Termination of unwanted Termination of unwanted pregnancy in dogspregnancy in dogs

MesallianceMesalliance• Estradiol bezonateEstradiol bezonate

– after matingafter mating

• Progesterone receptor antagonist: Progesterone receptor antagonist: Mifepristone(RU486), AglepristoneMifepristone(RU486), Aglepristone– mid-gestationmid-gestation

• Glucocorticoid: DexamethasoneGlucocorticoid: Dexamethasone– mid- andmid- and late gestation late gestation

MesallianceMesalliance

• PGFPGF22: Dinoprost, Cloprostenol: Dinoprost, Cloprostenol– mid- and late gestationmid- and late gestation

• Dopamine agonist: Cabergoline, Dopamine agonist: Cabergoline, BromocryptineBromocryptine– mid- and late gestationmid- and late gestation

Administration of Estradiol bezonateAdministration of Estradiol bezonate

• Risk after administration of estrogen Risk after administration of estrogen – PyometraPyometra– MetritisMetritis– Ovarian cystsOvarian cysts– Aplastic anemia, bone marrow suppressionAplastic anemia, bone marrow suppression– AlopeciaAlopecia

• Clinically, > 60% bitches after an unwanted Clinically, > 60% bitches after an unwanted mating are not pregnant mating are not pregnant Feldman Feldman et alet al. 1993. 1993

Administration of Estradiol bezonateAdministration of Estradiol bezonate

Estrogen prolongs the ovicduct transport Estrogen prolongs the ovicduct transport time and tightens the utero-tubular time and tightens the utero-tubular junction, resulting in implantation failure junction, resulting in implantation failure or embryonic death.or embryonic death.

• 0.01 mg/kg im or sc0.01 mg/kg im or sc• repeated injection at 3rd, 5th and 7th day repeated injection at 3rd, 5th and 7th day

after matingafter mating• 0.1-3 mg/kg for one injection within 4 0.1-3 mg/kg for one injection within 4

days of mating?days of mating?

Progesterone receptor antagonistProgesterone receptor antagonist

Concannon Concannon et alet al. 1990. 1990

2.5 mg/kg mifepristone, sc, bid for 5 days2.5 mg/kg mifepristone, sc, bid for 5 days

32 days 32 days → abortion(5/5)→ abortion(5/5)

Sankai Sankai et alet al. . 19911991

10-22.7 mg/kg mifepristone, single sc, 10-22.7 mg/kg mifepristone, single sc,

~ 56 days ~ 56 days → abortion(8/8 mixed dogs)→ abortion(8/8 mixed dogs)

Fieni Fieni et alet al. . 19961996

aglepristone aglepristone → abortion(66/69)→ abortion(66/69)

Galac Galac et alet al. . 19991999

10 mg/kg aglepristone, sc, for 2 days10 mg/kg aglepristone, sc, for 2 days

30 days after ovulation 30 days after ovulation → abortion(5/5 → abortion(5/5 beagle bitches) within 4-7 daysbeagle bitches) within 4-7 days

Interestrus interval 155 ± 10 d vs 199 ± 15 dInterestrus interval 155 ± 10 d vs 199 ± 15 d

Plasma concentrations of prolactin(●) and progesterone (○)in a beagle bitch, starting from the day of ovulation (Day 1) to the end of the luteal phase. On Day 30 & 31, the bitch was treated with aglepristone. Galac et al. (1999)

Progesterone receptor antagonistProgesterone receptor antagonist

• Aglepristone is a safe, reliable and effective Aglepristone is a safe, reliable and effective abortifacient during abortifacient during mid-gestationmid-gestation..

• The only side-effect of treatment was some The only side-effect of treatment was some mucoid vaginal discharge in the 1st week.mucoid vaginal discharge in the 1st week.

