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Termination of unwanted pregnancy in dogs

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					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       2.5 mg/kg mifepristone, sc, bid for 5 days
et al. 1990     32 days → abortion(5/5)

Sankai et al.   10-22.7 mg/kg mifepristone, single sc,
1991            ~ 56 days → abortion(8/8 mixed dogs)
Fieni et al.    aglepristone → abortion(66/69)
1996
Galac et al.    10 mg/kg aglepristone, sc, for 2 days
1999            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   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
18 bitches   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           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 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 PGF 2 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 PGF 2 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 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      5-15 ug/kg, po daily for 5 days
3-6 weeks of   → no abortion, Prolactin  , P4 > 1
gestation      ng/ml

8 bitches      5 ug/kg, po daily for 5 days
> 6 weeks of   → 100% abortion 3-5 days after the
gestation      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.              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
Onclin &             pregnant beagle 25 ± 4 days after 1st mating mean
Verstegen 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
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 &              1                 2                3              4
Verstegen      Cabergoline      Bromocryptine     Cabergoline    Bromocryptine
1999           oral for 10      oral tid for 10   oral for 10    oral tid for 10
               days +           days +            days +         days +
               Cloprostenol     Cloprostenol      Cloprostenol   Cloprostenol
                5 beagles         5 beagles         5 beagles      5 beagles
Dose(ug/kg)
Cabergoline          5                                 5
Cloprostenol        2.5               2.5         1(28th, 32nd) 1(28th, 32nd)
Bromocryp-
tine                                  30                               30
Days of
pregnancy
-Start of      28th day after   28th day after    28th day after 28th day after
treatment      LH peak          LH peak           LH peak        LH peak
-Normal
whelpings            0                0                 2               0
                        1                2                3              4
                 Cabergoline     Bromocryptine     Cabergoline    Bromocryptine
                 oral for 10     oral tid for 10   oral for 10    oral tid for 10
                 days +          days +            days +         days +
                 Cloprostenol    Cloprostenol      Cloprostenol   Cloprostenol



Side effect      trembling, hyperpnoea, mild          none        2/5 (mild
                 prostration, hypersalivation,                    hypersalivation,
                 vomiting, diarrhea                               trembling, and
                                                                  vomiting after
                                                                  the 1st injection
Interestrus
interval(days)
-Pretreatment               209 ± 46 days vs control group 205 ± 37 days

-After treat-       150 ± 11          138 ± 10        136 ± 33        168 ± 50
ment
Mean plasma progesterone concentra-
tions in 5 control untreated bitches and
in groups of 5 bitches treated with
bromocriptine.




Mean plasma progesterone concentra-
tions 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
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