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Effect of Stage of Anestrus On The Induc PDF
Effect of Stage of Anestrus On The Induc PDF
ELSEVIER
ABSTRACT
Beagle bitches were administered the dopamine D 2 receptor agonist cabergoline in 3 groups
of 5 animals each, starting on known days of the estrous cycle. Cabergoline treatment was started
in either early anestrus (Days 93 to 108), mid-anestrus (Days 123 to 156), or late anestrus (Days 161
to 192) at doses of 5 ug/kg/d, per os, and was continued until the confirmation of induced proestrus
or for 40 d. Reproductive parameters were compared with those in 5 control anestrous bitches (Days
90 to 150). In control bitches, the mean (± SEM) interval to the next proestrus (73 + 11 d) resulted
in an interestrus interval (192 -4-9 d) similar to that of the previous cycles (196 + 11 d). In 14 of the
15 cabergoline-treated bitches, the next proestrus occurred within 4 to 30 d, was premature in early
and mid-anestrous bitches and developed with low variability within groups. The resulting
intervals to proestrus in bitches treated with cabergoline in early anestrus (20 ± 2 d), mid-anestrus
(14 ± 3 d) and late anestrus (6 + 1 d) resulted in interestrus intervals in those groups of 131 ± 5,
166 ± 7 and 196 + 2 d, respectively. In response to treatment, interestrus intervals were reduced
(P<0.05) and more synchronous (P<0.05) in early and mid-anestrus bitches, and were more
synchronous (P<0.05) in late-anestrous bitches compared with those of control bitches or those of
the previous cycle. Per±ovulatory estradiol and progesterone profiles of induced cycles in treated
bitches were similar to those of spontaneous cycles in control bitches. Four of 5 control bitches and
12 of the 14 responding cabergoline-treated bitches became pregnant and produced normal litters.
Plasma prolactin concentrations at Days 2 and 5 of treatment (0.3 ± 0.1 ng/mL) and at the onset of
proestrus shortly before the end of treatment (0.4 ± 0.1 ng/mL) were lower (P<0.05) than those
present in anestrus prior to treatment (1.7 ± 0.6 ng/mL) or in control bitches. Prolactin was also low
at the onset ofproestrus in control bitches (0.5 ± 0.2 ng/mL). The results demonstrate that prolactin-
lowering doses of the dopamine agonist cabergoline can terminate the normal obligate anestrus in
dogs, and that the effect occurs more slowly in early anestrus than in mid or late anestrus.
© 1999 by ElsevierScience Inc.
Key words: ovary, estrus, prolactin, dopamine
INTRODUCTION
The ovarian cycle of the dog is unique among those of domestic animals in that there is an
obligatory anestrus following the termination of the luteal phase. A similar anestrus also occurs
following withdrawal of exogenous progestin (5,10). Canine anestrus varies in duration from 3 to
10 mo among bitches, and can vary slightly or greatly among cycles within the same bitch (1,36).
The luteal phase lasts about 2 mo. Normal interestrus intervals range from 5 to 12 mo and average
about 7 mo in both fertile and nonbred cycles (8,34). Except in 1 or 2 breeds there is no evidence
of pronounced seasonality, and bitches of most breeds may cycle any month of the year (1,3,5,6,36).
Anestrus in the bitch is characterized by apparent ovarian inactivity, low levels of estrogen
and elevated levels of FSH (6,16). The termination of anestrus appears to be associated with
increased secretion of gonadotropin (6) and/or increased sensitivity to GnRH (39), but the
mechanisms responsible for such changes are not known. The mechanisms controlling the
reinitiation of folliculogenesis and its timing in dogs may differ from those proposed for other
species, since initiation of the follicular phase is temporally dissociated from the preceding luteal
phase. However, progesterone withdrawal is more than just permissive in dogs, in that
prostaglandin-induced or dopamine agonist-induced premature luteolysis results in shortened
interestrus intervals and possibly a shortened duration of anestrus (27,28,32).
