strong> <strong>the</strong> initial leucocytosis could be observed in allaffected animals until <strong>the</strong> fourth consultation.A distinctive increase <strong>of</strong> vaginal discharge could be detectedin all bitches <strong>with</strong>in <strong>the</strong> first 24 h after application <strong>of</strong><strong>aglepristone</strong>. The uterus lumen <strong>of</strong> 48 animals showed adistinctive reduction up to day 7. The ultrasonographic finding<strong>of</strong> <strong>the</strong> uterus was inconspicuous in <strong>the</strong>se animals upon <strong>the</strong>fourth consultation. Ultrasonographic examination <strong>of</strong> threepatients showed nei<strong>the</strong>r an increase in a reduction <strong>of</strong> <strong>the</strong> uteruslumen n<strong>or</strong> an increase in vaginal discharge <strong>with</strong>in <strong>the</strong> first fewdays. In <strong>the</strong>se animals ovariohysterectomy was perf<strong>or</strong>med.Cystic changes <strong>of</strong> <strong>the</strong> ovaries and cystic endometrial hyperplasiacould be detected intra operationem (Fig. 2). One <strong>of</strong> <strong>the</strong>bitches was oestrogen-pretreated, two animals were in <strong>the</strong>phase <strong>of</strong> dioestrus.In 48 <strong>of</strong> <strong>the</strong> 52 bitches, a clinical healing <strong>of</strong> <strong>the</strong> pyometracould be achieved. This c<strong>or</strong>responds to a sh<strong>or</strong>t-term successrate <strong>of</strong> 92.3% (Table 2).Medium-term success up to month 3 after treatmentThe general and reproduction health <strong>of</strong> 41 bitches could befollowed (Table 2). Four <strong>of</strong> <strong>the</strong>se animals developed a recurrence<strong>with</strong>in 3 months (recurrence rate <strong>of</strong> 9.8%). In <strong>the</strong>seanimals an ovariohysterectomy was perf<strong>or</strong>med. In three cases,a cystic change <strong>of</strong> <strong>the</strong> ovaries and <strong>the</strong> endometrium could bedetected. None <strong>of</strong> <strong>the</strong> bitches was pretreated <strong>with</strong> h<strong>or</strong>mones.The remaining 37 bitches did not show any abn<strong>or</strong>malities <strong>or</strong>signs <strong>of</strong> a new metropathy during this period <strong>of</strong> time.Long-term success during, at least, 1 year after treatmentThe fur<strong>the</strong>r course could be observed in 37 bitches. Seven <strong>of</strong><strong>the</strong>se animals developed a pyometra <strong>with</strong>in 1 year (recurrenceTable 2. Recurrence and healing rates <strong>of</strong> bitches <strong>with</strong> pyometra up to21 days, 3 month and at least 1 year after medical treatment <strong>with</strong><strong>aglepristone</strong>n (%)Sh<strong>or</strong>t-term up to day 21Total no. <strong>of</strong> bitches 52 (100.0)Dead (on second day <strong>of</strong> treatment) 1 (1.9)No emptying <strong>of</strong> <strong>the</strong> uterus 3 (5.8)Initial emptying <strong>of</strong> <strong>the</strong> uterus 49 (94.2)Healing rate 48 (92.3)Medium-term up to month 3Total no. <strong>of</strong> bitches 41 (100.0)Recurrence rate 4 (9.8)Long-term, at least 1 yearTotal no. <strong>of</strong> bitches 37 (100.0)Recurrence rate 7 (18.9)rate 18.9%). In five <strong>of</strong> <strong>the</strong>se animals, ovariohysterectomy wasperf<strong>or</strong>med by general veterinary practitioners. F<strong>or</strong> this reason,<strong>the</strong> findings <strong>of</strong> <strong>the</strong> ovaries and <strong>the</strong> uterus are unknown. In twoanimals, <strong>the</strong> treatment <strong>with</strong> <strong>aglepristone</strong> was successfullyrepeated; <strong>the</strong>y did not show new signs <strong>of</strong> an uteropathy overa period <strong>of</strong>, at least, 12 months (Table 2).Data on <strong>the</strong> fur<strong>the</strong>r reproductive behaviour <strong>of</strong> totally37 bitches are available. In 22 bitches, <strong>the</strong> next heat startedat <strong>the</strong> expected time. The course <strong>of</strong> <strong>the</strong> heat in <strong>the</strong>se animalswas n<strong>or</strong>mal. Five <strong>of</strong> <strong>the</strong>se animals developed a pyometra in <strong>the</strong>stage <strong>of</strong> dioestrus following oestrus. Seven animals showedpremature signs <strong>of</strong> subsequent heat. One <strong>of</strong> this bitchesdeveloped a pyometra 8 weeks after oestrous behaviour. Ineight bitches <strong>the</strong> period <strong>of</strong> anoestrus was prolonged. In onebitch <strong>the</strong> following heat was delayed by 6 months so that <strong>the</strong>length <strong>of</strong> <strong>the</strong> interoestrus interval was 12 months. However, aregulation to <strong>the</strong> n<strong>or</strong>mal cycle could be detected in sevenanimals until <strong>the</strong> second heat after treatment. One bitch <strong>with</strong>delayed interoestrus interval developed a pyometra.Six <strong>of</strong> <strong>the</strong> bitches were bred during <strong>the</strong> time until <strong>the</strong> end <strong>of</strong><strong>the</strong> observation period, five delivered at least one litter <strong>of</strong>whelps.Fig. 2. Cystic endometrial hyperplasia in a bitch, which develops apyometra after initial successful medical treatment <strong>of</strong> pyometra <strong>with</strong><strong>aglepristone</strong>.DiscussionThe aim <strong>of</strong> this clinical study was to evaluate <strong>the</strong> success <strong>of</strong> <strong>the</strong>treatment <strong>of</strong> canine pyometra by <strong>the</strong> antigestagen <strong>aglepristone</strong>and to document <strong>the</strong> lasting <strong>the</strong>rapeutic success in differenttime stages.The inf<strong>or</strong>mation obtained by anamnesis and <strong>the</strong> clinicalfindings reflect <strong>the</strong> already known data from literature(Blendinger and Bostedt, 1991; Berchtold, 1997). Theref<strong>or</strong>e,it can be assumed that <strong>the</strong> population examined in this study isrepresentative <strong>of</strong> bitches diseased <strong>with</strong> pyometra.The fact that a conservative treatment <strong>of</strong> <strong>the</strong> closed f<strong>or</strong>m <strong>of</strong>pyometra can be successfully carried out, in contradiction to<strong>the</strong> recommendations made by Johnston et al. (2001), seems tobe notew<strong>or</strong>thy. In seven <strong>of</strong> <strong>the</strong> eight animals diseased <strong>with</strong> thisf<strong>or</strong>m <strong>of</strong> pyometra, <strong>the</strong> opening <strong>of</strong> <strong>the</strong> cervix and thus anemptying <strong>of</strong> <strong>the</strong> uterus could be induced. Only one bitch had toundergo surgery beca<strong>use</strong> no vaginal discharge occurred. None<strong>of</strong> <strong>the</strong> seven successfully treated bitches developed a reccurrence.These data confirm <strong>with</strong> H<strong>of</strong>fmann et al. (2000) and
378 K. Trasch et al.Fieni et al. (2001a), who have been shown that bitches <strong>with</strong> aclosed f<strong>or</strong>m <strong>of</strong> pyometra can be treated successfully.In 98.1% <strong>of</strong> <strong>the</strong> treated bitches, an improvement <strong>of</strong> <strong>the</strong>general condition developed <strong>with</strong>in <strong>the</strong> first two days after <strong>the</strong>first application. In 94.2% <strong>of</strong> <strong>the</strong> cases an initial induction <strong>of</strong><strong>the</strong> emptying <strong>of</strong> <strong>the</strong> uterus could be realized <strong>with</strong>in 12–24 h,along <strong>with</strong> an increase in <strong>the</strong> vaginal discharge.A n<strong>or</strong>malization <strong>of</strong> leucocytosis could be realized in eachcase during <strong>the</strong> following 21 days after beginning <strong>of</strong> treatment.In none <strong>of</strong> <strong>the</strong> animals an increase in renal parameters <strong>or</strong>undesired effects were observed.With a sh<strong>or</strong>t-term healing success rate <strong>of</strong> 92.3% <strong>the</strong> <strong>use</strong> <strong>of</strong><strong>aglepristone</strong> is certainly justifiable, at least in <strong>or</strong>der to gain <strong>the</strong>possibility <strong>of</strong> postponing surgery in <strong>the</strong> case <strong>of</strong> a po<strong>or</strong> generalhealth condition and associated increased surgical and anaes<strong>the</strong>ticrisk. F<strong>or</strong> medium and long-term success, however, it isimp<strong>or</strong>tant that <strong>the</strong> participation <strong>of</strong> relatively <strong>or</strong> absolutelyincreased oestrogen values can be excluded. In case <strong>of</strong> anabsolutely <strong>or</strong> relatively increased oestrogen concentration,such as in relation to <strong>the</strong> ovarian cysts, a successful treatmentcannot be expected. Lemmer (1999) also indicated already thata conservative treatment <strong>of</strong> pyometra is not successful in <strong>the</strong>presence <strong>of</strong> ovarian cysts.In most cases <strong>of</strong> recurrence, <strong>the</strong> presence <strong>of</strong> cystic changes <strong>of</strong><strong>the</strong> ovaries and <strong>the</strong> endometrium could be detected. Unf<strong>or</strong>tunately,it was not possible to examine <strong>the</strong> individual plasmah<strong>or</strong>mone concentrations. It is concluded that <strong>the</strong> recurrencerate can be minimized by <strong>the</strong> selection <strong>of</strong> bitches <strong>with</strong>outovarian cysts and cystic endometrial hyperplasia. One possibility<strong>of</strong> detecting oestrogen influence <strong>with</strong>out determining <strong>the</strong>exact oestrogen value is <strong>the</strong> perf<strong>or</strong>mance <strong>of</strong> an exfoliativevaginal cytology (Tammer et al., 1994). Ultrasonographicdiagnosis <strong>of</strong> ovarian cysts is also possible in some cases. Butit is not possible to differenciate between oestrogen-producingovarian cysts, clinically irrelevant paraovarian cysts andc<strong>or</strong>p<strong>or</strong>a lutea <strong>with</strong> a fluid filled cavity by ultrasonography(Wehrend and Bostedt, 2002).To compare <strong>the</strong> healing and recurrence rate in <strong>the</strong> presentstudy <strong>with</strong> <strong>the</strong> results <strong>of</strong> o<strong>the</strong>r auth<strong>or</strong>s it might be helpful tocalculate <strong>the</strong> final recurrence rate from our data. In ouropinion this give false inf<strong>or</strong>mation beca<strong>use</strong> not all <strong>of</strong> <strong>the</strong>animals could be followed up f<strong>or</strong> <strong>the</strong> same period <strong>of</strong> time.There is a significantly higher number <strong>of</strong> recurrences after<strong>aglepristone</strong> treatment in <strong>the</strong> present study in comparison <strong>with</strong><strong>the</strong> study by H<strong>of</strong>fmann et al. (2000). In this study, 21 <strong>of</strong> 22successfully treated bitches could be fur<strong>the</strong>r examined during aperiod <strong>of</strong> 14 months on average. Potential recurrence in three<strong>of</strong> <strong>the</strong>se animals could not be commented on, as <strong>the</strong>y werekilled due to ano<strong>the</strong>r clinical picture. In seven animals, n<strong>or</strong>epeated heat could be detected <strong>with</strong>in <strong>the</strong> observation period.In only one case <strong>of</strong> <strong>the</strong> residual 11 animals, purulent vaginaldischarge occurred again. Two <strong>of</strong> <strong>the</strong> bitches were bred; one <strong>of</strong><strong>the</strong>m had a miscarriage f<strong>or</strong> unknown reasons during <strong>the</strong> lastquarter <strong>of</strong> pregnancy. Unf<strong>or</strong>tunately, <strong>the</strong> data do not showduring which period <strong>of</strong> time recurrence took place. Only a totalaverage observation period <strong>of</strong> 14 months and no individualcourses <strong>of</strong> time are given. Fieni et al. (2001a) treated bitches<strong>with</strong> <strong>the</strong> closed and open f<strong>or</strong>m <strong>of</strong> pyometra <strong>with</strong> a combination<strong>of</strong> <strong>aglepristone</strong> and cloprostenol in comparison <strong>with</strong> <strong>the</strong>treatment <strong>with</strong> only <strong>aglepristone</strong>. The global success rate onday 90 after first treatment was 87% <strong>with</strong> cloprostenol and<strong>aglepristone</strong> versus 63% <strong>with</strong> <strong>aglepristone</strong> alone. Never<strong>the</strong>less,<strong>the</strong>y <strong>use</strong>d very small doses <strong>of</strong> cloprostenol, 68% <strong>of</strong> <strong>the</strong> bitchesshowed side-effects like vomiting. The auth<strong>or</strong>s gave no clearinf<strong>or</strong>mation about <strong>the</strong> recurrence rate after day 90 following<strong>the</strong> first treatment.Johnston et al. (2001) gave an overview <strong>of</strong> healing successand recurrence rates after conservative treatment <strong>of</strong> pyometra<strong>with</strong> prostaglandins. However, <strong>the</strong> underlying clinical studiesincluded only low number <strong>of</strong> bitches. The <strong>the</strong>rapeutic successvaries between 100% (n ¼ 10) and 46% (n ¼ 15); all knownside-effects such as restlessness, hypersalivation, vomiting anddiarrhoea were described in <strong>the</strong>se studies. The recurrence ratesare 10% on average. There are regularly no data described on<strong>the</strong> times <strong>of</strong> <strong>the</strong> recurrence <strong>of</strong> <strong>the</strong> disease. Only Meyers-Wallenet al. (1989) <strong>of</strong>fer m<strong>or</strong>e details on <strong>the</strong> number <strong>of</strong> recurrences.They describe a <strong>the</strong>rapeutic success in all <strong>of</strong> <strong>the</strong> 10 treatedanimals. In 40% <strong>of</strong> <strong>the</strong> bitches under follow-up examinations arecurrence could be observed <strong>with</strong>in 1 year, in 77% <strong>of</strong> <strong>the</strong>bitches pyometra symptoms recurred <strong>with</strong>in 27 months.Bef<strong>or</strong>e starting antigestagen treatment, <strong>the</strong> advantages anddisadvantages <strong>of</strong> <strong>the</strong> treatment have to be discussed <strong>with</strong> <strong>the</strong>owner. Due to <strong>the</strong> distinctive improvement <strong>of</strong> <strong>the</strong> generalcondition a trial <strong>of</strong> <strong>the</strong> treatment can be justified, beca<strong>use</strong> asurgery at a later time, after health condition has improved, isstill possible. The good conception rate <strong>of</strong> <strong>the</strong> subsequentbreedings allow <strong>the</strong> <strong>use</strong> <strong>of</strong> antigestagens especially in breedingbitches; however, <strong>the</strong> results regarding fur<strong>the</strong>r fertility have tobe secured by fur<strong>the</strong>r examinations in a higher number <strong>of</strong>bitches.ReferencesBerchtold, M., 1997:Pyometra der Hu¨ ndin. In:Freudiger, U., E. G.Gru¨ nbaum, E. Schimke (Hrsg.), Klinik der Hundekrankheiten. 2.,u¨ berarb. Enke, Aufl. – Stuttgart.Blendinger, K., and H. Bostedt, 1991:Zum Alter und Zyklusstadiumbei Hu¨ ndinnen mit Pyometra. Tierärztl. Prax. 19, 307–310.Blendinger, K., H. Bostedt, and B. H<strong>of</strong>fmann, 1994:Ab<strong>or</strong>teinleitungund konservative Behandlung der Fibroadenomatose bei einerKatze unter Verwendung des Antigestagens RU 46534. Kleintierpraxis39, 495–499.Blendinger, K., H. Bostedt, and B. H<strong>of</strong>fmann, 1997:H<strong>or</strong>monal stateand effects <strong>of</strong> <strong>the</strong> <strong>use</strong> <strong>of</strong> an antiprogestin in bitches <strong>with</strong> pyometra.J. Reprod. Fertil. Suppl. 51, 317–325.Breitkopf, M., B. H<strong>of</strong>fmann, and H. Bostedt, 1997:Treatment <strong>of</strong>pyometra (cystic endometrial hyperplasia) in bitches <strong>with</strong> anantiprogestin. J. Reprod. Fertil. Suppl. 51, 327–331.Fieni, F., J. F. Bruyas, D. Tainturnier, and I. Battut, 2001a:<strong>Clinical</strong><strong>use</strong> <strong>of</strong> antigestagins in <strong>the</strong> treatment <strong>of</strong> metritis/pyometra in <strong>the</strong>bitch. EVSSAR Newslett. 1, 13–14.Fieni, F., P. G. Marnet, B. Siliart, N. Touzeau, J. F. Bruyas, and D.Tainturier, 2001b:Comparison <strong>of</strong> two protocols <strong>with</strong> a progesteroneantagonist <strong>aglepristone</strong> (RU 534) to induce parturition inbitches. J. Reprod. Fertil. Suppl. 57, 237–242.Funkquist, B., A.-S. Lagerstedt, C. Linde, and N. Obel, 1983:Intrauterinedrainage f<strong>or</strong> treatment <strong>of</strong> pyometra in <strong>the</strong> bitch. Zbl. Vet.Med. A 30, 72–80.Hardy, R. M., and C. A. Osb<strong>or</strong>ne, 1974:Canine pyometra:pathophysiology,diagnosis and treatment <strong>of</strong> uterine and extrauterinelesions. J. Am. Anim. Hosp. Assoc. 10, 245–268.Hecker, B. R., A. Wehrend, and H. Bostedt, 2000:KonservativeTherapie der Pyometra bei der Katze mit dem AntigestagenAglépristone. Kleintierpraxis 45, 845–848.H<strong>of</strong>fmann, B., and S. Gerres, 1989:Modellversuch zur Darstellung derantigestagenen Wirkung von RU 38486 bei der Hu¨ ndin. Wien.Tierärztl. Mschr. 76, 10–14.
Treatment <strong>of</strong> Canine Pyometra <strong>with</strong> Aglepristone 379H<strong>of</strong>fmann, B., W. Lemmer, H. Bostedt, and K. Failing, 2000:DieAnwendung des Antigestagens Aglépristone zur konservativenBehandlung der Pyometra bei der Hu¨ ndin. Tierärztl. Prax. 28,323–329.Hubler, M., and S. Arnold, 2000:Prevention <strong>of</strong> pregnancy in bitches<strong>with</strong> <strong>the</strong> progesterone antagonist aglépristone (Alicine). Schweiz.Arch. Tierheilk. 142, 381–386.Hubler, M., S. Arnold, M. Casal, M. Flu¨ ckinger, B. Ha<strong>use</strong>r, L.C<strong>or</strong>boz, and P. Ru¨ sch, 1991:Anwendung von niedrig dosiertemProstaglandin F2 a bei Hu¨ ndinnen. Schweiz. Arch. Tierheilk. 133,323–329.Johnston, S. D., M. V. RootKustritz, and P. N. S. Olson, 2001. Dis<strong>or</strong>ders<strong>of</strong> <strong>the</strong> canine uterus. In:Johnston, S. D., M. V. RootKustritz, P. N. S. Olson (eds), Canine and Feline Theriogenology.W. B. Saunders Company, Philadelphia, pp. 206–224.Kraft, W., and U. M. Du¨ rr, 1999:Klinische Lab<strong>or</strong>diagnostik in derTiermedizin – 5., u¨ berarb. und erw. Schattauer, New Y<strong>or</strong>k, Aufl. –Stuttgart.Kraft, W., and M. Kuffer, 1995:Behandlung schwerer Neutropenienbei Hund und Katze mit Filgrastim. Tierärztl. Prax. 23, 609–613.Legendre, A. M. 1976:Estrogen-induced bone marrow hypoplasia in adog. J. Am. Ani. Hosp. Assoc. 12, 525–527.Lemmer, W. 1999:Untersuchungen zur konservativen Pyometrabehandlungder Hu¨ ndin mittels eines Antigestagens im Rahmen einer<strong>of</strong>fenen klinischen Studie. Diss. Med. Vet. Gießen.Meyers-Wallen, V. N., M. H. Goldschmidt, and G. L. Flickinger,1989:Prostaglandin F2a treatment <strong>of</strong> canine pyometra. J. Am. Vet.Med. Assoc. 189, 1557–1561.Nolte, I., S. Mo¨ ller, A. Brass, N. Schossier, H.-A. Schoon, andW. Gru¨ nberg, 1993:Zur Therapie des Endometritis-Pyometra-Komplexes der Hu¨ ndin mit niedrig dosiertem ProstaglandinF2 a . Kleintierpraxis 38, 363–372.Querol, M. 1981:Die Behandlung der Pyometra der Hu¨ ndin mitdem Mastitis- und Metritispräparat Ubrocelan Ò , Entamast Ò undEntamast Ò Uterino. Tierärztl. Umsch. 36, 359–360.Riesenbeck, A., R. Klein, B. H<strong>of</strong>fmann, and R. Hospes, 1999:Geburtsinduktion infolge verla¨ ngerter Gravidität bei einer Hu¨ ndinunter Verwendung eines Antigestagens. Tierärztl. Prax. 27, 186–188.Tammer, I., K. Blendinger, A. Sobiraj, and H. Bostedt, 1994:U¨ ber denEinsatz der exfoliativen Vaginalzytologie im Rahmen der gynäkologischenBefunderhebung bei der Hu¨ ndin. Tierärztl. Prax. 22,199–207.Threlfall, W. R. 1995:Diagnosis and medical management <strong>of</strong> pyometra.Semin. Vet. Med. Surg. Small Anim. 10, 21–29.Watson, M. 1942:Stilboestrol in pyometra <strong>of</strong> <strong>the</strong> bitch. Vet. Rec. 54,489.Wehrend, A., and H. Bostedt, 2002:Zur Bedeutung und Behandlungdes Ovarialzystensyndroms bei der Hu¨ ndin. Proceedings, 48.Jahrestagung der FK-DVG vom 30.08. bis 01.09.2002 Magdeburg,261–264.Wehrend, A., R. Hospes, and A. Gruber, 2001:Alternative treatment<strong>of</strong> feline fibroadenomatous hyperplasia <strong>with</strong> a progesteron antagonist.Vet. Rec. 148, 346–347.
