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Reproduction

PRACTICAL USE OF HORMONES IN SMALL ANIMAL


REPRODUCTION
Prof. Stefano Romagnoli, DVM, MS, Ph.D, Dipl. ECAR
Department of Animal Medicine, Production and Health,
University of Padova, Agripolis, Legnaro, 35020 (PD)
stefano.romagnoli@unipd.it

PROSTAGLANDINS
Prostaglandin F2alpha (PGF) compounds have been available for over 30 years as
veterinary compounds for use in food animals and horses. Their luteolytic and
uterotonic actions make them unique, and very useful also in small animals, although
no pharmaceutical company has yet even taken into consideration marketing a
prostaglandin product for use in dogs and cats. PGF compounds can be used in small
animals with the folliwng indications:
1) early pregnancy termination in bitches
The abortifacient efficacy of prostaglandins (PGF) involves induction of luteolysis,
stimulation of uterine contraction and cervical dilation. Of these, the luteolytic effect
is the most important in the bitch, while the cervical dilating action has never quite
been demonstrated in this species. In dogs, the progesterone supporting pregnancy is
entirely from the corpora lutea throughout gestation. PGF will induce luteolysis and
depress progesterone concentrations to nearly non-detectable levels very easily after
day 25 or 30, although also earlier in pregnancy. The later in the cycle PGF is
administered, the easier and more rapidly the induction of luteolysis. Use of PGF
requires subcutaneous administration 2 or 3 times a day, for 6 days or longer. No
PGF products are marketed with an indication for use in dogs or cats. The dosage
varies depending on the type of PGF: natural PGF should be given a maximum
dosage of 80-100 mcg/kg twice daily, starting gradually with 1/3 to the dose for
the first day (or the first 2 administrations), while cloprostenol is currently being used
at a dose of 1 mcg/kg (once every 24-48 hour intervals) and while alphaprostol must
be used at the dose of 20 mcg/kg twice daily for several days like natural PGF. Side
effects (which include emesis, salivation, defecation, urination and slight tachipnea)
are dose dependent (displayed in 75% of bitches using doses of 250 mcg/kg and only
in 25% of bitches using doses of 50 mcg/kg) and self-limiting, decreasing in intensity
with repeated dosing.
2) late pregnancy termination in bitches and queens
Canine late pregnancy termination is generally adopted as a treatment when either a
mismating was not observed,the female was not in the ovulatory phase or fertility of
the male is unknown. In cats, the result of a serum progesterone assay done on a
blood sample collected within 3-7 days following mismating can be used as an
indrecet indication of pregnancy, as ovulation is induced in this species. Dosage of
PGF compounds is the same as for early abortion, the only difference being that
treatment must be continued until verification of efficacy by ultrasound as partial

abortion of litters can occur if treatment is discontinued prematurely. With most