Elevations in prolactin are associated with seasonal anestrus in some species, and
hyperprolactinemia is a cause ofamenorrhea in women (33). Administration ofprolactin-lowering
doses of the dopamine agonist bromocriptine throughout the luteal phase and anestrus reduced the
duration of both the luteal phase and of anestrus (25). Bromocriptine administered beginning in
anestrus terminated anestrus within 50 d in one study (38) and within 28 d in another (6). Another
ergot alkaloid, metergoline, reduced the interestrus interval when administered repeatedly in
anestrus in one study (15) but not in another (24). However, both bromocriptine and metergoline
are not selective dopamine agonists. Bromocriptine is a dopamine D 2 receptor agonist, but it also
affects serotonergic and adrenergic receptors (22). Metergoline is primarily a serotonin receptor
antagonist which has dopaminergic activity only at doses much higher than those required for anti-
serotonergic effects (19,22). Furthermore, both readily cross the blood-brain barrier. Therefore,
studies using those compounds leave it unclear whether their ability to terminate anestrus in dogs
is limited to action in the median eminence and pituitary, or involves higher centers, and whether
the actions on neuroendocrine elements involve receptors other than dopamine receptors.
The ergot alkaloid and dopamine agonist cabergoline has a bio-potency and D 2 receptor
affinity greater that ofbromocriptine, a lower affinity for serotonergic 5 HT-2 receptors and a longer
duration ofaction (11,12,22,31). Furthermore, cabergoline has fewer central nervous system effects
than bromocriptine. Side effects of dopamine agonist therapy in dogs and humans include nausea
and emesis, apparently secondary to central nervous system effects. At doses which terminate
clinical pseudopregnancy in dogs, cabergoline has fewer and milder side-effects than bromocriptine
(17,27,30). Moreover, in vivo, cabergoline does not affect striatal dopaminergic activity whereas
bromocriptine does (11). Administration ofcabergoline was reported to terminate anestrus in dogs
with an abnormally prolonged anestrus but to have no effect on cycle duration when administered
during anestrus in normal cycles (17). Such observations suggested that additional studies were
warranted to confirm and evaluate the potential role of dopaminergic pathways in the regulation of
obligate anestrus in normal ovarian cycles of dogs. To better understand the process of obligate
anestrus in dogs, it would also be helpful to know whether stage of anestrus affects response to
dopamine agonist treatment. An effect of stage would suggest that in normal anestrus there are
changes in sensitivity to endogenous dopamine or dopamine-regulated elements. Prior reports on
termination of anestrus with ergot alkaloids in dogs have varied in the time course of the response
and have not examined the possible effect of the stage of anestrus on the response (6,17,25).
Theriogenology 599
The present study was conducted 1) to determine the effects on interestrus intervals of
prolactin-lowering doses of cabergoline administered at known days of the cycle during early,
middle, or late anestrus in beagle bitches; 2) to evaluate the resulting proestrus and estrus in terms
of timing, behavior, vaginal cytology, fertility and peripheral concentrations of estradiol and
progesterone; and 3) to confirm prolactin suppression in relation to prolactin levels present in
anestrus.
Animals
The study utilized 20 mature beagle bitches, 3 to 8 yr of age. All the animals were bom,
housed and provided routine veterinary examinations in animal facilities at the University of Liege.
All animal experimentation was conducted in accordance with the Guide for the Care and Use of
Laboratory Animals promulgated by the US National Research Cotmcil. Health examinations were
provided every 1 to 2 mo, and immediately prior to treatment. Bitches were housed in groups of 2
to 5 in indoor-outdoor runs (3.5 x 10 m), exposed to natural light (50.50 N latitude), provided water
• . . a
ad llbltmn and fed a commercial dry food once daily in amounts sufficient to maintain body weight.
For each bitch, the cycle of treatment and the previous cycle had been characterized in terms of
proestrous and estrous vaginal cytology, the day ofpreovulatory rise in progesterone, and plasma
progesterone concentrations during the luteal phase, including those on the first day of metestrus.
The days of the cycle were designated relative to the estimated day of the preovulatory LH surge,
i.e., the day on which plasma progesterone increased rapidly above 1.0 to 2.0 ng/mL from relatively
unchanged concentrations of 0.4 to 0.9 ng/mL observed on the previous 2 to 3 d (9,27). The
interestrus interval was calculated as the period between the estimated days of preovulatory LH
surges of successive cycles.