Theriogenology 60 (2003) 901–908A study <strong>of</strong> two protocols combining <strong>aglepristone</strong>and cloprostenol to treat open cervix pyometrain <strong>the</strong> bitchCristina Gobello a,* , Gervasio Castex a,1 , Liliana Klima b ,Raúl Rodríguez b , Yanina C<strong>or</strong>rada ba Small Animal Clinic, Faculty <strong>of</strong> Veterinary Medicine, National University <strong>of</strong> La Plata, CC 296,La Plata B1900 AVVW, Argentinab Image Diagnostic Service, Faculty <strong>of</strong> Veterinary Medicine, National University <strong>of</strong> La Plata, CC 296,La Plata B1900 AVVW, ArgentinaReceived 21 June 2002; accepted 9 December 2002AbstractTo compare <strong>the</strong> efficacy and safety <strong>of</strong> two protocols using a combination <strong>of</strong> <strong>aglepristone</strong> andcloprostenol f<strong>or</strong> <strong>the</strong> treatment <strong>of</strong> open cervix pyometra in <strong>the</strong> bitch and to describe <strong>the</strong>progesterone (P 4 ) serum pr<strong>of</strong>iles bef<strong>or</strong>e and during treatments, 15 bitches were randomly allocatedinto two treatment groups: I (n ¼ 8): <strong>aglepristone</strong> was administered at 10 mg/kg, s.c., on Days 1,3, 8, and 15 (if not cured), combined <strong>with</strong> cloprostenol at <strong>the</strong> dose <strong>of</strong> 1 mg/kg, s.c., on Days 3 and8, and II (n ¼ 7): received <strong>the</strong> same treatment <strong>with</strong> <strong>aglepristone</strong> as Treatment I but cloprostenol onDays 3, 5, 8 10, 12, and 15 (if not cured). Bef<strong>or</strong>e <strong>the</strong> beginning <strong>of</strong> <strong>the</strong> treatments and <strong>the</strong>n on Days8, 15, and 29 all bitches were evaluated f<strong>or</strong> clinical signs, side effects, hemogram, serum P 4concentrations, and uterus diameters. Bitches in both treatment groups, <strong>with</strong> (n ¼ 6) <strong>or</strong> <strong>with</strong>out(n ¼ 9; 1.2 ng/ml) initial basal P 4 serum concentrations, achieved treatment success <strong>with</strong>out sideeffects and no significant differences, ei<strong>the</strong>r on Day 15 (6/8 f<strong>or</strong> Treatment I and 4/7 f<strong>or</strong> TreatmentII) <strong>or</strong> on Day 29 (2/8 f<strong>or</strong> Treatment I and 3/7 f<strong>or</strong> Treatment II). In both treatments groups, clinicalsigns, blood parameters, and uterine diameters improved to n<strong>or</strong>mal values throughout <strong>the</strong>experiments. A significant interaction between day and treatment was found f<strong>or</strong> percentagechange in P 4 when all bitches were considered toge<strong>the</strong>r. Redevelopment <strong>of</strong> pyometra in <strong>the</strong> nextestrous cycle occurred in 20% <strong>of</strong> <strong>the</strong> bitches. One nonrecurrent bitch was mated and whelped an<strong>or</strong>mal litter. It is concluded that <strong>the</strong>se two combined protocols proved to be efficient and safe inreversing clinical signs <strong>of</strong> open cervix pyometra independently <strong>of</strong> initial P 4 concentrations and* C<strong>or</strong>responding auth<strong>or</strong>. Fax: þ54-221-4259780.E-mail address: cgobello@fcv.unlp.edu.ar (C. Gobello).1 Gervasio Castex is a Research Fellow <strong>of</strong> <strong>the</strong> Comisión de Investigaciones Científicas (CIC) de la provinciade Bs As, Argentina.0093-691X/$ – see front matter # 2003 Elsevier Science Inc. All rights reserved.doi:10.1016/S0093-691X(03)00094-3
902 C. Gobello et al. / Theriogenology 60 (2003) 901–908that <strong>the</strong> number <strong>of</strong> cloprostenol administrations seemed to have an effect on P 4 serum changesthroughout treatments.# 2003 Elsevier Science Inc. All rights reserved.Keyw<strong>or</strong>ds: Pyometra; Bitch; Aglepristone; Cloprostenol1. IntroductionThe cystic endometrial hyperplasia—pyometra complex (CEH-P) is a common progesterone(P 4 )-dependent disease <strong>of</strong> <strong>the</strong> genital tract that appears clinically ei<strong>the</strong>r in <strong>the</strong>diestrous <strong>or</strong> anestrous period <strong>of</strong> <strong>the</strong> canine estrous cycle [1–4]. Medical treatment <strong>of</strong> CEH-P is usually required f<strong>or</strong> bitches intended f<strong>or</strong> breeding. Ei<strong>the</strong>r prostaglandins (PG) <strong>or</strong>antiprogestins have been proved to be effective f<strong>or</strong> this purpose [3,5–8]. Prostaglandinsincrease myometrial contractions, may enhance cervical relaxation and have a luteolyticeffect after Day 5 <strong>of</strong> diestrus, decreasing serum P 4 concentrations [2]. Cloprostenol sodiumis a syn<strong>the</strong>tic PG F2a analogue that has a luteolytic effect and potent uterotonic activity[2,8].Antiprogestins are syn<strong>the</strong>tic steroids which bind <strong>with</strong> great affinity to P 4 recept<strong>or</strong>s<strong>with</strong>out any effects <strong>of</strong> P 4 [9]. Aglepristone (RU 534) is an antiprogestin, recently marketedf<strong>or</strong> veterinary <strong>use</strong>, which competes f<strong>or</strong> uterine recept<strong>or</strong>s <strong>with</strong> a fixating rate three-fold that<strong>of</strong> P 4 in <strong>the</strong> bitch [10]. In human beings, a combination <strong>of</strong> antiprogestin (mifepristone, RU486) and PGs have been successfully <strong>use</strong>d to induce ab<strong>or</strong>tion [11]. A combination <strong>of</strong> PGand <strong>aglepristone</strong> has shown <strong>the</strong> best results f<strong>or</strong> <strong>the</strong> treatment <strong>of</strong> canine CEH-P as recentlyrep<strong>or</strong>ted in two studies [12,13]. In <strong>the</strong> first study, an improvement in success rate <strong>of</strong> 22 and32% was found on Days 14 and 28, respectively, when compared <strong>with</strong> antiprogestin-treatedbitches [12]. Progesterone serum concentrations during <strong>the</strong>se combined protocols,although potentially <strong>use</strong>ful to describe <strong>the</strong>ir mechanism <strong>of</strong> action, have not been rep<strong>or</strong>ted.M<strong>or</strong>eover, fur<strong>the</strong>r w<strong>or</strong>k is necessary to determine <strong>the</strong> optimum administration <strong>of</strong> <strong>the</strong>secombined treatments.Theref<strong>or</strong>e, <strong>the</strong> objective <strong>of</strong> this study was two-fold: to compare <strong>the</strong> clinical efficacy andsafety <strong>of</strong> two different administration intervals f<strong>or</strong> cloprostenol combined <strong>with</strong> <strong>aglepristone</strong>f<strong>or</strong> <strong>the</strong> treatment <strong>of</strong> open cervix CEH-P, and to describe <strong>the</strong> P 4 serum pr<strong>of</strong>iles bef<strong>or</strong>eand during treatment in this species.2. Materials and methods2.1. AnimalsFifteen mixed and purebred bitches, ranging from 16 months to 15 years <strong>of</strong> age,weighing 4–50 kg, <strong>with</strong> open cervix CEH-P (defined as an enlarged fluid-filled uterus andvaginal discharge) were recruited and included in this study. Diagnosis <strong>of</strong> CEH-P wasconfirmed by routine uterine ultrasound findings [14]. All <strong>the</strong> bitches had serum urea andcreatinine
C. Gobello et al. / Theriogenology 60 (2003) 901–908 9032.2. ProcedureThe bitches were randomly allocated to one <strong>of</strong> <strong>the</strong> following groups: Treatment I(n ¼ 8): <strong>aglepristone</strong> (Alizine 1 , Virbac, Carros, France) was administered at 10 mg/kg,s.c., on Days 1, 3, 8, and 15 (if not cured) and cloprostenol (Estrumate 1 , Schering Plough,Bs. As, Argentina) far from feeding time was administered at <strong>the</strong> dose <strong>of</strong> 1 mg/kg, s.c., onDays 3 and 8; <strong>or</strong> Treatment II (n ¼ 7): <strong>the</strong> bitches received <strong>the</strong> same treatment <strong>with</strong><strong>aglepristone</strong> as f<strong>or</strong> Treatment I, but <strong>the</strong> cloprostenol (same dose) was administered in <strong>the</strong>same way on Days 3, 5, 8, 10, 12, and 15 (if not cured). Day 1 was considered as <strong>the</strong> day <strong>of</strong>presentation <strong>of</strong> <strong>the</strong> bitch.A combination <strong>of</strong> amoxycillin–clavulanate at 12.5 mg/kg (bid p.o., Clavamox 1 ,Pfizer,Bs. As, Argentina) and supp<strong>or</strong>tive hydration were administered during both <strong>the</strong>rapeuticprotocols. Bef<strong>or</strong>e <strong>the</strong> beginning <strong>of</strong> <strong>the</strong> treatments on Day 1 and <strong>the</strong>n on Days 3, 8, 15, and29 (if not cured), all bitches were evaluated f<strong>or</strong> body weight and temperature, hydration,an<strong>or</strong>exia, polyuria/polydipsia, uterus total, and lumen diameters assessed by ultrasonography(Pie Medical S100, 5 MHz transducer, Maastricht, The Ne<strong>the</strong>rlands), and vulvardischarge. On Days 1, 8, 15, and 29 (if not cured), blood samples were taken f<strong>or</strong> hemogramand serum P 4 concentrations (Coat-A-Count, DPC 1 , Los Angeles, CA) determinations.Animals were observed f<strong>or</strong> possible side effects during <strong>the</strong> treatments. All <strong>the</strong> bitches werefollowed up to <strong>the</strong>ir next estrous cycle.2.3. Statistical analysesCateg<strong>or</strong>ical data f<strong>or</strong> <strong>the</strong> frequency <strong>of</strong> bitches achieving clinical success (defined asrecovery to general health and ultrasonographic observation <strong>of</strong> n<strong>or</strong>mal uterus) and sideeffects ei<strong>the</strong>r f<strong>or</strong> Treatments I and II, <strong>or</strong> f<strong>or</strong> bitches <strong>with</strong> initial basal <strong>or</strong> nonbasal P 4 serumconcentrations were analyzed by PROC FREQ [15] on Days 15 <strong>or</strong> 29 (bitches not cured onDay 15). F<strong>or</strong> this purpose, P 4 serum concentrations on Day 1 were categ<strong>or</strong>ized as basal <strong>or</strong>nonbasal (< <strong>or</strong> 1.2 ng/ml, respectively).Percent change <strong>of</strong> serum P 4 concentrations ((final value [Days 8, 15, <strong>or</strong> 29] initial value[Day 1]/initial value) 100) was analyzed by least-squares analysis <strong>of</strong> variance using <strong>the</strong>General Linear Model procedure PROC GLM [15]. The ma<strong>the</strong>matical model included <strong>the</strong>main effects <strong>of</strong> treatment (I <strong>or</strong> II) and day (8, 15, <strong>or</strong> 29) and <strong>the</strong> treatment by dayinteraction. Descriptive statistics <strong>of</strong> all parameters assessed were analyzed by PROCMEANS [15] and expressed as LSM S:E:M: The level <strong>of</strong> significance was set atP < 0:05.3. ResultsAll bitches in Treatments I (8/8) and II (7/7) achieved treatment success ei<strong>the</strong>r on Day 15(6/8 f<strong>or</strong> Treatment I and 4/7 f<strong>or</strong> Treatment II) <strong>or</strong> 29 (2/8 f<strong>or</strong> Group I and 3/7 f<strong>or</strong> Treatment II)<strong>of</strong> <strong>the</strong> protocols. No significant differences in achieving success was found betweentreatments <strong>or</strong> initial P 4 concentrations ei<strong>the</strong>r on Day 15 <strong>or</strong> 29. None <strong>of</strong> <strong>the</strong> bitches showedei<strong>the</strong>r systemic <strong>or</strong> local side effects in relation to <strong>the</strong> treatment (0/15).
904 C. Gobello et al. / Theriogenology 60 (2003) 901–908Vulvar discharge was increased in all <strong>the</strong> bitches <strong>with</strong>in <strong>the</strong> 24–48 h after <strong>the</strong> firstadministration <strong>of</strong> <strong>aglepristone</strong> <strong>with</strong> an improvement in general health condition. Bodytemperature, hydration, appetite, and polyuria/polydipsia began to improve markedly ton<strong>or</strong>malcy from Day 3 in both groups. Hemogram parameters had a clear tendency towardn<strong>or</strong>mal values at <strong>the</strong> end <strong>of</strong> <strong>the</strong> treatments, being <strong>the</strong> white blood cells <strong>with</strong>in physiologicalrange at that time (Fig. 1). Uterine diameters diminished to n<strong>or</strong>mal size and <strong>the</strong> lumen wasundetectable <strong>or</strong> <strong>with</strong>out contents on Days 15 <strong>or</strong> 29 in both groups (Fig. 2).Progesterone serum concentrations bef<strong>or</strong>e and during Treatments I and II in bitchesei<strong>the</strong>r <strong>with</strong> basal <strong>or</strong> nonbasal initial P 4 are represented in Fig. 3. Progesterone showed adecreasing tendency in three <strong>of</strong> <strong>the</strong> four subgroups.A significant interaction between day and treatment was found f<strong>or</strong> P 4 percentage changewhen all <strong>the</strong> bitches were considered toge<strong>the</strong>r and when only <strong>the</strong> bitches <strong>with</strong> nonbasalinitial P 4 concentrations (n ¼ 9) were analyzed (P > 0:05). The number <strong>of</strong> bitches (n ¼ 6)<strong>with</strong> basal initial P 4 concentrations was statistically insufficient to be analyzed.Redevelopment <strong>of</strong> CEH-P in <strong>the</strong> next estrous cycle occurred in 3/15 old bitches (7–15years old); two <strong>of</strong> <strong>the</strong>se had had m<strong>or</strong>e than two previous episodes <strong>of</strong> CEH-P. One bitch wasovariohysterectomized bef<strong>or</strong>e her next cycle. Nonrecurrence in <strong>the</strong> next cycle occurred in11/15 bitches; four <strong>of</strong> <strong>the</strong>se were treated <strong>with</strong> amoxicillin during <strong>the</strong> next open cervixperiod (proestrus and estrus). One (2 years old) <strong>of</strong> <strong>the</strong>se four bitches was mated andwhelped a n<strong>or</strong>mal litter.Fig. 1. Least square means <strong>of</strong> <strong>the</strong> white blood cells (WBC) <strong>of</strong> 15 bitches suffering cystic endometrialhyperplasia—pyometra complex treated <strong>with</strong> two combined protocols <strong>of</strong> PG and <strong>aglepristone</strong> bef<strong>or</strong>e and duringtreatments. No significant differences in WBC were found between treatment, so <strong>the</strong>y were represented toge<strong>the</strong>r.Bars on symbols represent <strong>the</strong> c<strong>or</strong>responding S.E.M.