dosages, 9 or more days may be required to terminate some pregnancies, although 5
to 7 days is usually sufficient. A study of 67 pregnant bitches demonstrated a 100%
efficacy in termination of pregnancy using cloprostenol at the dose of 2.5 ug/kg
subcutaneously, administered three times, at 48 h intervals, starting at day 30 of
pregnancy. Cloprostenol at even lower doses has been used in combination with
dopamine agonist treatment to terminate pregnancy in dogs shortly after implantation
(which in bitches and queens occurs around 15-18 days after ovulation) starting
around day 23 from ovulation. Although the use of premedication with atropine
sulphate or prifinium bromide is reported prior to administration of natural PGF
compounds, we have never used it and feel that its use is almost always unnecessary.
Mismated queens can be treated with natural PGF at a dose of 2 mg/cat IM once a
day, beginning at day 33 of pregnancy, as this will induce luteolysis and terminate
pregnancy by expulsion of fetuses in pregnant cats. Side effects included prostration,
vomiting and diarrhea. The PGF analogue cloprostenol has been studied in
combination with the dopamine agonist cabergoline in cats, at the dose of 5 mcg/kg
administered once daily from mid pregnancy on.
3) shortening of diestrus in bitches
The use of a 6-10 day course of PGF starting after day 10 of cytological diestrus will
complete luteolysis. The consequent reduction of the length of the luteal phase wil
cause a shortening of anestrus. We have observed bitches treated with PGF early in
their luteal phase coming back in heat after 70-90 days following the onset of
proestrus. If a PGF treatment (shortening the duration of diestrus) is then followed
by a cabergoline treatment (shortening the duration of anestrus), the interestrous
interval can be substantially shortened. We have succeded in significantly shortening
the duration of interestrous interval in a kennel of Rough Collies using this technique
thus increasing the nuber of litter/year.
4) emptying of uterine content in bitches and queens
The mioconctracting action of PGF compounds is well known, and can become
useful when dealing with cases of open-cervix pyometra or late abortions with
incomplete fetal expulsion. Dosage are the same as listed above. We frequently use
PGF compounds combined with aglepristone when late pregnant bitches are
presented for induction of abortion, as such combined treatments are shorter and
more efficacious. Care should be taken to make sure that the cervix is open, as
causing uterine contractions on a closed cervix may cause uterine rupture or force
uterine content up into the oviducts. Therefore, aglepristone is administered first (see
over) and then PGF are used once uterine evacuation has started.
5) improving semen quality in the dog
The use of PGF at the dose of 100 mcg/kg 15 minutes prior to semen collection
results in an increase of 270% of total sperm numbers when compared to saline
treated controls, with no deleterious effect on refrigeration and freezing. PGF can
also be used to obtain an ejaculate from a reluctant or inexperienced dog (Hess, 2006)

ANTIPROLACTINICS
Prolactin secretion by the lactotroph cells of the anterior pituitary gland is regulated
by multiple neuro-transmitters and hormones, with the major control mechanism
being the activation of prolactin-inhibiting dopaminergic neurons in the
hypothalamus. Prolactin is a major luteotrophic hormone and appears to be an
absolute requirement for canine and feline progesterone secretion by day 30 after
ovulation. Dopamine agonists like bromocriptine or cabergoline are ergot alkaloids,
with strong dopamine D2-receptor agonist activity, and thus can reduce prolactin
secretion thereby suppressing progesterone levels. The seretonin antagonist
metergoline stimulates endogenous dopamine secretion and thus can inhibit prolactin
secretion as well.
Cabergoline has a slow clearance, which allows for a single oral daily administration.
Furthermore, its action is longer than 48 hours due to its particularly long (minimum
48 hours) half-life at the hypophyseal level. Because of its more specific D2-type
action, cabergoline presents only few side effects when used at clinical dosages.
Bromocryptine mesylate inhibits PRL secretion during relatively short periods of
time (half-life: 4-6 hours) and in a dose-dependent mode. In order to effectively
inhibit PRL tone in a continuous fashion for therapeutic purposes, bromocryptine
should be administered at least twice a day, administered orally at doses 10-50 g/kg.
Its lack of specificity leads to side effects on the cardiorespiratory system, causing
hypotension due to vasodilatation (adrenergic type effect), or emesis due to
stimulation of the Chemioreceptive Trigger Zone (CTZ). Attemps to improve side
effects by gradually increasing an initially low dose, or by pre-treating with an antiemetic drug have proved only partially effective. Although its effectiveness has
never been questioned, bromocryptine is not approved in most countries as an antiPRL in small animals and its extra-label use has not caught on, in spite of its worldwide availability as a human drug.
Metergoline is essentially a serotoninergic antagonist with dopaminergic agonist
properties when used orally at doses of 0.1 mg/kg BID. Its shorter half-life requires
at least administrations twice a day. Its antiserotoninergic properties can induce
marked central effects such as depression, nervousness, increased excitability,
changes in appetite (anorexia or bulimia), psychotic effects (escaping from home,
aggressiveness). Gastrointestinal side effects due to stimulation of the CTZ are
evaluated by the emetic dosage in 50% of the bitches or DE50. The DE50 of
cabergoline and bromocryptine are identical. However, when considering dosages
commonly used in a clinical setting, the emetic effect of bromocryptine is almost
always present while it is negligeable with cabergoline. The DE50 of metergoline is
much higher, but it is very close to the therapeutic dosage. Therefore, emetic effects
are sometimes observed when using metergoline, especially when overdosing it.

