Transcript Termination of unwanted pregnancy in dogs

Termination of unwanted
pregnancy in dogs
Mesalliance
• Estradiol bezonate
– after mating
• Progesterone receptor antagonist:
Mifepristone(RU486), Aglepristone
– mid-gestation
• Glucocorticoid: Dexamethasone
– mid- and late gestation
Mesalliance
• PGF2: Dinoprost, Cloprostenol
– mid- and late gestation
• Dopamine agonist: Cabergoline,
Bromocryptine
– mid- and late gestation
Administration of Estradiol bezonate
• Risk after administration of estrogen
–
–
–
–
–
Pyometra
Metritis
Ovarian cysts
Aplastic anemia, bone marrow suppression
Alopecia
• Clinically, > 60% bitches after an unwanted
mating are not pregnant
Feldman et al. 1993
Administration of Estradiol bezonate
Estrogen prolongs the ovicduct transport
time and tightens the utero-tubular
junction, resulting in implantation failure
or embryonic death.
• 0.01 mg/kg im or sc
• repeated injection at 3rd, 5th and 7th day
after mating
• 0.1-3 mg/kg for one injection within 4 days
of mating?
Progesterone receptor antagonist
Concannon
et al. 1990
2.5 mg/kg mifepristone, sc, bid for 5 days
32 days → abortion(5/5)
Sankai et al.
1991
10-22.7 mg/kg mifepristone, single sc,
~ 56 days → abortion(8/8 mixed dogs)
aglepristone → abortion(66/69)
Fieni et al.
1996
Galac et al.
1999
10 mg/kg aglepristone, sc, for 2 days
30 days after ovulation → abortion(5/5
beagle bitches) within 4-7 days
Interestrus 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 antagonist
• Aglepristone is a safe, reliable and effective
abortifacient during mid-gestation.
• The only side-effect of treatment was some
mucoid vaginal discharge in the 1st week.
• Aglepristone do not impair future fertility?
(but only 1/6 bred later)
Administration of Dexamethasone
Wanke et al. 74 pregnant bitches (day 30-35)
1997
6 pregnant bitches (day 45-50)
62 bitches
18 bitches
0.1-0.2 mg/kg ,po, bid for 2 days
→ decrease to 0.02 mg/kg for 5 days
→5 bitches failed to abort
0.2 mg/kg ,po, bid for 7 days
→ decrease to 0.02 mg/kg for 5 days
→ 100% abortion
Administration of Dexamethasone
• Side effects: polydipsia, polyuria, vaginal
discharge, restlessness, anorexia or vomiting
• 20 bitches were mated and had normal
pregnancies and normal litters.
Wanke et al. 1997
Administration of PGF2
- more resistant to the luteolytic effect of
PGF2 and susceptible to its deleterious side
effects (→ atropine 50 ug/kg, im)
- the narrow margin between a LD50(5 mg/kg,
2-12 hrs after inj.) and therapeutic one
- side effects such as vomiting, diarrhea, pupil
dilation, hyperpnoea, salivation, urination,
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
40
27
56
60, bid
30, bid
250, sid
250, bid
3
3
6
4
1
1
1
1
0
100%
100%
0
+
+
+
++
13
250, bid
4
15
80%
++
10
35
250, bid
250, bid
5
5
5
5
0
100%
++
++
5-17
25-51
55-58
400-1000, sid
400-1000, sid
200-500, sid
1-2
1-5
1-2
8
7
9
25%
14%
88%
+
++
++
Administration of PGF2
• The rapidly developing CL during the early
luteal phase are more resistant to the
luteolytic effects of PGF2 than are fully
developed CL after 25-30 days.
• Even with 250-400 ug/kg, abortive efficacy
is dependent on an injection frequency
greater than sid.
- repeated administration with low to modest dose
for 4-10 days
Efficacy of repeated administration of PGF2 in 30 case of
misalliance at University of Pretoria (1982-1987)
Days after
Mating
administration
No. of dogs
of Dinoprost(sc, bid)
efficacy%
21-27
150-250ug/kg for 4-5 days
30ug/kg for 5-7 days
8
2
100
100
28-34
250ug/kg for 4-8 days
150ug/kg for 4-5 days
30ug/kg for 4 days
6
4
2
100
100
50
35-55
250ug/kg for 4 days
50ug/kg for 3-4 days
2
2
100
100
Efficacy of repeated administration of PGF2 in 18 dogs of 14
breeds from Edward et al. (1993)
Days after
Mating
30-35
administration
of Dinoprost (sc)
No. of dogs
efficacy%
I. 0.1 mg/kg, tid
until abortion
6
100
II. 0.25 mg/kg, bid
until abortion
6
100
6
100
III. 0.1 mg/kg, tid for 2 days,
then 0.2 mg/kg, tid
until abortion
Plasma progesterone concentration after initiating PGF2
treatment. Day 0 represents the pretreatment concentration.
Edward et al. (1993)
Administration of PGF2
• All dogs aborted all fetuses within 9 days of
beginning treatment.
• Plasma progesterone concentration  2.0
ng/ml would result in termination of
pregnancy in bitches.
• Hospitalization is recommended to allow
observation of the bitch and to avoid having
the owner witness the abortion process.
Dopamine agonist
• Prolactin, interacting with lipoproteins to
enhance P4 production in the luteal cells, is
one of the important luteotropic hormones
in pregnant dogs, especially in the 2nd half
of pregnancy.
Concannon et al. 1987
Anti-prolactin agents, such as dopamine
agonists, have been used to induce abortion,
from 30-40 days after LH surge.