C. Gobello et al. / Theriogenology 60 (2003) 901–908 905Fig. 2. Least square means <strong>of</strong> uterine total and lumen diameters assessed by ultrasonography <strong>of</strong> <strong>the</strong> sameanimals (n ¼ 15) bef<strong>or</strong>e and during <strong>the</strong> treatments. Bars on symbols represent <strong>the</strong> c<strong>or</strong>responding S.E.M.Fig. 3. Least square means <strong>of</strong> serum P 4 concentrations <strong>of</strong> <strong>the</strong> same animals (n ¼ 15) divided into four subgroupsacc<strong>or</strong>ding to treatment (I <strong>or</strong> II) and initial (Day 1) P 4 concentrations (basal <strong>or</strong> nonbasal, < <strong>or</strong> 1.2 ng/ml,respectively) bef<strong>or</strong>e and during treatment. Bars on symbols represent <strong>the</strong> c<strong>or</strong>responding S.E.M.
906 C. Gobello et al. / Theriogenology 60 (2003) 901–9084. DiscussionThe prop<strong>or</strong>tion <strong>of</strong> bitches <strong>with</strong> initial basal P 4 concentrations in <strong>the</strong> present trial washigher than that rep<strong>or</strong>ted in two previous studies [3,12]. Although this finding was probablyincidental, it does confirm that this complex can become clinically evident ei<strong>the</strong>r duringdiestrus <strong>or</strong> anestrus [1,6].In line <strong>with</strong> a recent study but in contradiction <strong>with</strong> a previous one, in which only<strong>aglepristone</strong> was <strong>use</strong>d, no relationship between initial basal P 4 concentrations andtreatment success was found in this study [12,16].Some bitches were cured <strong>with</strong>out achieving basal P 4 serum concentrations at <strong>the</strong> end <strong>of</strong><strong>the</strong> treatments. M<strong>or</strong>eover, pregnancy termination <strong>with</strong> <strong>aglepristone</strong> in <strong>the</strong> bitch occurs in<strong>the</strong> presence <strong>of</strong> high P 4 serum concentrations [17]. These findings seem to confirm thatantiprogestins decrease intrauterine P 4 through <strong>the</strong> number <strong>or</strong> sensitivity <strong>of</strong> P 4 recept<strong>or</strong>sand not through <strong>the</strong> serum concentrations <strong>of</strong> this h<strong>or</strong>mone [12]. The initial serum rise(on Day 8) <strong>of</strong> a nonbasal group could be explained by <strong>the</strong> blocking <strong>of</strong> uterine recept<strong>or</strong>s and<strong>the</strong> consequent elevation <strong>of</strong> P 4 in blood. Ecbolic PG effect could have also contributed tosuccess in <strong>the</strong>se cases.M<strong>or</strong>e difficult to explain is <strong>the</strong> clinical improvement in bitches <strong>with</strong> basal P 4 concentrationsthroughout treatments. Although <strong>the</strong> uterotonic effect <strong>of</strong> PG could have ca<strong>use</strong>d<strong>the</strong> success in <strong>the</strong>se cases, clinical improvement and <strong>the</strong> increase in <strong>the</strong> vaginal dischargewas seen bef<strong>or</strong>e <strong>the</strong> first treatment <strong>with</strong> PG on Day 3.Although in <strong>the</strong> present study, cloprostenol was administered at 48 h <strong>or</strong> longer intervals,<strong>the</strong> results on Day 15 (6/8 and 4/7 f<strong>or</strong> Treatments I and II, respectively) were better thanthose rep<strong>or</strong>ted in ano<strong>the</strong>r study (50%), using <strong>the</strong> same drug and doses on a daily basis [12].In <strong>the</strong> current study, based on two treatment protocols f<strong>or</strong> cloprostenol, <strong>the</strong> number <strong>of</strong>treatments did not seem to be crucial in <strong>the</strong> resolution <strong>of</strong> <strong>the</strong> clinical cases, although a largernumber <strong>of</strong> treated bitches would be necessary to ei<strong>the</strong>r confirm <strong>or</strong> reject this initial finding.Conversely, <strong>the</strong> number <strong>of</strong> PG treatments seemed to influence P 4 serum changes during <strong>the</strong>different days <strong>of</strong> <strong>the</strong> study.In disagreement <strong>with</strong> two recent studies [2,12], but in line <strong>with</strong> a previous rep<strong>or</strong>t inwhich only <strong>aglepristone</strong> was <strong>use</strong>d [5], nosideeffectswererep<strong>or</strong>tedinthisstudy.Theadministration <strong>of</strong> a low dose <strong>of</strong> a potent PG at a time far from feeding could haveaccounted f<strong>or</strong> <strong>the</strong>se differences. M<strong>or</strong>eover, all <strong>the</strong> bitches were in a better conditionon <strong>the</strong> day <strong>of</strong> <strong>the</strong> first cloprostenol injection (Day 3) than at <strong>the</strong> beginning <strong>of</strong> <strong>the</strong>treatments.In this study, recurrence rate was higher than in a similar previous study in which n<strong>or</strong>edevelopment appeared in 12 bitches that were followed up to <strong>the</strong> next estrous cycle [12],and also higher than in one study in which only <strong>aglepristone</strong> was <strong>use</strong>d [16]. The higherrecurrence rate may be due to <strong>the</strong> advanced age <strong>of</strong> most <strong>of</strong> <strong>the</strong> bitches <strong>use</strong>d in <strong>the</strong> presentstudy. Conversely, <strong>the</strong> present results were in <strong>the</strong> lower limit range <strong>of</strong> recurrence f<strong>or</strong> bitchestreated only <strong>with</strong> PG (10–77%) [6,7]. These findings suggest that <strong>the</strong> uterotonic effect <strong>of</strong>PG does not reverse CEH and many dogs may have a decrease in clinical signs towardssubclinical levels which <strong>the</strong>n becomes undetectable. We hypo<strong>the</strong>sized that antiprogestintreatment might better manage endometrial abn<strong>or</strong>malities depending on <strong>the</strong> depth <strong>of</strong>inflammat<strong>or</strong>y infiltration measured using Dow’s classification [18]. Conversely, a study in
C. Gobello et al. / Theriogenology 60 (2003) 901–908 907which histological examination <strong>of</strong> uteri was carried out revealed no differences between 6days-antiprogestin-treated and control bitches [3].Consistent <strong>with</strong> a previous rep<strong>or</strong>t [5], fertility after treatment did not seem to be affectedby endometrial pathology in <strong>the</strong> young bitch that was mated. This young bitch was one <strong>of</strong><strong>the</strong> most representative <strong>of</strong> <strong>the</strong> population f<strong>or</strong> which <strong>the</strong>se combined protocols aremainly intended in clinical practice. Fur<strong>the</strong>r studies including larger number <strong>of</strong> bitches<strong>of</strong> different ages, <strong>with</strong> <strong>or</strong> <strong>with</strong> out past episodes <strong>of</strong> CEH-P are required to evaluate fertilityafter treatment.We concluded that <strong>the</strong>se two combined protocols proved to be efficient and safe inreversing clinical signs and abn<strong>or</strong>mal uterine ultrasonographic findings in bitches sufferingCEH-P, independently <strong>of</strong> initial P 4 serum concentrations. Also, <strong>the</strong> number <strong>of</strong> PG administrationsseemed to have an effect on P 4 serum concentrations throughout treatments.Fur<strong>the</strong>r w<strong>or</strong>k <strong>with</strong> a larger number <strong>of</strong> bitches is necessary to confirm <strong>the</strong>se initial findings.AcknowledgementsThe auth<strong>or</strong>s thank Virbac, France f<strong>or</strong> its supp<strong>or</strong>t and Alizine 1 supply, Schering Plough,Argentina f<strong>or</strong> Estrumate 1 supply and all <strong>the</strong> owners who participated in this study.References[1] Dow C. The cystic hyperplasia—pyometra complex in bitch. Vet Rec 1957;69:1409–15.[2] van der H<strong>or</strong>st CJ, Vogel F. Some effects <strong>of</strong> PG F2a on c<strong>or</strong>p<strong>or</strong>a lutea and on <strong>the</strong> uterus in <strong>the</strong> cycling dog.Tijdsschr Dierge-neeskd 1977;102:117–23.[3] Blendinger K, Bostedt H, H<strong>of</strong>fmann B. H<strong>or</strong>monal effects <strong>of</strong> <strong>the</strong> <strong>use</strong> <strong>of</strong> an antiprogestin in bitches <strong>with</strong>pyometra. J Reprod Fertil Suppl 1997;51:317–25.[4] Noakes DE, Dhaliwal GK, England GC. Cystic endometrial hyperplasic/pyometra in dogs: a review <strong>of</strong> <strong>the</strong>ca<strong>use</strong>s and pathogenesis. J Reprod Fertil Suppl 2001;57:395–406.[5] Breitkopt M, H<strong>of</strong>fmann B, Bostedt H. Treatment <strong>of</strong> pyometra in bitches <strong>with</strong> an antiprogestin. J ReprodFertil Suppl 1997;51:327–31.[6] Renton JP, Boyd JS, Harvey MJ. Observation <strong>of</strong> <strong>the</strong> treatment and diagnosis <strong>of</strong> open pyometra in <strong>the</strong> bitch.J Reprod Fertil Suppl 1993;47:465–9.[7] Nelson RW, Feldman EC, Stabenfeldt GH. Treatment <strong>of</strong> canine pyometra <strong>with</strong> PG F2a. J Am Vet MedAssoc 1982;181:899–903.[8] Tainturier D, Treboz D. Traitement del la metrite chronique de la chienne para un analogue de la F2a. PratMed Chir Anim Comp 1985;20:239–44.[9] H<strong>of</strong>fmann B, Schuler G. Recept<strong>or</strong> blockers—general aspects <strong>with</strong> respect to <strong>the</strong>ir <strong>use</strong> in domestic animalreproduction. Anim Reprod Sci 2000;60/61:295–312.[10] Philibert D. RU 46534. Affinité relative de liaison pour les récepteurs stéroïdiens—activité antiprogestéronein vivo. Rapp<strong>or</strong>t d’étude interne Roussel Uclaf 1994; pp. 4.[11] Cadepond F, Ulmann A, Beaulieu EE. RU 486 (mifepristone): mechanism <strong>of</strong> action and clinical <strong>use</strong>s. AnnRev Med 1997;48:129–56.[12] Fieni F, Bruyas D, Tainturier D, Battut I. <strong>Clinical</strong> <strong>use</strong> <strong>of</strong> antiprogestins in <strong>the</strong> treatment <strong>of</strong> metrits/pyometra in <strong>the</strong> bitch. In: Proceedings <strong>of</strong> <strong>the</strong> Fifth Annual Conference <strong>of</strong> <strong>the</strong> European Society <strong>of</strong>Domestic Animal Reproduction. Vienna, Austria; 2001.[13] Gobello C, C<strong>or</strong>rada Y, Castex G, Klima L, Rodríguez R, Giannoni M. A study <strong>of</strong> two combined protocols<strong>of</strong> <strong>aglepristone</strong> and cloprostenol to treat open cervix pyometra in <strong>the</strong> bitch. In: Proceedings <strong>of</strong> <strong>the</strong> AnnualSymposium <strong>of</strong> European Society <strong>of</strong> Small Animal Reproduction. Liege, Belgium; 2002. p. 130–1.