Treatments
Three groups of 5 bitches each were administered cabergoline starting at known days after the
day of the preovulatory LH surge. Treatment was initiated in either early anestrus (Days 93 to 108),
mid-anestrus (Days 123 to 156) or late-anestrus (Days 161 to 192). The mean day of treatment
initiation in these groups was 102 + 6, 142 + 13 and 188 -4-5 d of the cycle, respectively. The treated
bitches and the 5 untreated bitches designated as the controls were monitored daily for signs of
proestrus. The control bitches at the start of study ranged from 90 to 150 d post estrus. The first day
of treatment was considered to be treatment Day 0. Treatment for all dogs was initiated in the same
week in November of the same year to preclude potential effects of season among groups. Bitches
were assigned to treatment and control groups semi-randomly to ensure that there were no
differences between groups in mean age, body weight or body condition.
aHill's Canine Maintenance Scientific Diet, Hill's Animal Feeds, Brussels, Belgium•
600 Theriogenology
Cabergolineb was administered daily at a dose of 5 ug/kg, per os, by application of the
solution (50 ug/mL) directly into the mouth using a medicine dropper. Cabergoline administration
was continued until 3 to 8 d after the onset of the first signs of proestrus and until the progress of
proestrus was confirmed by both external signs (i.e., vulval swelling and serosanguinous discharge)
and vaginal cytology (i.e., > 50% intermediate or superficial type epithelial cells), or until 40 d
without signs ofproestrus.
Observations
The first day of induced proestrus was defined as the first day with evidence of vulval swelling
or serosanguinous discharge, and vaginal smear containing erythrocytes and intermediate or
superficial cells which represented >30% of epithelial cells present in increased numbers. The first
day of estrus and first day of the cycle (Cycle Day 0) was defined endocrinologically as the
estimated day of the preovulatory LH surge based on an abrupt increase in plasma progesterone
above 1 ng/mL. The first day ofmetestrus (diestrus) was the day characterized by an abrupt 10 to
60% decrease in superficial cells and the reappearance of intermediate and parabasal cells in vaginal
smears collected at the end of estrus (7).
For the bitches in the 3 treatment groups and the control group the previous cycle and
interestrus interval was well characterized, and parameters did not differ among groups. The
preceding mean interestrus interval was 194 ± 5 d; mean proestrus length was 8.4 ± 0.5 d; and
estrus length was 7.6 a: 0.2 d.
Blood samples (5 to 7 mL) were obtained by jugular venipuncture into heparinized tubes,
centrifuged at 1000 x g for 15 min within 30 min of collection, and the multiple plasma aliquots
(500 uL) stored at -20°C until assay. Plasma samples were obtained from all animals once a week
for 1 or more cycles prior to study. With few exceptions, samples were obtained from cabergoline-
treated bitches every 2 to 4 d for 1 to 3 wk prior to treatment, and daily from start of treatment until
1 week after the onset ofmetestrus. Samples were obtained from control animals every 3 to 4 d or
more frequently during anestrus, and daily during proestrus and estrus. Most of the samples were
assayed for both estradiol and progesterone content, with attention to estradiol during treatment and
to progesterone in late proestrus and estrus. In some instances, estradiol and progesterone were
assayed in alternating samples in order to conserve samples. Values were aligned to Day 0 of
treatment and, retrospectively, also to the day of the ovulatory LH surge of the subsequent cycle.
Mean values were determined for each day with values available for > 3 animals. Values for days
with _<2 animals represented were included with values for the next day. Each mean included only
a single value per animal.
Plasma Prolactin
Prolactin content was assayed in the plasma samples obtained at Days 0, 2 and 5 of treatment
and at the onset ofproestrus in the treated bitches, and in samples obtained at Days 0, 2, 5 and 21
of study and at the onset of proestrus in control bitches. This was done to confirm prolactin
suppression in treated bitches and to compare concentrations during anestrus and early proestrus.
Prolactin was measured using ~acommercial canine prolactin immunoenzymometric assay and as
described by the manufacturer-and recently validated (29). The sensitivity of the prolactin assay
at 95% binding was 0.25 ng/mL. The intra- and inter-assay coefficients of variation were 5 and 8%,
respectively.