Wichtel et al. 1990
Effects of bromocriptine on the pregnancy of the bitch
Concannon et 0.1 mg/kg im for 6 days
al. 1987
8-22 days, decreasing P4 for 4-6 days
→ no abortion
42 days, decreasing P4 → abortion
Wichtel et al. 20-30 mg/kg, po, bid for 4 days
1990
42 days → abortion
62.5 mg/kg, po, bid for 6 days
42-45 days → 50% abortion
Effects of cabergoline on the pregnancy of the bitch
6 beagle
Cabergoline 5 ug/kg, po for 28 days
after mating
→ no abortion
4 bitches
3-6 weeks of
gestation
5-15 ug/kg, po daily for 5 days
→ no abortion, Prolactin  , P4 > 1
ng/ml
8 bitches
> 6 weeks of
gestation
5 ug/kg, po daily for 5 days
→ 100% abortion 3-5 days after the
treatment, P4 < 1 ng/ml
Post et al. 1988
Dopamine agonist
• The CL of the bitch are not sufficiently
sensitive to the luteolytic effect of
cabergoline or bromocriptine during the
early to mid stage of gestation.
• The administration of cabergoline or
bromocriptine has few side effects and may
be preferable over the use of PGF2.
PGF2 + Dopamine agonist
• Recently, a treatment combining reduced
doses of PGF2 (25 ug/kg → 2.5 or 1 ug/kg
once daily) and a dopamine agonist which
inhibits pituitary prolacin secretion was
shown to terminate early pregnancy.
Onclin & Verstegen 1996
PGF2 + Dopamine agonist
• The regression of the CL is achieved
directly by the PGF2 and indirectly by the
carbergoline by withdrawing its main
luteotropic support, prolactin.
Okkens et al. 1990
15 pregnant beagle administrated cabergoline together with selective
dose of alphaprostol or cloprostenol daily for 5 days
Onclin et al.
1994
1
2
3
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
treated
134 ± 18
186 ± 20
125 ± 21
173 ± 5
126 ± 44
Control group
198 ± 12
Onclin &
Verstegen 1996
pregnant beagle 25 ± 4 days after 1st mating mean
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
206
52
194 ± 9
98 ± 41
205 ± 37
Mode of termination
Interestrus interval
pretreatment (days)
treated
Control group
resorption of all fetuses
187
122
198
144
183
113
198
57
Progesterone concentrations in
the 5 control bitches
Progesterone concentrations in
the 5 beagles bitches treated
with cabergoline (5 ug/kg daily)
and cloprostenol (1 ug/kg/2
days). Arrow indicates start of
treatment (25th day after LH
surge)
PGF2 + Dopamine agonist
• The start treatment in the early pregnancy:
Day 25 after the 1st mating; a mean of 28
days after the LH surge.
– close to the earlest time at which pregnancy can
be diagnosed by palpation or by ultrasound
– treatment at this time terminating pregnancy
by resorption
Onclin &
Verstegen
1999
Dose(ug/kg)
Cabergoline
Cloprostenol
Bromocryptine
Days of
pregnancy
-Start of
treatment
-Normal
whelpings
1
Cabergoline
oral for 10
days +
Cloprostenol
2
Bromocryptine
oral tid for 10
days +
Cloprostenol
3
Cabergoline
oral for 10
days +
Cloprostenol
5 beagles
5 beagles
5 beagles
5
2.5
2.5
28th day after
LH peak
0
0
5 beagles
5
1(28th, 32nd) 1(28th, 32nd)
30
28th day after
LH peak
4
Bromocryptine
oral tid for 10
days +
Cloprostenol
30
28th day after 28th day after
LH peak
LH peak
2
0
1
Cabergoline
oral for 10
days +
Cloprostenol
Side effect
trembling, hyperpnoea, mild
prostration, hypersalivation,
vomiting, diarrhea
Interestrus
interval(days)
-Pretreatment
-After treatment
2
Bromocryptine
oral tid for 10
days +
Cloprostenol
3
Cabergoline
oral for 10
days +
Cloprostenol
4
Bromocryptine
oral tid for 10
days +
Cloprostenol
none
2/5 (mild
hypersalivation,
trembling, and
vomiting after
the 1st injection
209 ± 46 days vs control group 205 ± 37 days
150 ± 11
138 ± 10
136 ± 33
168 ± 50
Mean plasma progesterone concentrations in 5 control untreated bitches and
in groups of 5 bitches treated with
bromocriptine.
Mean plasma progesterone concentrations in 5 control untreated bitches and
in groups of 5 bitches treated with
cabergoline. One bitch, Dog 77, treated
with cabergoline and 2 inj. of PG had
higher P4 levels than the other dogs in
this group.
PGF2 + Dopamine agonist
• A reduced interestrus interval of treated
dogs suggests that inhibiting circulating
prolactin, combined with direct luteolysis by
PGF2 , may release the inhibitory
mechanisms responsible for prolonging the
obligatory anestrus phase of a dog’s estrus
cycle.
Conclusions
• Advantage:
– safe for the bitch
– terminating pregnancy by resorption rather
than by abortion
– effective as early as 25 days after the 1st mating
• All the treated bitches returned in heat and
become pregnant and had normal litters.
Thus, this treatment did not compromise
the fertility of the treated animals.
The bitch became Bromocryptine(30ug/kg), po, tid for 10 days
and an injection of Cloprostenol(2.5 ug/kg) about 33-35 days
after mating. Five fetus were delivered 6 days after treatment.
Chan et al. 2003
Thanks for your attention!