908 C. Gobello et al. / Theriogenology 60 (2003) 901–908[14] Yeager AE, Concannon P. Ultrasonography <strong>of</strong> <strong>the</strong> reproductive tract <strong>of</strong> <strong>the</strong> female dog and cat. In:Bonagura JD, Kirk KW, edit<strong>or</strong>s. Current veterinary <strong>the</strong>rapy, vol. XII. Philadelphia: Saunders; 1995.p. 1040–52.[15] SAS Institute Inc., SAS/STAT 1 . User’s guide, version 6, vol. 189. 4th ed. Cary, NC: SAS Institute Inc.;1989.[16] H<strong>of</strong>fmann B, Lemmer W, Bostedt H, Failing K. Application <strong>of</strong> <strong>the</strong> antiprogestin <strong>aglepristone</strong> f<strong>or</strong> <strong>the</strong>conservative treatment <strong>of</strong> pyometra in <strong>the</strong> dog. Tierarztl Prax 2000;28:323–9.[17] Fieni F, Martal J, Marnet PG, Siliart B, Bernard F, Riou M, et al. H<strong>or</strong>monal variations in bitches after early<strong>or</strong> mid pregnancy termination <strong>with</strong> <strong>aglepristone</strong> (Ru 534). J Reprod Fertil Suppl 2001;57:243–8.[18] Dow C. The cystic hyperplasia—pyometra complex in <strong>the</strong> bitch. J Comp Pathol 1959;69:237–50.
Close this window to return to IVISwww.ivis.<strong>or</strong>gABSTRACTS6 th International Symposium onCanine and Feline Reproduction&6 th Biennial EVSSAR CongressEuropean Veterinary Society f<strong>or</strong> Small Animal Reproduction"Reproductive biology and medicine <strong>of</strong>domestic and exotic carniv<strong>or</strong>es"University <strong>of</strong> Veterinary Sciences9 th – 11 th July 2008Vienna, AustriaEdit<strong>or</strong>s: G. England, P. Concannon, S. Schäfer-SomiReprinted in IVIS <strong>with</strong> <strong>the</strong> permission <strong>of</strong> <strong>the</strong> Symposium Organizers
Reprinted in IVIS <strong>with</strong> <strong>the</strong> permission <strong>of</strong> <strong>the</strong> Symposium OrganizersClose this window to return to IVISDIAGNOSIS OF ENDOMETRITIS IN THE INFERTILE BITCH: A NEWAPPROACHFontaine E.(1), Levy X.(1), Grellet A.(1), Luc A.(1), Bernex F.(1), Fontbonne A.(1)(1) Ecole Nationale Vétérinaire, 7 avenue du Général de Gaulle, 94700 Maisons-Alf<strong>or</strong>t,France E-mail : efontaine@vet-alf<strong>or</strong>t.frIntroduction - Very few rep<strong>or</strong>ts have been made about endometritis in <strong>the</strong> bitch; itsrelationship <strong>with</strong> failure to conceive remains unclear. It may be due to <strong>the</strong> difficulty to collectuterine samples f<strong>or</strong> fur<strong>the</strong>r investigations. Today, transcervical ca<strong>the</strong>terization by vaginalendoscopy allows us to evaluate <strong>the</strong> endometrium in infertile bitches. Diagnosis criteria weredetermined acc<strong>or</strong>ding to previous studies on uterine cytology and bacteriology[1-3]. The aim<strong>of</strong> our study was to test <strong>the</strong> efficiency <strong>of</strong> this technique to diagnose endometritis in <strong>the</strong> bitchand fur<strong>the</strong>rm<strong>or</strong>e, to evaluate <strong>the</strong> incidence <strong>of</strong> endometritis <strong>with</strong>in infertile bitches.Material and methods - 26 bitches presented f<strong>or</strong> infertility in Alf<strong>or</strong>t Veterinary College wereincluded in this study. Classical infertility investigations were not indicative: time <strong>of</strong> matinghad been c<strong>or</strong>rectly determined by progesterone assays, male <strong>use</strong>d had sired successfully,clinical examination and genital ultrasonography revealed no abn<strong>or</strong>malities. A vaginalendoscopy was perf<strong>or</strong>med and presence <strong>of</strong> vaginitis and cervical discharge was evaluated. Inall bitches, a transcervical ca<strong>the</strong>terization was perf<strong>or</strong>med using a human ureteral ca<strong>the</strong>ter(Ureteral CRU® ch.6 223602). Flushing <strong>of</strong> <strong>the</strong> uterine lumen was realized <strong>with</strong> sterile salinefluid (NaCl 0.9%, 2mL/10 kg instilled <strong>the</strong>n reabs<strong>or</strong>bed) and collected samples were <strong>use</strong>d f<strong>or</strong>uterine cytology and aerobic bacteriology (Amies agar gel <strong>with</strong> charcoal).The n<strong>or</strong>mal leucocyte sc<strong>or</strong>e, which reflected absolute and relative numbers <strong>of</strong> leucocytesversus endometrial cells, was defined by Watts [3]. All cytologies exceeding n<strong>or</strong>mal sc<strong>or</strong>eswere considered as endometritis.If cytology pointed out an inflammat<strong>or</strong>y state c<strong>or</strong>related to bacterial heavy growth, <strong>the</strong> bitchwas considered to suffer from infectious endometritis. A cytologic inflammat<strong>or</strong>y state <strong>of</strong> <strong>the</strong>uterus in <strong>the</strong> absence <strong>of</strong> bacterial growth was considered to be a non infectious endometritis.Results - Fourteen different breeds were concerned, from Shi-Tsu (5kg) to Mastiff (96kg).Bitches were mainly large and giant breeds and were aged 1 to 7 years (mean 4years/SD=1.5). Uterine investigations were realized in dioestrus (21 bitches), anoestrus (4)and pro-oestrus (1). 10/26 bitches suffered from endometritis. Among <strong>the</strong>m, seven sufferedfrom infectious endometritis. Three bitches had a bacterial heavy growth <strong>with</strong>out cytologicabn<strong>or</strong>malities and we considered that it was a sign <strong>of</strong> contamination by <strong>the</strong> n<strong>or</strong>mal vaginalfl<strong>or</strong>a. In 4/10 bitches suffering from endometritis, a cervical discharge was observed byvaginal endoscopy. Surprisingly, ano<strong>the</strong>r bitch negative towards cytological andbacteriological criteria was found to show also a purulent cervical discharge. A clear cervicalinflammation was also observed in 3/7 bitches suffering from infectious endometritis. Signs<strong>of</strong> vaginitis were visualised in two bitches, both <strong>of</strong> <strong>the</strong>m suffering from infectious (1/10) andnon infectious (1/10) endometritis. One bitch suffering from infectious endometritis presentedsigns <strong>of</strong> vaginitis, cervicitis and cervical discharge. Infectious endometritis was diagnosedduring dioestrus (6/7) and prooestrus (1/7). Non infectious endometritis was diagnosed indioestrus (2/3) and anoestrus (1/3). Four bitches f<strong>or</strong> which endoscopy was perf<strong>or</strong>med indioestrus encountered pyometra after flushing, two <strong>of</strong> which were not initially suffering fromendometritis. Five bitches suffering from endometritis were fur<strong>the</strong>r bred after treatmentcombining antibiotics +/- <strong>aglepristone</strong> (Alizine ®) and <strong>the</strong>y all went pregnant. 4/5 bitcheswhelped n<strong>or</strong>mally and 1/5 had a premature parturition at 59 days <strong>of</strong> pregnancy.Proceedings <strong>of</strong> <strong>the</strong> 6th International Symposium on Canine and Feline Reproduction &6th Biannual European Veterinary Society f<strong>or</strong> Small Animal Reproduction Congress2008 - Vienna, Austria
Reprinted in IVIS <strong>with</strong> <strong>the</strong> permission <strong>of</strong> <strong>the</strong> Symposium OrganizersClose this window to return to IVISDiscussion - In our study, endometritis seemed to have in most cases an infectious <strong>or</strong>igin(70% <strong>of</strong> affected bitches), but <strong>the</strong>se results may be underestimated, as some o<strong>the</strong>r pathogens(anaerobic bacteria, mycoplasms, fungi), were not searched f<strong>or</strong>. Dioestrus seems to be <strong>the</strong> bestperiod to diagnose endometritis. However, <strong>the</strong> endometrium impregnated <strong>with</strong> progesterone ism<strong>or</strong>e sensitive and despite all precautions, this could explain that we got induced pyometraafter endoscopy. Early anoestrus may be a m<strong>or</strong>e adequate period to perf<strong>or</strong>m thoseinvestigations, as progesterone impregnation is over. One bitch showed a purulent cervicaldischarge <strong>with</strong>out a positive endometrial cytology. Our diagnosis technique lacks comparison<strong>with</strong> histology, which should be done to ensure a m<strong>or</strong>e accurate diagnosis. Indeed, impact <strong>of</strong>endometritis is underestimated. Endometritis, in our opinion, should be investigated in eachunexplained case <strong>of</strong> infertility in bitches. The technic <strong>use</strong>d here seems reliable: all bitchestreated were bred successfully whereas previous infertility treatments had not succeeded.Defining m<strong>or</strong>e accurate criteria will improve <strong>the</strong> efficiency <strong>of</strong> this non invasive technique thatcould help to treat unexplained infertility cases.References(1). Watts JR, W.P., Investigating uterine disease in <strong>the</strong> bitch: uterine cannulation f<strong>or</strong>cytology, microbiology and hysteroscopy. J. Small Anim. Pract., 1995. 35: p. 201-206.(2). Watts JR, W.P., Whi<strong>the</strong>ar KC, Uterine, cervical and vaginal micr<strong>of</strong>l<strong>or</strong>a <strong>of</strong> <strong>the</strong> n<strong>or</strong>malbitch throughout <strong>the</strong> reproductive cycle. J. Small Anim. Pract., 1996. 37: p. 54-60.(3). Watts JR; Wright, P., Endometrial cytology <strong>of</strong> <strong>the</strong> n<strong>or</strong>mal bitch throughout <strong>the</strong>reproductive cycle. J. Small Anim. Pract., 1998. 39: p. 2-9.Proceedings <strong>of</strong> <strong>the</strong> 6th International Symposium on Canine and Feline Reproduction &6th Biannual European Veterinary Society f<strong>or</strong> Small Animal Reproduction Congress2008 - Vienna, Austria
CLINICAL UPDATEMedical Treatment <strong>of</strong> PyoD1etraand<strong>the</strong> Use <strong>of</strong> AglepristoneSteven Metcalfe and Claudia VischeraApplecross Veterinary Hospital9 Sleat Rd, Canning Bridge, WA 6153aTechnicalServices Manager - Companion AnimalsVirbac Australia, 15 Pritchard Place, Peakhurst, NSW 2010Pyometra is a common disease in bitches over eightyears <strong>of</strong> age. The disease generally occurs during <strong>the</strong> dioestrousphase <strong>of</strong> <strong>the</strong> reproductive cycle (Blendiger et al1997). Currently, it is generally accepted that cysticendometrial hyperplasia(CEH)-pyometra complex isvery closely associated <strong>with</strong> increased circulating bloodprogesterone concentrations (Noakes et al 2001).Progesterone promotes multiplication <strong>of</strong> <strong>the</strong> glandularcells in <strong>the</strong> uterus, which may result in cysticendometrial hyperplasia. Progesterone also depresseslocal mechanisms that clear bacteria from <strong>the</strong> genitaltract. Infections <strong>with</strong> E. coli, ascending <strong>the</strong> urogenitaltract, from <strong>the</strong> bowel, have been identified as <strong>the</strong> mostcommon bacterial component <strong>of</strong> <strong>the</strong> canine pyometracomplex (Hagman & Kunh, 2002, Wadas et al 1996).Pyometra is associated <strong>with</strong> inflammation <strong>of</strong> <strong>the</strong>endometrium <strong>with</strong> <strong>the</strong> accumulation <strong>of</strong> purulent and/<strong>or</strong>haem<strong>or</strong>rhagic secretions in <strong>the</strong> uterus. Depending on <strong>the</strong>degree <strong>of</strong> cervical opening, a vaginal discharge may bepresent. Without treatment <strong>the</strong> infection has highm<strong>or</strong>bidity and m<strong>or</strong>tality due to endotoxaemia andsepticaemia (Hagman et al2006).Surgical treatment <strong>of</strong> pyometra by ovariohysterectomy iscurative. Anaes<strong>the</strong>tic and surgical risk may be increaseddue to <strong>the</strong> systemic effects <strong>of</strong> pyometra and <strong>the</strong>se mustbe addressed bef<strong>or</strong>e, during and after surgery.Due to <strong>the</strong> luteolytic and uterotonic properties <strong>of</strong> prostaglandin-F2alpha (PGF2a), <strong>the</strong> repeated administration<strong>of</strong> PGF2a has been <strong>use</strong>d to treat pyometra (Gilbert et al1989, Meyers et al 1986). To avoid <strong>the</strong> risk <strong>of</strong> seriousside effects, prostaglandins are only recommended f<strong>or</strong><strong>use</strong> in young bitches <strong>with</strong> no liver, kidney <strong>or</strong>cardiovascular disease. The duration <strong>of</strong> treatment and<strong>the</strong> onset <strong>of</strong> side "effects related to <strong>the</strong> action <strong>of</strong> <strong>the</strong>prostaglandins on smooth muscle, causing diarrhoea,salivation and vomiting, do not make it an ideal singlemodality treatment option f<strong>or</strong> pyometra.Ph: 08 93647666. Fax: 08 93611662Email: applecrossvet@aapt.net.auGiven <strong>the</strong> maj<strong>or</strong> role <strong>of</strong> progesterone in inducing CEHpyometracomplex, anti-progestins such as <strong>aglepristone</strong>l,could be expected to be <strong>use</strong>ful in a medical treatmentprotocol. Aglepristone is a potent progesterone antagonist,<strong>with</strong> an affinityf<strong>or</strong> progesteronerecept<strong>or</strong>s in vitrothree times greater than that <strong>of</strong> progesterone.Aglepristone binds to uterine progesterone recept<strong>or</strong>s<strong>with</strong>out producing <strong>the</strong> biological effects <strong>of</strong> progesterone.Aglepristone has been shown to effectively suppress <strong>the</strong>biological action <strong>of</strong> progesterone during gestation,interruptinggestation(Fieni et al1996, Galac et al 2000,"Fieni et al 200la), and causing cervical opening andinducing parturition (Fieni et al 200lb). The moleculehas been effectively <strong>use</strong>d in <strong>the</strong> treatment <strong>of</strong> uterineinfections associated <strong>with</strong> <strong>the</strong> presence <strong>of</strong> a high level <strong>of</strong>plasma progesterone (Blendiger et al 1997, Breitkopf etal1997, H<strong>of</strong>fman et al200l). Recent w<strong>or</strong>k has described<strong>the</strong> <strong>use</strong> <strong>of</strong> <strong>aglepristone</strong> to treat pyometra, f<strong>or</strong> a sh<strong>or</strong>t <strong>or</strong>medium term after <strong>the</strong> initial acute recovery (Trasch et al2003), including its combined <strong>use</strong> <strong>with</strong> cloprostenol(Gobello et al 2003).In a recent large clinical study (Fieni, 2006) <strong>the</strong> <strong>use</strong> <strong>of</strong><strong>aglepristone</strong>, alone and in combination <strong>with</strong> low doses <strong>of</strong>cloprostenol, was evaluated in <strong>the</strong> treatment <strong>of</strong> metritispyometra.Sixty-seven bitches, aged 8.2 :t 3.5 years,<strong>with</strong> a uterine infection were acc<strong>or</strong>dingly allocated intothree groups: group 1 - metritis (n=15); group 2 - openpyometra (n=35); and group 3 - closed pyometra (n=17).All bitches were injected subcutaneously three times<strong>with</strong> lOmg/kg <strong>of</strong> <strong>aglepristone</strong> on Days 1,2 and 8. It was<strong>the</strong> only treatment administered to bitches <strong>with</strong> metritis.In addition to this treatment, half <strong>the</strong> bitches <strong>with</strong> openand closed pyometra were injected daily from Day 3 toDay 7 <strong>with</strong> If.lglkg cloprostenoJ2 subcutaneously. Allpyometra bitches were concurrently treated <strong>with</strong>amoxicillinlclavulinic acid antibioties3. All bitches were1Alizin, Virbac2Estrumate, Schering-Plough Animal Health3Synulox, PfizerAust Vet Practit 36(4) December 2006 - 171
PYOMETRARESPONSE TO TREATMENT WITH AGLEPRISTONE WITH AND WITHOUT PROSTAGLANDINSSpecies Single Standard Standard + PG Extended Extended + PGBitches 3/5 (60.0) 27/31 (87.1) 2/3 (66.7) 4/5 (80.0) 1/1 (100.0)Queens 2/2 (100.0) 8/8 (100) (0) 1/1 (100.0) (0)TABLE 1: Number (%) <strong>of</strong> bitches and queens that achieved successful outcomes based on <strong>aglepristone</strong> treatment protocolsat Applecross VeterinaryHospital (2001-2006).closely monit<strong>or</strong>ed <strong>with</strong> regular clinical andgynaecological examinations and full blood counts. Theefficacy criteria were assessed as recovery <strong>of</strong> generalhealth, lack <strong>of</strong> vulvar discharge and lack <strong>of</strong> uterinelumen enlargement. If necessary an additional treatment<strong>with</strong> <strong>aglepristone</strong> was administered on Days 14 and 28.The final examination was on Day 90.At Day 90, 80.6% (54/67) <strong>of</strong> <strong>the</strong> bitches were curedincluding all <strong>of</strong> <strong>the</strong> bitches <strong>with</strong> metritis (15/15),receiving only <strong>aglepristone</strong>; <strong>the</strong> closed pyometra cases(17/17) had cervical opening <strong>with</strong>in 48 hours <strong>of</strong>receiving <strong>aglepristone</strong>. In <strong>the</strong> bitches <strong>with</strong> open <strong>or</strong>closed pyometra, additional treatment <strong>with</strong> cloprostenolfrom Days 3 to 7 significantly improved <strong>the</strong> globalsuccess rate at Day 90 to 84.4% (27/32) compared to60% (12/20) in bitches <strong>with</strong>out cloprostenol (p
Theriogenology 66 (2006) 1550–1556www.journals.elsevierhealth.com/periodicals/<strong>the</strong><strong>Clinical</strong> <strong>evaluation</strong> <strong>of</strong> <strong>the</strong> <strong>use</strong> <strong>of</strong> <strong>aglepristone</strong>, <strong>with</strong> <strong>or</strong><strong>with</strong>out cloprostenol, to treat cystic endometrialhyperplasia-pyometra complex in bitchesF. Fieni *Lab<strong>or</strong>at<strong>or</strong>y <strong>of</strong> Biotechnology and Pathology <strong>of</strong> Reproduction, National Veterinary School,BP 40706, 44307 Nantes Cedex 03, FranceAbstractThe aim <strong>of</strong> <strong>the</strong> study was to evaluate <strong>the</strong> efficacy <strong>of</strong> <strong>aglepristone</strong> (10 mg/kg on days 1, 2 and 8) f<strong>or</strong> <strong>the</strong> treatment <strong>of</strong> metritis <strong>or</strong>pyometra in bitches (n = 67) ei<strong>the</strong>r alone f<strong>or</strong> cases <strong>of</strong> metritis (n = 15), <strong>or</strong> in cases <strong>of</strong> pyometra (n = 52) <strong>with</strong> (n = 32) <strong>or</strong> <strong>with</strong>out(n = 20) <strong>the</strong> addition <strong>of</strong> low doses (1 mg/kg) <strong>of</strong> cloprostenol f<strong>or</strong> 5 days (days 3–7). Examinations perf<strong>or</strong>med on day 90, in addition todays 8, 14 and 28, determined that treatments had been curative in <strong>the</strong> long term in 54/67 bitches (80.6%). Bitches in whompyometra did not resolve, were given additional <strong>aglepristone</strong> on day 14 (n = 38) and day 28 (n = 20). Aglepristone alone wascurative in 15/15 bitches <strong>with</strong> metritis. In 17/17 bitches <strong>with</strong> closed pyometra, cervical opening occurred <strong>with</strong>in 48 h <strong>of</strong> <strong>aglepristone</strong>administration. Amongst <strong>the</strong> 52 bitches <strong>with</strong> open (n = 35) <strong>or</strong> closed (n = 17) pyometra, <strong>the</strong> additional treatment <strong>with</strong> cloprostenolfrom days 3 to 7, significantly improved <strong>the</strong> overall success rate at day 90, which was 27/32 (84.4%), compared to 12/20 (60.0%) inbitches <strong>with</strong>out cloprostenol (P < 0.05). The leucocyte count and plasma progesterone concentrations significantly decreased over<strong>the</strong> course <strong>of</strong> treatment. Thirteen <strong>of</strong> 15 bitches in whom plasma progesterone concentrations were initially low (
F. Fieni / Theriogenology 66 (2006) 1550–1556 1551kidney dysfunction <strong>or</strong> cardiac disease. Some auth<strong>or</strong>salso suggested that <strong>the</strong> cervix must be open and <strong>the</strong>uterus non-hypertrophied [5]. The duration <strong>of</strong> treatmentand <strong>the</strong> onset <strong>of</strong> side effects related to <strong>the</strong> action <strong>of</strong> <strong>the</strong>prostaglandins on smooth muscle (diarrhea, salivationand vomiting) make this a demanding course <strong>of</strong>treatment, which usually requires hospitalization <strong>of</strong><strong>the</strong> bitch.Given <strong>the</strong> maj<strong>or</strong> role <strong>of</strong> progesterone in inducingcystic endometrial hyperplasia-pyometra complex,antiprogestins such as <strong>aglepristone</strong> could be expectedto be <strong>use</strong>ful in a medical treatment protocol. Aglepristonehas been shown to effectively suppress <strong>the</strong>biological action <strong>of</strong> progesterone during gestation,interrupting gestation [6–8], causing cervical opening,and inducing parturition [9]. The molecule has beeneffectively <strong>use</strong>d in <strong>the</strong> treatment <strong>of</strong> uterine infectionsassociated <strong>with</strong> elevated plasma progesterone concentrations(n = 6, 7 and 31) [1,10,11]. Recent w<strong>or</strong>k hasdescribed <strong>the</strong> <strong>use</strong> <strong>of</strong> <strong>aglepristone</strong> to treat pyometra inbitches, in terms <strong>of</strong> <strong>the</strong> sh<strong>or</strong>t <strong>or</strong> medium term result after<strong>the</strong> initial acute recovery (n = 52) [12], and including itscombined <strong>use</strong> <strong>with</strong> cloprostenol (n =15)[13]. However,to be suitable f<strong>or</strong> medical <strong>use</strong> by practitioners, atreatment needs to be efficient, fast, and prescribed on<strong>the</strong> basis <strong>of</strong> immediate clinical findings, <strong>with</strong>out <strong>the</strong>need f<strong>or</strong> lengthy lab<strong>or</strong>at<strong>or</strong>y testing.The aim <strong>of</strong> this clinical study was to evaluate <strong>the</strong>efficacy and safety <strong>of</strong> <strong>the</strong> treatment <strong>of</strong> metritis/pyometrain bitches by <strong>the</strong> administration <strong>of</strong> <strong>aglepristone</strong> inbitches <strong>with</strong> various f<strong>or</strong>ms <strong>of</strong> infectious uterinediseases, that were presented to <strong>the</strong> clinics at <strong>the</strong>Veterinary School in Nantes, and to evaluate it incomparison <strong>with</strong> <strong>the</strong> administration <strong>of</strong> combined<strong>aglepristone</strong> and low dose cloprostenol. The lattertreatment strategy was designed to improve outcomesand hasten recovery <strong>with</strong>out <strong>the</strong> side effects usuallyinduced by prostaglandins in bitches <strong>with</strong> open <strong>or</strong>closed pyometra.2. Materials and methods2.1. AnimalsThis study involved 67 bitches <strong>of</strong> different breeds,aged 8.5 3.2 years, <strong>with</strong> ‘‘open’’ <strong>or</strong> ‘‘closed’’ f<strong>or</strong>ms <strong>of</strong>metritis <strong>or</strong> cystic endometrial hyperplasia-pyometracomplex. The diagnosis was confirmed by <strong>the</strong> observation<strong>of</strong> purulent <strong>or</strong> hem<strong>or</strong>rhagic vaginal dischargeassociated in some, but not all, cases <strong>with</strong> enlargement<strong>of</strong> <strong>the</strong> uterine lumen detected using uterine ultrasonography.Irrespective <strong>of</strong> <strong>the</strong>ir general health, all bitchestreated had a serum concentration <strong>of</strong> urea and creatinine<strong>of</strong> less than 0.6 g/L and 10 mg/L, respectively.2.2. ProcedureThe bitches were allocated into three groups basedon clinical observation: Group 1, metritis (putridvaginal discharge <strong>with</strong> no enlargement <strong>of</strong> <strong>the</strong> uterinelumen detected on uterine ultrasonography, n = 15);Group 2, open pyometra (putrid vaginal discharge wi<strong>the</strong>nlargement <strong>of</strong> <strong>the</strong> uterine lumen, n = 35) and Group 3,closed pyometra (enlargement <strong>of</strong> <strong>the</strong> uterine lumen<strong>with</strong>out vaginal discharge, n = 17).Treatment varied, depending on <strong>the</strong> clinical situation,but all <strong>the</strong> bitches received one subcutaneousinjection <strong>of</strong> 10 mg/kg body weight <strong>of</strong> <strong>aglepristone</strong>(Alizine 1 ; Virbac, Carros, France) once daily on days1, 2 and 8. This was <strong>the</strong> only treatment administered inbitches <strong>with</strong> metritis (Group 1). In addition to thistreatment, two-thirds <strong>of</strong> each group <strong>of</strong> <strong>the</strong> bitches <strong>with</strong>open (Group 2, n = 10/17) <strong>or</strong> closed (Group 3, n = 21/35) pyometra were given daily subcutaneous injectionsfrom days 3 to 7, <strong>with</strong> 1 mg/kg <strong>of</strong> cloprostenol(Estrumate 1 ; Schering-Plough, Levallois-Perret,France). Bitches <strong>with</strong> hyper<strong>the</strong>rmia <strong>or</strong> dehydrationand all bitches <strong>with</strong> closed pyometra received additionaltreatment, i.e. intravenous infusion <strong>of</strong> ringer lactate atday 1 and 24 mg/kg/day <strong>of</strong> amoxicillin-clavulanic acidfrom days 1 to 5 (Synulox 1 ; Pfizer, Paris, France).The bitches from all three groups were checked ondays 14, 28 and 90. Bitches in whom pyometra did notresolve, were given additional <strong>aglepristone</strong> on day 14(n = 38) and day 28 (n = 20). The efficacy criteria wererecovery <strong>of</strong> good general health, absence <strong>of</strong> uterinelumen enlargement and absence <strong>of</strong> vaginal discharge.At <strong>the</strong> beginning <strong>of</strong> <strong>the</strong> trial and at various stages during<strong>the</strong> study, <strong>the</strong> bitches underwent a general clinicalexamination, gynecological examination and an ultrasoundexamination <strong>of</strong> <strong>the</strong> uterus (Aloka Echo CameraSSD-500 <strong>with</strong> 5 MHz transducer; Aloka, Cergy St.Christophe, France). A blood sample was also takenfrom <strong>the</strong> jugular vein. Mean white and red blood cellcounts were measured using an impedance counter(MS9; Melet Schloesing Lab<strong>or</strong>atoire, Cergy-Pointoise,France). An automated biochemistry analyzer (BP144;Ph Diagnostics, Montpellier, France) was <strong>use</strong>d todetermine <strong>the</strong> plasma concentrations <strong>of</strong> urea andcreatinine via photospectrometry. Peripheral progesteroneconcentrations were measured using a commercialRIA kit (Diria-progk kit from Dias<strong>or</strong>in, Antony,France). The assay sensitivity was 0.3 nmol/L andassay specificity was 97.5%.
1552F. Fieni / Theriogenology 66 (2006) 1550–15562.3. Statistical <strong>evaluation</strong>Qualitative results, such as <strong>the</strong> success <strong>of</strong> <strong>the</strong>treatment, were rep<strong>or</strong>ted <strong>with</strong> a confidence interval <strong>of</strong>95%. Quantitative results were rep<strong>or</strong>ted as means S.D. Data were analyzed by Statview (SAS InstituteInc., Cary, NC, USA). Treatment efficacy and <strong>the</strong>clinical response <strong>of</strong> metritis/pyometra were comparedusing a Chi-square test. A Student-Fisher test was <strong>use</strong>dto compare <strong>the</strong> mean decrease in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong>uterine lumen, <strong>the</strong> mean leucocyte count and <strong>the</strong> meanperipheral plasma progesterone concentration betweentreatments at various times during <strong>the</strong> experiment.Values were considered statistically significant whenP < 0.05.3. ResultsWhen measuring efficacy at day 90, 54/67 bitcheswere cured (i.e. 80.6%, <strong>with</strong> a confidence interval range<strong>of</strong> 71.1–90.1%). The overall recovery rate was lower(P < 0.001) at day 14 (24/68, 35.3%) than at day 28 (46/67, 68.6%) and day 90 (54/67, 80.6%). The effectiveness<strong>of</strong> <strong>the</strong> treatment was not dependent on <strong>the</strong> clinicalf<strong>or</strong>m <strong>of</strong> uterine disease (Table 1).In bitches <strong>with</strong> metritis, treatment <strong>with</strong> <strong>aglepristone</strong>alone gave a high cure rate, <strong>with</strong> clinical resolution inover half <strong>of</strong> <strong>the</strong> bitches (9/15) <strong>with</strong>in 2 weeks and <strong>with</strong>in4 weeks f<strong>or</strong> <strong>the</strong> remainder <strong>with</strong>, one exception. Thebitch cured at day 90 had only a slight serous dischargeon day 28. This was visible by <strong>the</strong> clinician during <strong>the</strong>genital exam but not by <strong>the</strong> owner.<strong>Clinical</strong>ly, <strong>the</strong> administration <strong>of</strong> <strong>aglepristone</strong> incases <strong>of</strong> pyometra led to changes in <strong>the</strong> nature <strong>of</strong> <strong>the</strong>vaginal discharge, which changed from purulent, tomucous-like, bef<strong>or</strong>e finally becoming serous, <strong>with</strong> aconcurrent decrease in volume. The last clinical signrec<strong>or</strong>ded was self-cleaning <strong>of</strong> <strong>the</strong> vulval area by <strong>the</strong>bitch. F<strong>or</strong> all bitches <strong>with</strong> closed pyometra, cervicalopening was induced following <strong>the</strong> first two <strong>aglepristone</strong>treatments (18/18). The mean time to cervicalopening was 25.8 12.2 h. The sh<strong>or</strong>test time was 4 hafter <strong>the</strong> first administration <strong>of</strong> <strong>aglepristone</strong>; however,Table 1Number <strong>of</strong> bitches cured, at various stages in <strong>the</strong> trial, based on <strong>the</strong>f<strong>or</strong>m <strong>of</strong> uterine diseaseDay 14 Day 28 Day 90Metritis (%) 9/15 (60.0) 14/15 (93.3) 15/15 (100)Open pyometra (%) 13/35 (37.1) 20/35 (57.1) 26/35 (74.3)Closed pyometra (%) 2/18 (11.1) 12/17 (70.6) 13/17 (76.5)cervical opening was complete <strong>with</strong>in 48 h in all <strong>of</strong> <strong>the</strong>bitches. Cervical opening induced enabled <strong>the</strong> evacuation<strong>of</strong> large volumes <strong>of</strong> purulent discharge, which wasassociated <strong>with</strong> an immediate improvement in generalcondition and, in most cases, <strong>with</strong> increased appetite.F<strong>or</strong> bitches <strong>with</strong> open <strong>or</strong> closed pyometra, additionaltreatment <strong>with</strong> cloprostenol from days 3 to 7 improved<strong>the</strong> overall success rate at day 90 (P < 0.05); 27/32(84.4%) <strong>with</strong> cloprostenol versus 12/20 (60.0%) <strong>with</strong>outcloprostenol (Table 2). Recovery was accompanied by agradual decrease in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong> uterine lumen,which became non-detectable ultrasonographically. Themean decrease in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong> uterine lumen overtime depended on <strong>the</strong> treatment <strong>use</strong>d (Fig. 1) and wassignificantly greater between days 8 and 14 in bitchesreceiving <strong>the</strong> combined <strong>aglepristone</strong>–cloprostenol treatmentthan in those treated <strong>with</strong> <strong>aglepristone</strong> alone(84.8 20.7% versus 64.6 41.0%).The general condition <strong>of</strong> bitches suffering frommetritis was not altered; it remained good throughout <strong>the</strong>trial. Bitches suffering from open <strong>or</strong> closed pyometrapresented were depressed and an<strong>or</strong>exic in 41/53 (77.3%)and 34/53 (64.1%) cases, respectively. In all animalstreated, <strong>the</strong>re was a marked improvement in this criterionby <strong>the</strong> second day <strong>of</strong> treatment. On day 8, moderatelethargy was observed in 9 bitches (17.3%) and 14bitches (26.9%) showed loss <strong>of</strong> appetite. On day 15, allbitches still receiving treatment were in good generalcondition, <strong>with</strong> only one showing any loss <strong>of</strong> appetite. Noside effects were observed after treatment <strong>with</strong> cloprostenolin 15/33 bitches (45.5%). In <strong>the</strong> remainder, na<strong>use</strong>awas <strong>the</strong> most commonly observed side effect (12/33), andvomiting occurred in six bitches.None <strong>of</strong> <strong>the</strong> bitches had a noticeable change in redblood cell count. The mean white blood cell counts inbitches suffering from metritis were n<strong>or</strong>mal and,remained lower (P < 0.05) than <strong>the</strong> counts in bitches<strong>with</strong> open <strong>or</strong> closed pyometra (Fig. 2) throughout <strong>the</strong>trial. In bitches recovering from pyometra, a markeddecrease in leucocytosis was observed over <strong>the</strong> course<strong>of</strong> treatment. This mean decrease was significant on dayTable 2Number <strong>of</strong> bitches <strong>with</strong> open <strong>or</strong> closed pyometra (Group 1 + Group 2)cured by <strong>the</strong> administration <strong>of</strong> <strong>aglepristone</strong> alone compared to <strong>the</strong>combined administration <strong>of</strong> <strong>aglepristone</strong> + cloprostenolTreatment Day 14 Day 28 Day 90Aglepristone (%) 3/20 (15.0) 9/20 (45.3) 12/20 (60.0)Aglepristone +cloprostenol (%)12/33 (36.4) 23/32 (71.9) 27/32 (84.4)Difference in cure rate between <strong>the</strong> two treatments on day 90(P < 0.05).
F. Fieni / Theriogenology 66 (2006) 1550–1556 1553Fig. 1. Mean (S.E.M.) rates <strong>of</strong> decreases in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong> uterine lumen at various stages in <strong>the</strong> trial, in bitches <strong>with</strong> open <strong>or</strong> closed pyometra(Group 1 + Group 2) cured by <strong>the</strong> administration <strong>of</strong> <strong>aglepristone</strong> alone (n = 12), in comparison <strong>with</strong> those receiving a combination <strong>of</strong><strong>aglepristone</strong> + cloprostenol (n = 27). (*) Differences (P < 0.05).Fig. 2. Mean (S.E.M.) concentration <strong>of</strong> leucocytes at various stages in <strong>the</strong> trial, in bitches <strong>with</strong> metritis (n = 15), open pyometra (n = 26) <strong>or</strong> closedpyometra (n = 13) cured by treatment <strong>with</strong> <strong>aglepristone</strong> <strong>or</strong> <strong>aglepristone</strong> + cloprostenol. F<strong>or</strong> each day, <strong>the</strong> mean white blood cell count wassignificantly lower in cases <strong>of</strong> metritis than in cases <strong>of</strong> open <strong>or</strong> closed pyometra. In bitches <strong>with</strong> closed pyometra, <strong>the</strong> white blood cell count waslower at day 14 (P < 0.01) and at day 28 (P < 0.001) than at day 0.