Antiprolactinic drugs can be used in the bitch and the queen with three indications:
pseudopregnancy, induction of abortion and induction of estrus.
1) Pseudopregnancy
The anti-lactogenic action of both metergoline and cabergoline is well kinown. Their
administration for 4-5 days at pharmacological doses is effective in treating
pseudopregnancy signs and reducing milk production. Occasional failures can be
dealt with by repeating the treatment protocol and extending it to 8 to 10 days, and
also by administering at the same time metergoline (at the usual antigalactogenic
dosage of 100 mcg/kg BID) or bromocriptine (10-20 mcg/kg BID) (see table n 1).
Antiprolactinics are currently considered the treatment of choice for
pseudopregnancy. Until the last part of last century, when antiprolactinics became
commercially available, progestogens were thought to be an appropriate treatment for
false pregnancy due to their lowering action on PRL concentrations at the end of the
luteal phase; infact, progestogen administration is clinically demonstrated to be
effective in preventing the occurrence of lactation and of pseudopregnancy as well as
in eliminating related clinical signs. However, a rebound effect is frequently
observed following treatment withdrawal, similarly to what occurs at the end of a
normal luteal phase, when the progesterone decline triggers a PRL peak. Therefore,
progestins should not be used as a treatment for false pregnancy.
Antiprolactinic
drug
Cabergoline

Daily dosage in the Side effects


bitch/queen
(incidence)
5 mcg/kg MID
Emesis, anorexia (20%)

Bromocriptine

10-30 mcg/kg BID


(*)
100 mcg/kg BID
(*)

Metergoline

Emesis, anorexia (50%)


Emesis, anorexia
(20%), behavioral
changes

Commercial name,
Company
Galastop, Ceva
Vetem
Parlodel, Novartis
Contralac, Virbac

Table n 1 Daily dosages, side effects and commercial name (in Europe) of the 3
antiprolactinics most commonly used in small animals: cabergoline (Galastop,
CEVA-VETEM, a veterinary compound) and bromocriptine (Parlodel, Novartis, a
human compound) are dopamine agonists (they increase the concentration of
dopamine, a PRL-inhibiting factor) while metergoline (Contralac, Virbac, a
veterinary compound) is a serotonine antagonist (it lowers the concentration of
serotonine, a PRL-stimulating factor). (*) There is no scientific information
available for the queen.
2)
Induction of abortion
The abortion induction properties of antiprolactinic drugs have been well studied for
cabergoline, while not as much is known for metergoline. Cabergoline is effective
in terminating pregnancy in dogs when administered at mid-gestation (as prolactin