• Aglepristone do not impair future fertility? Aglepristone do not impair future fertility? (but only 1/6 bred later)(but only 1/6 bred later)

Administration of DexamethasoneAdministration of Dexamethasone

Wanke Wanke et alet al. . 19971997

74 pregnant bitches (day 30-35)74 pregnant bitches (day 30-35)

6 pregnant bitches (day 45-50)6 pregnant bitches (day 45-50)

62 bitches62 bitches 0.1-0.2 mg/kg ,po, bid for 2 days0.1-0.2 mg/kg ,po, bid for 2 days

→ → decrease to 0.02 mg/kg for 5 daysdecrease to 0.02 mg/kg for 5 days

→→5 bitches failed to abort5 bitches failed to abort

18 bitches18 bitches 0.2 mg/kg ,po, bid for 7 days0.2 mg/kg ,po, bid for 7 days

→ → decrease to 0.02 mg/kg for 5 daysdecrease to 0.02 mg/kg for 5 days

→ → 100% abortion100% abortion

Administration of DexamethasoneAdministration of Dexamethasone

• Side effects: polydipsia, polyuria, vaginal discharge, restlessness, anorexia or vomiting

• 20 bitches were mated and had normal pregnancies and normal litters.

Wanke Wanke et alet al. 1997. 1997

Administration of PGFAdministration of PGF22

- - more resistant to the luteolytic effect ofmore resistant to the luteolytic effect of

PGFPGF22 and susceptible to its deleterious side and susceptible to its deleterious side effects (effects (→ atropine 50 ug/kg, im→ atropine 50 ug/kg, im))

- - the narrow margin between a LD50the narrow margin between a LD50(5 (5 mg/kg, 2-12 hrs after inj.)mg/kg, 2-12 hrs after inj.) and therapeutic and therapeutic one one

- side effects such as vomiting, diarrhea, - side effects such as vomiting, diarrhea, pupil dilation, hyperpnoea, salivation, pupil dilation, hyperpnoea, salivation, urination, anxiety and ataxiaurination, anxiety and ataxia

Reports on experimental use of PGF2 to determinate pregnancy in bitches days of Dinoprost Days No. of Abortions side Pregnancy (ug/kg) treated Dogs effects

30-58 30, bid 3 7 60% +

26-55 50, bid 4-10 6 83% +

6 60, bid 3 1 0 + 40 30, bid 3 1 100% + 27 250, sid 6 1 100% + 56 250, bid 4 1 0 ++

13 250, bid 4 15 80% ++

10 250, bid 5 5 0 ++ 35 250, bid 5 5 100% ++

5-17 400-1000, sid 1-2 8 25% + 25-51 400-1000, sid 1-5 7 14% ++ 55-58 200-500, sid 1-2 9 88% ++

Administration of PGFAdministration of PGF22

• The rapidly developing CL during the early The rapidly developing CL during the early luteal phase are more resistant to the luteal phase are more resistant to the luteolytic effects of PGFluteolytic effects of PGF22 than are fully than are fully developed CL developed CL after 25-30 daysafter 25-30 days..

• Even with 250-400 ug/kg, abortive efficacy Even with 250-400 ug/kg, abortive efficacy is dependent on an injection frequency is dependent on an injection frequency greater than sid.greater than sid.

- - repeated administration with low to modest dose repeated administration with low to modest dose for 4-10 daysfor 4-10 days

Efficacy of repeated administration of PGF2 in 30 case of misalliance at University of Pretoria (1982-1987)

Days after administration No. of dogs efficacy% Mating of Dinoprost(sc, bid)

21-27 150-250ug/kg for 4-5 days 8 100 30ug/kg for 5-7 days 2 100

28-34 250ug/kg for 4-8 days 6 100 150ug/kg for 4-5 days 4 100 30ug/kg for 4 days 2 50

35-55 250ug/kg for 4 days 2 100 50ug/kg for 3-4 days 2 100

Efficacy of repeated administration of PGF2 in 18 dogs of 14 breeds from Edward et al. (1993)

Days after administration No. of dogs efficacy% Mating of Dinoprost (sc)

30-35 I. 0.1 mg/kg, tid 6 100 until abortion II. 0.25 mg/kg, bid 6 100 until abortion

III. 0.1 mg/kg, tid for 2 days, then 0.2 mg/kg, tid until abortion 6 100

Plasma progesterone concentration after initiating PGF2 treatment. Day 0 represents the pretreatment concentration. Edward et al. (1993)

Administration of PGFAdministration of PGF22

• All dogs aborted all fetuses All dogs aborted all fetuses within 9 dayswithin 9 days of of beginning treatment.beginning treatment.