Bitches in estrus were mated naturally on the first day of acceptance of the male and every
other day thereafter until metestrus, except for 2 control bitches. The latter were inseminated with
fresh or frozen semen at 3 and 5 d after the estimated day of the preovulatory LH peak, and both
became pregnant. Pregnancy was detected and monitored by ultra-sonographyg at 20, 30 and 40 d
after the last mating as previously described (40). All means are reported + standard error of the
mean (SEM). Differences in ovarian cycle parameters within groups were determined by paired or
unpaired t-tests or by Chi-square tests of equality of variance, and those between treatment groups
were determined by one-way analysis of variance and LSD (least significant difference) tests or by
Chi-square tests of variance (20,35).
RESULTS
The onset of proestrus and of estrus in cabergoline-treated bitches occurred earlier during
study than in control bitches, with the exception of 1 experimental bitch. The onset ofproestrus in
the cabergoline-treated bitches occurred within 4 to 30 d compared with 48 to 105 d in control
bitches. In each treatment group, the interval from start of treatment to onset of proestrus was
shorter (P<0.05) and less variable (P<0.05) than in the control group (Table 1). In early and mid
anestrous bitches, cabergoline treatment resulted in interestrus intervals which were shorter (P<0.05)
than in control bitches or in previous cycles. In late-anestrous bitches, cabergoline treatment
resulted in interestrus intervals that were less variable (P<0.05) but not shorter than in control
bitches or in previous cycles (Table 1). The 1 cabergoline-treated early-anestrous bitch which did
not respond to treatment was repeatedly observed to vomit following administration of treatment.
Treatment was stopped after 40 d and the results for this animal were not included in mean results
for that group. No other side effects were observed, except for apparent apathy and reduced food
intake in 2 bitches during the first 4 days of treatment. In each of the 14 cabergoline-treated bitches
which responded to treatment, erythrocytes were observed in vaginal smears beginning at 4 to 7 d
of treatment, were variable in amounts, and were either present continuously (n=9) or intermittently
(n=5). Early proestrus smears in treated bitches typically had more debris and leucocytes than those
in control bitches but were otherwise similar to those in controls, as regards erythrocytes and
epithelial cell changes. Differences in vaginal cytology were not quantified, and were assumed to
be due to the earlier than normal occurrence of proestrus.
Among cabergoline-treated bitches, the interval to onset ofproestrus based on vulval swelling
and comification of vaginal smears varied with the stage of the cycle at the start of treatment
Table 1. Mean (+ SEM) intervals and durations of reproductive responses and resulting
interestrus intervals associated with termination of anestrus by oral administration
of cabergoline (5 ug/kg/d) in beagle bitches
(Table 1). Onset ofproestrus in bitches treated during late anestrus occurred within 3 to 9 d, and
earlier (P<0.05) during treatment than in bitches treated during mid-anestrus (6 ± 1 versus
14 4- 3 d). In bitches treated during early anestrus, onset of the induced proestrus occurred within
12 to 24 d and tended to occur the latest in the course of treatment (20 + 3 d), albeit not significantly
later (P= 0.14) than the 6 to 20 d in bitches treated in mid-anestrus. However, the resulting number
of days of cabergoline treatment until confirmed proestrus differed (P<0.05) among the 3 treatment
groups (Table 1).
There were no differences between cabergoline-treated animals and controls in the durations
ofproestrus or estrus, in plasma progesterone at the start ofmetestrus, or in fertility (Table 1). Each
of the 14 responding cabergoline-treated bitches ovulated, based on plasma progesterone results, and
was mated; 12 of the 14 became pregnant and produced normal litters of 4 to 8 pups each. In the
early-anestrus treatment group, 1 bitch which ovulated developed a pyometra and was subsequently
ovariectomized. There was no evidence of pregnancy at surgery. Mating or insemination resulted
in pregnancy in 4 of the 5 control bitches.
Mean concentrations of estradiol and progesterone were evaluated in relation to the day of
cabergoline treatment (Figure 1). Concentrations of both hormones were low at the start of
treatment in early, mid, and late anestrous bitches. Estradiol increased in each group, but the time
of the increase appeared to vary depending on the stage ofanestrus at treatment. Estradiol increased
above pretreatment values within 1 to 3 d after the start of treatment in late-anestrous bitches but not
until 6 to 12 d in mid-anestrous bitches, and 12 to 18 d in early anestrous bitches. Changes in mean
concentrations of estradiol and of progesterone, examined in relation to the day of the subsequent
estimated day of the LH surge, were similar in cabergoline-treated and control groups (Figure 2).
The increase in estradiol occurred shortly before the onset ofproestrus in treated and control bitches.