secretion starts around day 25) or later. When administered after day 40 at doses of
5 mcg/kg, PO, for 5 days cabergoline is effective in causing abortion in all bitches
treated. If cabergoline administration is started earlier in pregnancy, at day 25,
treatments that are effective later in pregnancy fail in most bitches and the
pregnancy continues until terminated by retreatment at day 40. Cabergoline
produces little if any side affects at pharmacological doses. Combination treatment
of cabergoline and prostaglandins have been used for induction of late abortion both
in bitches and queen. Treatments include alternating drugs on consecutive days, and
are knon to be quite effective especially since the dosage of PGF can be reduced.
3)
Estrus induction
The estrus inducing action of antiprolactinic drugs was initially thought to be due to
the lowering of prolactin concentrations, but studies done at Utrecht have
demonstrated that shortening of anestrus occurs irrespective of prolactin
concentrations. All the 3 antiprolactinic products (cabergoline bromocriptine and
metergoline) have been used for oestrus induction in the bitch. Cabergoline and
bromocriptine have consistently given positive results, while metergolines results
have been more variable depending on dosage. Using low dose (0.1 mg/kg BID) of
the commercial oral preparation of metergoline administered from 100 days after
ovulation until the following proestrus, the interoestrous interval can be
significantly shortened. The administration of bromocriptine in anoestrus will
induce oestrus within 28-50 days We have used bromocriptine at the dose of 10-25
g/kg in 5 bitches with prolonged anoestrus: 4/5 came in oestrus within 13-28
days, and all 4 conceived and whelped. Using cabergoline (5 g/kg, once daily for
up to 28 days) or natural PGF2alpha (100 g/kg SC, BID for 5 days starting on
cytological dioestrus day 10) we achieved an interoestrous interval of 6 months in 6
treated bitches as opposed to an interval of 9 months in 9 control bitches. We have
also used cabergoline (5 g/kg, once daily for up to 28 days) in 9 bitches (7 Rough
Collies, 1 Shetland sheepdog and 1 English Setter) for a total of 11 cycles: fertile
oestrus was induced in 10/11 cycles in 24+11 days with a reduction of the
interoestrous interval of 1.8+0.2 months. In our experience, the clinical use of
antiprolactinics to induce oestrus has proven to be safe and highly effective. Side
effects are minimal (particularly with cabergoline), being mostly related to the
gastrointestinal tract (nausea, rare vomiting) with no other reproductive effect.
LACTOGENETIC DRUGS1
Antiemetics
Metoclopramide is a central nervous system (CNS) dopamine D2 receptor
antagonist used as a human antiemetic drug. Recommended dosages for
galactogenic effect in women are 10-15 mg/day TID, per os for 3-4 weeks. Its
antagonizing action on the main PRL inhibitor dopamine causes a powerful, albeit
indirect stimulus to PRL release (for a review see Zuppa et al., 2010) with reported
high efficacy rates especially when metoclopramide is associated with oxytocin
1

Excerpts of this paper are taken from the article Control of mammary function in the bitch and queen from Romagnoli S. and Lopate C., in
press, Clinical Theriogenology, 2012

nasal spray. In lactating women, metoclopramide is transferred to breast milk


where it quickly becomes more concentrated than in plasma (milk-to-plasma ratio
of 1.8:1), although this is not regarded as critical for babies since the milk level is
below pharmacological doses. Metoclopramide acts also as an antagonist of
serotoninergic receptors (although this does not prevent PRL-releasing action), and
has some cholinergic effects on smooth muscle. Maternal side effects include
tiredness, headache, anxiety, nervousness and intestinal disorders. At higher doses
(2-5 mg/kg) the drug may penetrate the blood-brain barrier and extrapyramidal
signs (anxiety, agitation, movement disorders, dystonic reactions, ataxia) are
reported.
Metoclopramide is also normally used in dogs as an antiemetic drug at oral dosages
between 0.2-0.4 and 1-2 mg/kg divided in 2-3 administrations (Johnson et al.,
1994). It has been used also to stimulate canine PRL secretion, although scientific
data with pre- and post-treatment PRL concentrations are available only for male
dogs, in which a significant increase in serum PRL concentration is reported
following treatment with 0.2 mg/kg 3 times daily (Koivisto et al., 2009). Use of
metoclopramide in bitches with agalactia is anecdotal, with protocols varying from
low (0.2-0.5 mg/kg SC or PO, BID or TID - White, 2008a; Arus Marti and
Fernandez, 2010) to high dose regimens (1-5 mg/kg beginning PO or SC, every 6-8
hrs - Linde-Forsberg 2007). Efficacy seems to be adequate with (subjective)
improvement of milk production in >50% of cases, although no data on PRL
concentrations pre- and post- treatment is available. Extrapyramidal signs may
occur in canines, and are a concern in nursing bitches, therefore higher dosages
should best be avoided. Improvement in milk production is generally noticeable
within 24 48 hours. To minimize side effects, it is advisable to start at a lower
dose (0.5 2 mg/kg/day divided TID) for the first 24-48 hours and then if there is
no improvement gradually increase the dose every other day until an effect or
abnormal clinical signs are noted, at which point the dose is dropped to the prior
days dose or discontinued. Extrapyramidal signs are much more common at doses
above 2 mg/kg/day. Bitches should be monitored carefully when being treated with
metoclopramide to ensure injury to the pups does not occur. Treatment should be
continued for at least 2-3 days beyond when milk production appears to be resulting
in adequate daily weight gain for the pups without supplementation.
Domperidone is a peripheral dopamine receptor antagonist developed as an
antiemetic agent and used for the treatment of nausea and vomiting. In women,
domperidone significantly increases PRL secretion thereby enhancing breast milk
production, and is therefore used (off-label) as a galactogogue in most Western
countries (Zuppa et al., 2010). In 2004, a few cases of cardiac arrythmia and sudden
death were observed in US patients suffering from cancer and with low potassium
who were receiving high IV doses of domperidone concurrently with
chemotherapy. This prompted an FDA warning that breastfeeding women should