• Plasma progesterone concentration Plasma progesterone concentration 2.0 2.0 ng/mlng/ml would result in termination of would result in termination of pregnancy in bitches.pregnancy in bitches.

• Hospitalization is recommended to allow Hospitalization is recommended to allow observation of the bitch and to avoid having observation of the bitch and to avoid having the owner witness the abortion process.the owner witness the abortion process.

Dopamine agonistDopamine agonist

• Prolactin, interacting with lipoproteins to Prolactin, interacting with lipoproteins to enhance P4 production in the luteal cells, is enhance P4 production in the luteal cells, is one of the important luteotropic hormones one of the important luteotropic hormones in pregnant dogs, especially in the 2nd half in pregnant dogs, especially in the 2nd half of pregnancyof pregnancy..

Concannon et al. 1987 Concannon et al. 1987

Anti-prolactin agents, such as dopamine Anti-prolactin agents, such as dopamine agonists, have been used to induce abortion, agonists, have been used to induce abortion, from 30-40 days after LH surge.from 30-40 days after LH surge.

Wichtel et al. 1990Wichtel et al. 1990

Concannon Concannon et et alal. 1987. 1987

0.1 mg/kg im for 6 days0.1 mg/kg im for 6 days

8-22 days, decreasing P4 for 4-6 days 8-22 days, decreasing P4 for 4-6 days → no abortion→ no abortion

42 days, decreasing P4 → abortion42 days, decreasing P4 → abortion

Wichtel Wichtel et alet al. . 19901990

20-30 mg/kg, po, bid for 4 days20-30 mg/kg, po, bid for 4 days

42 days 42 days → abortion→ abortion

62.5 mg/kg, po, bid for 6 days62.5 mg/kg, po, bid for 6 days

42-45 days → 50% abortion42-45 days → 50% abortion

Effects of bromocriptine on the pregnancy of the bitch

6 beagle6 beagle Cabergoline 5 ug/kg, po for 28 days Cabergoline 5 ug/kg, po for 28 days after matingafter mating

→ → no abortionno abortion

4 bitches4 bitches

3-6 weeks of 3-6 weeks of gestationgestation

5-15 ug/kg, po daily for 5 days5-15 ug/kg, po daily for 5 days

→ → no abortionno abortion, Prolactin , Prolactin , P4 > 1 , P4 > 1 ng/mlng/ml

8 bitches8 bitches

> 6 weeks of > 6 weeks of gestationgestation

5 ug/kg, po daily for 5 days5 ug/kg, po daily for 5 days

→ → 100% abortion100% abortion 3-5 days after the 3-5 days after the treatment, P4 < 1 ng/mltreatment, P4 < 1 ng/ml

Effects of cabergoline on the pregnancy of the bitch

Post Post et alet al. 1988. 1988

Dopamine agonistDopamine agonist

• The CL of the bitch are not sufficiently The CL of the bitch are not sufficiently sensitive to the luteolytic effect of sensitive to the luteolytic effect of cabergoline or bromocriptine during the cabergoline or bromocriptine during the early to mid stageearly to mid stage of gestation. of gestation.

• The administration of cabergoline or The administration of cabergoline or bromocriptine has bromocriptine has few side effectsfew side effects and may and may be preferable over the use of PGFbe preferable over the use of PGF22. .