In each group there was typically a low and sometimes transient elevation in estradiol concentration
1 to 4 d prior to the observed onset of proestrus. The pre-proestrus elevation in estradiol in
individual bitches averaged 14.2 4- 1.5 pg/mL and was significant (P<0.05) in comparison with
pretreatment values of 2.3 4- 0.6 pg/mL. Preovulatory peak concentrations ofestradiol ranged from
28 to 47 pg/mL in control animals and from 27 to 62 pg/mL in the 14 cabergoline-treated bitches
in which anestrus was prematurely terminated, and did not differ among groups.
Mean concentrations of progesterone at the onset of metestrus were similar in treated and
control animals (Table 1) and were similar to those of previous cycles (data not shown).
Progesterone concentrations between Days 10 and 20 of the cycle varied extensively within and
between bitches in each group. Peak levels.of progesterone ranged from 22 to 60 ng/mL in control
bitches, and 27 to 58 ng/mL in the 14 responding cabergoline-treated bitches. There were no
differences among treated or control groups in mean peak estradiol or progesterone concentrations.
Plasma prolactin concentrations at the start of treatment were similar in early, mid and late
anestrous bitches (1.8 + 0.9, 1.6 4- 0.7, and 1.6 + 0.8 ng/mL, respectively) and did not differ from
those of control anestrous bitches at the start of the study (1.7 + 0.1 ng/mL) or at Days 2, 5 and 21
(1.8 4- 0.7, 2.0 + 0.6, 1.9 4- 0.2 ng/mL, respectively). In all 14 bitches which tolerated cabergoline
treatment, prolactin concentrations at Day 2 of the study (0.4 4- 0.1 ng/mL) and Day 5 of the study
(0.3 4- 0.1 ng/mL) were subsequently reduced (P<0.05) compared with the pretreatment values, and
were lower (P<0.05) than in control bitches on those days. Prolactin concentrations shortly before
Theriogenology 605
60- -40
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Figure 1. Mean (4- SEM, n = 3 to 5) plasma concentrations of estradiol (o) and progesterone
(e) in groups of beagle bitches administered cabergoline (5 ug/kg/day, po) beginning
in early anestrus (n = 4), mid-anestrus (n = 5), or late anestrus (n = 5). Error bar not
shown when smaller than symbol size.
606 Theriogenology
ESTRADIOL PROGESTERONE
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Days Days
Figure 2. Mean (4- SEM, n = 3 to 5) plasma concentrations of estradiol (left panels) and
progesterone (right panels), relative to the estimated day of the subsequent
preovulatory LH surge (Day 0), in groups of 4 to 5 beagle bitches administered
cabergoline (5 ug/kg/d, po) beginning in early anestrus (upper panels), mid-anestrus
(second panels), or late anestrus (third panels), and in 5 untreated control bitches
(bottom panels). The mean (4- SEM) time of the initiation of treatment in treated
bitches was, respectively, at 294- 2, 214- 3 and 104- 2 days prior to Day O. The day
of LH surge was estimated as the time of the initial increase in progesterone above
1 ng/mL. Error bar not shown when smaller than symbol size.
Theriogenology 607
the end of treatment, i.e., at the onset ofproestrus (0.3 + 0.1 ng/mL), were likewise lower (P<0.05)
than those of control bitches around that time, i.e., at Day 21 of the study. Prolactin at the onset of
proestrus in control bitches (0.5 -4-0.3 ng/mL) was also reduced (P<0.05) in comparison with that
present previously during anestrus.
DISCUSSION
The present results confirm and extend observations that daily administration of prolactin-
lowering doses of a dopamine agonist can hasten the termination of anestrus in dogs as reported
previously with administration of bromocriptine (6,25,38). These results also demonstrate the
efficacy of the dopamine agonist cabergoline in this regard. The rapid, 3- to 9-d response of bitches
treated with cabergoline in late anestrus is more rapid than previously reported but is similar to the
observation that cabergoline administration for 5 to 15 d resulted in proestrus in bitches treated
clinically for abnormal and prolonged anestrus at 7 to 19 mo after the last estrus (17). The
termination of anestrus in bitches treated in early and mid anestrus in our present study is in contrast
with the previously reported absence of treatment effect for beagle bitches treated with similar doses
for 14 d beginning at 4 to 6 mo after estrus (17). The difference in results could be due to
differences in formulation, mode of oral administration, or duration of administration. The
treatment period required to induce proestrus in many of the early and mid-anestrous bitches in the
present study was longer than 14 d.