not use domperidone, after which the drug was subsequently withdrawn from the
US human market. Subsequent research has shown that domperidone is safe when
used by lactating mothers (see Campbell-Yeo et al., 2010 for a review). The
maximum approved treatment protocol of domperidone in lactating women is 20
mg given 4 times daily, although most authors advice using doses of 10 mg orally
TID for 1-2 weeks. However, the minimum effective dose and the minimum
duration of therapy have not been identified yet. Domperidone causes a significant
increase in serum PRL concentrations and milk production in treated vs control
mothers, which has been estimated at 75% in a recent meta-analysis (Osadchy et
al., 2012). Unlike metoclopramide, domperidone is less permeable to the bloodbrain barrier and is transferred in moderate quantities to maternal milk (milk-toplasma ratio of 0.2-1.1), due to its high molecular weight and its 90% binding to
plasma proteins (Zuppa et al., 2010). No side effects are reported in infants of
mothers taking domperidone, while side effects in mothers include oral mucosal
dryness, skin eruption, itch, headache and gastrointestinal disorders; extrapyramidal
effects have been observed (dystonia) but are rare. No difference in milk quality of
mothers treated with domperidone is reported, except for significant increases in
carbohydrate and calcium (Campbell-Yeo et al., 2010).
Early experimental use of domperidone has been reported in the dog, with data on
pharmacokinetics and excretion and metabolism in Beagle dogs. However, there is
a lack of scientific as well as anecdotal information on clinical use of domperidone
in small animals with low milk production. This is surprising given the positive
results and the lack of side effects of this drug making it probably the best treatment
for increasing milk production in lactating mothers. Domperidone is known among
small animal clinicians by word of mouth to be effective in improving milk yield
at doses of 1.5-2.0 mg/kg in queens, and 2.2 mg/kg in bitches, per os for 1-3 weeks.
Treatment should be continued for at least 2-3 days beyond when milk production
appears to be resulting in adequate daily weight gain for the pups without
supplementation. In our experience, results of domperidone in increasing milk
production in agalactic bitches and queens appear to be positive, better than those
obtained with metoclopramide and devoid of extrapyramidal effects. Diarrhea is
the most common side effect in the bitch, although there are anectodal reports of
behavior changes in some bitches being medicated.
Antipsychotics
Chlorpromazine is an antagonist of D2 dopaminergic hypothalamic receptors,
commonly used for the treatment of human psychosis including schizophrenia and
depression. It is considered the prototype of the phenothiazine class of drugs. Its
action on dopaminergic receptors causes PRL release, which is the reason for its
off-label use in breastfeeding mothers. It is transferred to milk in low quantities
(milk:plasma ratio of 0.5), and its recommended dosage for galactogogic effect is
25 mg orally TID for one week (Zuppa et al., 2010). Chlorpromazine has a wide