PGFPGF22 + Dopamine agonist + Dopamine agonist

• Recently, a treatment combining reduced Recently, a treatment combining reduced doses of PGFdoses of PGF22 (25 ug/kg (25 ug/kg → 2.5 or 1 ug/kg → 2.5 or 1 ug/kg once dailyonce daily) and a dopamine agonist which ) and a dopamine agonist which inhibits pituitary prolacin secretion was inhibits pituitary prolacin secretion was shown to terminate early pregnancy. shown to terminate early pregnancy.

Onclin & Verstegen 1996Onclin & Verstegen 1996

PGFPGF22 + Dopamine agonist + Dopamine agonist

• The regression of the CL is achieved The regression of the CL is achieved directly by the PGFdirectly by the PGF22 and indirectly by the and indirectly by the carbergoline by withdrawing its main carbergoline by withdrawing its main luteotropic support, prolactin.luteotropic support, prolactin.

Okkens et al. 1990Okkens et al. 1990

Onclin et al. 1 2 3 1994 Cabergoline Cabergoline Cabergoline + + + Alphaprostol 20 Cloprostenol 2.5 Cloprostenol 1.0 n=5 n=5 n=5

Dose(ug/kg) Cabergoline 1.65 1.65 1.65 Days of treatment 32nd 25th 25th

Resorption/Expulsions 2/3 5/0 5/0

Side effects +++ ++ none

Interestrus interval (days) pretreatment 182 ± 11 186 ± 20 173 ± 5 treated 134 ± 18 125 ± 21 126 ± 44 Control group 198 ± 12

15 pregnant beagle administrated cabergoline together with selective dose of alphaprostol or cloprostenol daily for 5 days

Onclin & pregnant beagle 25 ± 4 days after 1st mating meanVerstegen 1996 1 2 3 4 5 ± SD

Cabergoline (days)5 ug/kg daily 9 9 9 11 9 9 ± 1

Cloprostenol inj. No. (1 ug/kg/2 days) 3 3 3 4 3 3 ± 1

Days to abortion 6 6 6 10 6 7 ± 2

Vulvar discharge(days) 15 13 17 18 18 16 ± 2

Mode of termination resorption of all fetuses

Interestrus interval pretreatment (days) 187 198 183 198 206 194 ± 9 treated 122 144 113 57 52 98 ± 41 Control group 205 ± 37

Progesterone concentrations in Progesterone concentrations in the 5 control bitchesthe 5 control bitches

Progesterone concentrations in Progesterone concentrations in the 5 beagles bitches treated the 5 beagles bitches treated with cabergoline (5 ug/kg daily) with cabergoline (5 ug/kg daily) and cloprostenol (1 ug/kg/2 and cloprostenol (1 ug/kg/2 days). Arrow indicates start of days). Arrow indicates start of treatment (25th day after LH treatment (25th day after LH surge) surge)

PGFPGF22 + Dopamine agonist + Dopamine agonist• The start treatment in the early pregnancy: The start treatment in the early pregnancy:

Day 25 after the 1st mating; a mean of 28 Day 25 after the 1st mating; a mean of 28 days after the LH surge.days after the LH surge.– close to the earlest time at which pregnancy can close to the earlest time at which pregnancy can

be diagnosed by palpation or by ultrasoundbe diagnosed by palpation or by ultrasound– treatment at this time terminating pregnancy treatment at this time terminating pregnancy

by resorptionby resorption

Onclin & Onclin & Verstegen Verstegen 19991999

11

Cabergoline Cabergoline oral for 10 oral for 10 days + days + CloprostenolCloprostenol

22

Bromocryptine Bromocryptine oral tid for 10 oral tid for 10 days + days + CloprostenolCloprostenol

33

Cabergoline Cabergoline oral for 10 oral for 10 days + days + CloprostenolCloprostenol

44

Bromocryptine Bromocryptine oral tid for 10 oral tid for 10 days + days + CloprostenolCloprostenol

Dose(ug/kg)Dose(ug/kg)

CabergolineCabergoline

CloprostenolCloprostenol

Bromocryp-Bromocryp-tinetine

5 beagles5 beagles

55

2.52.5

5 beagles5 beagles

2.52.5

3030

5 beagles5 beagles

55

1(28th, 32nd)1(28th, 32nd)