The cycles resulting from cabergoline-induced termination of anestrus were normal in most
respects, since the resulting proestrus and estrus parameters, fertility and serum hormone profiles
were very similar to those of control bitches. The increased debris and leucocytes in vaginal smears
obtained during early proestrus in the cabergoline-treated bitches may have been due to earlier than
normal proestrous endocrine changes. It is not uncommon to find leucocytes in vaginal smears in
early proestrus of some normal cycles (7). The rapid initial appearance of erythrocytes in vaginal
smears of cabergoline-treated bitches possibly represents uterine diapedesis in response to early
increases in estradiol, and may be similar to that which occurs in early proestrus of normal cycles
(7). If so, then increases in estradiol below the level of detection in the early and mid anestrous
bitches may be physiologically important.
The efficacy of dopamine agonists in terminating anestrus in the bitch may involve
suppression ofprolactin secretion. When bromocriptine administration induced premature proestrus
in 4 of 5 anestrous bitches, only in the 1 nonresponding bitch did the treatment fail to suppress
prolactin secretion (6). The time course ofprolactin suppression was not fully characterized in the
present study. However, the data obtained demonstrate reduced prolactin concentrations within 2
d of treatment and at the onset of proestrus shortly before the end of treatment, whereas prolactin
was not reduced at comparable times in the untreated controls. The reduced prolactin concentrations
during treatment confirm that the doses of cabergoline used in this study suppress circulating
concentrations ofprolactin in anestrous bitches, as previously reported for pregnant and for diestrous
bitches (29,30). The findings of reduced prolactin concentrations observed at the onset ofproestrus
in control bitches suggests that in normal cycles prolactin concentrations decline near the end of
anestrus.
608 Theriogenology
Because of the D2-receptor specificity of cabergoline, the results suggest that the efficacy of
the other ergot-alkaloids in terminating anestrus also involves effects on dopaminergic neurons or
dopaminergic receptors. That is presumably the case with bromocriptine (6,25). Metergoline is
primarily an anti-serotonin agent at low doses but can have direct dopaminergic effects at high doses
(22). Metergoline treatment induced premature proestrus in dogs in one study (15) but not in
another (24). In instances where metergoline appears to have been effective (15), the effect may
have been indirect and mediated by dopaminergic or other neurons, as observed in the serotonergic
control ofprolactin secretion in rats (18,19). Or, since high doses were used, it may have involved
a direct dopaminergic effect. In the present study, the observed prolactin suppression by
cabergoline was presumably due to a direct effect on lactotroph D2 receptors (31 ). Effects proximal
to the pituitary and median eminence, perhaps at the hypothalamic level, cannot be discounted,
although in vivo studies in rats suggest a limited ability of cabergoline to cross the blood-brain
barrier and bind to striatal D 2 receptors (11).
There were few apparent side effects except for the vomiting response in 1 dog. This is
similar to the low (4 to 25%) incidence of vomiting observed in bitches administered similar oral
doses for treatment of pseudopregnancy (2). The greater potency and fewer side effects of
cabergoline compared to bromocriptine in dogs are possibly related to the fact that cabergoline has
a greater affinity and specificity for the D 2 dopamine receptor (22) and more limited access to the
central nervous system (11).
Theriogenology 609
The effect of the stage of cycle on the duration of cabergoline treatment required to cause an
increase in estradiol and terminate anestrus suggests that during normal anestrus there are
progressive changes in hypothalamic, pituitary or gonadal function that affect the response to
dopamine agonist treatment. Relevant in that regard is the observation that pituitary sensitivity to
GnRH increases during the course of anestrus in dogs (39). More complete evaluation of bitches
administered dopamine agonist in early vs late anestrus is needed to elucidate the mechanism of
action and the endogenous factors that affect the response. In summary, the present study
demonstrates that treatment with the dopamine agonist cabergoline can be used to shorten interestrus
intervals in dogs, that it results in normal estrus and fertile ovulation, and that the duration of
treatment required depends on the stage ofanestrus. However, the mechanism of action and the role
prolactin suppression in the response have not been determined.
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