1554F. Fieni / Theriogenology 66 (2006) 1550–1556Table 3Means (S.D.) plasma progesterone concentrations (nmol/L) in bitches <strong>with</strong> open <strong>or</strong> closed pyometra (Group 1 + Group 2) treated <strong>with</strong> <strong>aglepristone</strong>alone, compared to those treated <strong>with</strong> a combination <strong>of</strong> <strong>aglepristone</strong> + cloprostenolTreatment Day 1 Day 8 Day 14 Day 28Aglepristone (n = 20) 12.8 14.4 a 5.6 6.6 bx 4.8 5.1 b 3.3 4.2 bAglepristone + cloprostenol (n = 32) 19.3 11.6 a 15.08 10.5 ay 4.7 1.1 b 3.96 2.8 bWithin a row, values <strong>with</strong> different superscript letters (a and b) differ (P < 0.05); <strong>with</strong>in a column, values <strong>with</strong> different superscript letters (x and y)differ (P < 0.05).15 f<strong>or</strong> bitches <strong>with</strong> closed pyometra (Fig. 2). Among <strong>the</strong>67 treated bitches, on day 1, 15 had plasma progesteroneconcentrations below 3.18 nmol/L. Treatment wassuccessful in all <strong>of</strong> <strong>the</strong>m, except f<strong>or</strong> two bitches <strong>with</strong>open pyometra. F<strong>or</strong> bitches <strong>with</strong> open <strong>or</strong> closedpyometra treated <strong>with</strong> cloprostenol (n = 32), <strong>the</strong>rewas a significant decrease in mean peripheral plasmaprogesterone concentration at day 8 (12.8 14.4 nmol/L versus 5.6 6.6 nmol/L on days 1 versus 8,respectively). However, in bitches treated <strong>with</strong>outcloprostenol (n = 20), no significant decrease in meanplasma progesterone concentration was observed untilday 14 (19.3 11.6 nmol/L versus 4.7 1.1 nmol/Lon days 1 versus 14; Table 3).Among <strong>the</strong> 13 failures using this treatment, onebitch did not present f<strong>or</strong> follow-up and recovery couldnot be confirmed. One bitch <strong>with</strong> open pyometratreated <strong>with</strong> <strong>aglepristone</strong> died on day 5 in <strong>the</strong> owner’sho<strong>use</strong>, and ano<strong>the</strong>r treated <strong>with</strong> <strong>aglepristone</strong> andcloprostenol was euthanized in a private clinic on day15 due to declining health. Ten bitches underwent anovariohysterectomy. In this last group, six had ovariancysts. After recovery, 23 bitches underwent follow-upvisits over <strong>the</strong> 24 months following <strong>the</strong> beginning <strong>of</strong>treatment. Three <strong>of</strong> <strong>the</strong>m developed pyometra between7 and 12 months later (3/23, 13.0%) and ano<strong>the</strong>rdeveloped it at 19 months (4/21, 19.0%). Two <strong>of</strong> <strong>the</strong>mreceived an additional, successful course <strong>of</strong> treatment(<strong>aglepristone</strong> + cloprostenol) and no pyometra wasobserved at <strong>the</strong> next cycle. We have kept in contact<strong>with</strong> <strong>the</strong> owners <strong>of</strong> three <strong>of</strong> <strong>the</strong> bitches <strong>use</strong>d in <strong>the</strong> trialf<strong>or</strong> some considerable time. They were treated m<strong>or</strong>ethan 6 years ago and have come into estrus n<strong>or</strong>mally,<strong>with</strong> no recurrence <strong>of</strong> uterine disease. Five bitcheswere mated at <strong>the</strong> first estrus after recovery; fourbecame pregnant.4. DiscussionThe <strong>use</strong> <strong>of</strong> <strong>aglepristone</strong> alone cured 27/35 (77.1%)bitches in 90 days. These results are equivalent tothoserep<strong>or</strong>tedbyH<strong>of</strong>fmannetal.[11] (25/31, 80.6%at day 30) and by Trasch et al. [12] (44/52, 84.6% atday 90). The number <strong>of</strong> animals treated is insufficientto show any difference in efficacy depending onclinical type (metritis, open pyometra and closedpyometra). This study, however, demonstrated <strong>the</strong>satisfact<strong>or</strong>y results obtained from<strong>the</strong><strong>use</strong><strong>of</strong><strong>aglepristone</strong>in bitches suffering from metritis (recovery rate,15/15). The <strong>use</strong> <strong>of</strong> <strong>aglepristone</strong> is also <strong>of</strong> particularinterest in <strong>the</strong> treatment <strong>of</strong> closed pyometra, since itinduces cervical opening, and <strong>the</strong> subsequent evacuation<strong>of</strong> purulent discharge <strong>with</strong> a marked improvementin <strong>the</strong> animal’s general condition. These resultsdemonstrated that surgery is no longer <strong>the</strong> onlytreatment f<strong>or</strong> closed pyometra. M<strong>or</strong>eover, even ifsurgery has been planned, it is possible to recommendmedication as a first-line treatment (<strong>aglepristone</strong> andrehydration) to improve <strong>the</strong> general health <strong>of</strong> <strong>the</strong> bitchand minimize surgical risk. In this study, <strong>the</strong> cervix <strong>of</strong>all <strong>the</strong> bitches <strong>with</strong> closed pyometra opened <strong>with</strong>in48 h. In a study <strong>of</strong> nine bitches <strong>with</strong> closed pyometra,Wehrend et al. [14] observed cervical opening <strong>with</strong>in72 h and <strong>the</strong> same marked improvement in <strong>the</strong>animal’s general condition.In bitches <strong>with</strong> open <strong>or</strong> closed pyometra, <strong>the</strong> repeatedadministration <strong>of</strong> low dose cloprostenol significantlyincreased <strong>the</strong> success rate at day 90 (27/32, 84.4%). Theuterotonic action <strong>of</strong> cloprostenol lead to a significantlyfaster decrease in <strong>the</strong> diameter <strong>of</strong> <strong>the</strong> uterine lumen andits luteolytic action ca<strong>use</strong>d a faster drop in mean plasmaprogesterone concentration. This decline in progesteronewas commonly observed in bitches treated f<strong>or</strong>pyometra <strong>with</strong> cloprostenol alone [15], <strong>or</strong> <strong>with</strong>cloprostenol associated <strong>with</strong> <strong>aglepristone</strong> [13]. In <strong>the</strong>present study, a decrease in progesterone concentrationswas also observed in bitches treated <strong>with</strong> <strong>aglepristone</strong>only, but at a later stage. Beca<strong>use</strong> <strong>of</strong> <strong>the</strong> antiprogesteroneproperties <strong>of</strong> <strong>aglepristone</strong>, this luteolysisdoes not seem to modify sh<strong>or</strong>t-term effectiveness.Between 30 and 90 days, we did not note any c<strong>or</strong>relationbetween blood progesterone concentration and successrate. The low dose <strong>of</strong> cloprostenol given (1 mg/kg) doesnot usually ca<strong>use</strong> any adverse reactions [16–18].Contrary to <strong>the</strong> results <strong>of</strong> a similar study [13], 56%<strong>of</strong> bitches treated had side effects, usually vomiting.
F. Fieni / Theriogenology 66 (2006) 1550–1556 1555This particular sensitivity to low doses <strong>of</strong> cloprostenolcan be explained by <strong>the</strong> po<strong>or</strong> general condition <strong>of</strong> <strong>the</strong>bitches. Never<strong>the</strong>less, <strong>the</strong> owners did not make anycomments.Among <strong>the</strong> treated bitches, 17 had basal progesteroneconcentrations. Cases <strong>of</strong> pyometra were observed atall stages <strong>of</strong> <strong>the</strong> reproductive cycle in a previous study[1]. The effects <strong>of</strong> <strong>aglepristone</strong> in pyometra have beenstudied in diestrus bitches selected <strong>with</strong> a progesteroneconcentration <strong>of</strong> m<strong>or</strong>e than 3.2 mm/L [1,10,11]. In <strong>the</strong>present study 15/17 bitches <strong>with</strong> a low progesteroneconcentration were cured after <strong>the</strong> administration <strong>of</strong><strong>aglepristone</strong>. Similar results were observed in ano<strong>the</strong>rrep<strong>or</strong>t [13]. This seems to confirm that, in <strong>the</strong>pathogenesis <strong>of</strong> pyometra in bitches, <strong>the</strong> action <strong>of</strong>progesterone on <strong>the</strong> uterus is dependent on <strong>the</strong> number<strong>of</strong> progesterone recept<strong>or</strong>s <strong>or</strong> <strong>the</strong>ir specific sensitivity,and not on <strong>the</strong> plasma progesterone concentration <strong>of</strong>this h<strong>or</strong>mone.The recurrence rate <strong>of</strong> pyometra after treatmentdiffered from results rep<strong>or</strong>ted in o<strong>the</strong>r studies. We didnot observe any recurrence between days 30 and 90,and <strong>the</strong> cure rate was higher, whereas Trasch et al.[12] rep<strong>or</strong>ted a recurrence rate <strong>of</strong> 9.8% (4/41) f<strong>or</strong> <strong>the</strong>same interval; this may be due to <strong>the</strong> length <strong>of</strong>treatment and <strong>the</strong> repeated administration <strong>of</strong> <strong>aglepristone</strong>until day 28 if needed (whereas Trasch onlyadministered <strong>aglepristone</strong> on days 1, 2 and 7). Therecurrence rate from 12 to 14 months after treatmentwas 18.9% (4/37) f<strong>or</strong> Trasch et al. [12], 9% (1/11) f<strong>or</strong>H<strong>of</strong>fmann et al. [11] and 21.4% (3/14) f<strong>or</strong> Gobelloet al. [13]. The mean age <strong>of</strong> <strong>the</strong> bitches (8 years) mayexplain <strong>the</strong> recurrence <strong>of</strong> pyometra in <strong>the</strong> 24 monthsfollowing <strong>the</strong> end <strong>of</strong> treatment, since age is a maj<strong>or</strong>epidemiological fact<strong>or</strong> in <strong>the</strong> onset <strong>of</strong> pyometra inbitches. However, treatment failure <strong>or</strong> recurrence <strong>of</strong><strong>the</strong> disease is closely linked to <strong>the</strong> presence <strong>of</strong> ovariancysts, which maintain a permanent endocrine imbalance.Ovariancystswereobservedin6<strong>of</strong>10bitcheswho underwent ovariohysterectomy due to <strong>the</strong> failure<strong>of</strong> medical treatment.Conservative treatment <strong>with</strong> prostaglandins, which isrecommended f<strong>or</strong> bitches <strong>with</strong> metritis <strong>or</strong> pyometra<strong>with</strong> mild dilatation <strong>of</strong> <strong>the</strong> uterine lumen, produces acure rate <strong>of</strong> 83–100%, <strong>with</strong> recurrence rates varyingfrom 10 to 40%. The treatment, which requires severaladministrations, produces discomf<strong>or</strong>t and is <strong>of</strong>tenassociated <strong>with</strong> side effects such as hypersalivation,vomiting and diarrhea [3,4].In conclusion, treatment <strong>with</strong> <strong>aglepristone</strong> alone wasa safe and effective treatment f<strong>or</strong> metritis, and aneffective means <strong>of</strong> inducing cervical opening in cases <strong>of</strong>closed pyometra. The combination <strong>of</strong> <strong>aglepristone</strong> andcloprostenol was m<strong>or</strong>e effective in <strong>the</strong> medicaltreatment <strong>of</strong> open and closed pyometra than <strong>aglepristone</strong>alone. Never<strong>the</strong>less, in all cases, we onlyrecommend such treatment in bitches <strong>with</strong> no liver <strong>or</strong>kidney dysfunction, and advise close clinical monit<strong>or</strong>ingthroughout <strong>the</strong> entire course <strong>of</strong> treatment.References[1] Blendiger K, Bostedt H, H<strong>of</strong>fmann B. H<strong>or</strong>monal effects <strong>of</strong> <strong>the</strong><strong>use</strong> <strong>of</strong> an antiprogestin in <strong>the</strong> bitches <strong>with</strong> pyometra. J ReprodFertil 1997;(Suppl. 51):317–25.[2] Noakes DE, Dhaliwal GK, England GC. Cystic endometrialhyperplasic/pyometra in dogs: a review <strong>of</strong> <strong>the</strong> ca<strong>use</strong>s andpathogenesis. J Reprod Fertil 2001;(Suppl. 57):395–406.[3] Gilbert RO, Nöthling JO, Oettlé EE. 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