5 beagles5 beagles

1(28th, 32nd)1(28th, 32nd)

3030

Days of Days of pregnancypregnancy

-Start of -Start of treatmenttreatment

-Normal -Normal whelpingswhelpings

28th day after 28th day after LH peakLH peak

00

28th day after 28th day after LH peakLH peak

00

28th day after 28th day after LH peakLH peak

22

28th day after 28th day after LH peakLH peak

00

11

Cabergoline Cabergoline oral for 10 oral for 10 days + days + CloprostenolCloprostenol

22

Bromocryptine Bromocryptine oral tid for 10 oral tid for 10 days + days + CloprostenolCloprostenol

33

Cabergoline Cabergoline oral for 10 oral for 10 days + days + CloprostenolCloprostenol

44

Bromocryptine Bromocryptine oral tid for 10 oral tid for 10 days + days + CloprostenolCloprostenol

Side effectSide effect trembling, hyperpnoea, mild trembling, hyperpnoea, mild prostration, hypersalivation, prostration, hypersalivation, vomiting, diarrheavomiting, diarrhea

nonenone 2/5 (mild 2/5 (mild hypersalivationhypersalivation, trembling, , trembling, and vomiting and vomiting after the 1st after the 1st injectioninjection

Interestrus Interestrus interval(days)interval(days)

-Pretreatment-Pretreatment

-After treat--After treat-mentment

209 209 ± 46 days vs control group 205 ± 37 days± 46 days vs control group 205 ± 37 days

150 ± 11 138 ± 10 136 ± 33 168 ± 50150 ± 11 138 ± 10 136 ± 33 168 ± 50

Mean plasma progesterone concentra-Mean plasma progesterone concentra-tions in 5 control untreated bitches and tions in 5 control untreated bitches and in groups of 5 bitches treated with in groups of 5 bitches treated with bromocriptine.bromocriptine.

Mean plasma progesterone concentra-Mean plasma progesterone concentra-tions in 5 control untreated bitches and tions in 5 control untreated bitches and in groups of 5 bitches treated with in groups of 5 bitches treated with cabergoline. One bitch, Dog 77, treated cabergoline. One bitch, Dog 77, treated with cabergoline and 2 inj. of PG had with cabergoline and 2 inj. of PG had higher P4 levels than the other dogs in higher P4 levels than the other dogs in this group.this group.

PGFPGF22 + Dopamine agonist + Dopamine agonist

• A reduced interestrus interval of treated A reduced interestrus interval of treated dogs suggests that inhibiting circulating dogs suggests that inhibiting circulating prolactin, combined with direct luteolysis prolactin, combined with direct luteolysis by PGFby PGF22 , may release the inhibitory , may release the inhibitory mechanisms responsible for prolonging the mechanisms responsible for prolonging the obligatory anestrus phase of a dog’s estrus obligatory anestrus phase of a dog’s estrus cycle.cycle.

ConclusionsConclusions

• Advantage: Advantage: – safe for the bitch safe for the bitch – terminating pregnancy by resorption rather terminating pregnancy by resorption rather

than by abortion than by abortion – effective as early as 25 days after the 1st matingeffective as early as 25 days after the 1st mating

• All the treated bitches returned in heat and All the treated bitches returned in heat and become pregnant and had normal litters. become pregnant and had normal litters. Thus, this treatment did not compromise Thus, this treatment did not compromise the fertility of the treated animals.the fertility of the treated animals.

The bitch became Bromocryptine(30ug/kg), po, tid for 10 days The bitch became Bromocryptine(30ug/kg), po, tid for 10 days and an injection of Cloprostenol(2.5 ug/kg) about 33-35 days and an injection of Cloprostenol(2.5 ug/kg) about 33-35 days after mating. Five fetus were delivered 6 days after treatment. after mating. Five fetus were delivered 6 days after treatment. Chan Chan et alet al. 2003. 2003

Thanks for your attention!Thanks for your attention!