action on different CNS receptors producing also anticholinergic, antihistaminic, as


well as weak antiadrenergic effects. The main side effects of chlorpromazine in
psychotic patients (who are treated with higher doses than lactating mothers) are
mostly due to its anticholinergic properties and include sedation, slurred speech,
dry mouth, constipation, urinary retention, possible lowering of the seizure
threshold, increased appetite and impaired glucose tolerance leading to increase in
weight. Not much is known about side effects of chlorpromazine in breastfeeding
mothers and their infants (Gentile, 2008), although lethargy, sleepiness and reduced
activity have been reported in a few babies (AAP, 2001). For these reasons, the
American Academy of Pediatrics (AAP) in 2001 stated that chlorpromazine is
included in the list of drugs whose effects on nursing infants may be of concern
(AAP, 2001), and some authors advice monitoring of infants whose mothers are
under chlorpromazine treatment (Briggs et al., 2006).
In small animals, chlorpromazine is used as a second choice antiemetic drug when
metoclopramide does not work and blood pressure is normal (Simpson, 2007).
Suggested antiemetic dosage is 0.2-0.5 mg/kg every 6-8 hrs. Only anecdotal
information on the use of chlorpromazine in cases of agalactia is available for small
animals (Johnston, Root-Kustritz and Olson, 2001). Some authors advice the use of
acepromazine at 0.125-0.5 (White, 2008b) or 0.5-2.0 mg/kg (Kutzler, 2009), SC 2-3
times/daily. No data on clinical efficacy in bitches or queens as well as
milk:plasma ratio of transfer are available for this drug.
Sulpiride is a substituted benzamide used as an antipsychotic drug for the treatment
of human psychosis including schizophrenia and depression. It is a strong
antagonist of serotoninergic receptors as well as of muscarinic, alpha-adrenergic
and histaminic receptors. Its administration (off-label) to breast-feeding women in
galactogenic doses of 50 mg orally 2-3 times/day for 1-4 weeks produces a strong
PRL-releasing effect with PRL reaching serum concentrations which may be up
90% higher than in the control group and infants of treated mother gaining
significantly more weight than control ones. Significant increases in milk
production are reported only for primiparous mothers, not multiparous. Milk of
treated mothers shows presence of the drug, although the milk:plasma ratio of
transfer is lower than with metoclopramide or chlorpromazine. Although side
effects are extremely rare in mothers and have never been reported in infants of
treated mothers, the AAP advises against use of sulpiride in breastfeeding women
as it does with all neurotropic drugs.
PROGESTERONE ANTAGONISTS
Antiprogestins can be used for:
1) early and late pregnancy termination in bitches and queens
2) open and closed-cervix pyometra in bitches and queens Conservative medical
treatment of bitches with pyometra can be achieved with the administration of 10

mg/kg of aglepristone on days 1, 2, 8 and then also 15 and 28 depending on the


clinical situation in bitches with both open cervix and closed-cervix pyometra
(Romagnoli et al., 2006). The use of aglepristone should be associated with
antibiotics if necessary, and can also be associated with PGF provided that cervical
opening has occurred. In bitches with closed cervix pyometra, administration of
aglepristone is often followed by cervical opening within 24-48 hrs. There is no
information on the effect of aglepristone on pyometra in the queen, but efficacy for
this indication is thought to be the same as in dogs.
3) Induction of parturition
4) treatment of feline mammary hypertrophy - Benign mammary hypertrophy is a
benign fibroglandular proliferation of one or more mammary glands which typically
occurs in young queens at their first luteal phase. The proliferation of the mammary
gland is due to an excessive response to the action of progesterone which is present
in presumably normal concentrations in affected animals. Mammary glands will
start swelling rapidly and within 2-3 days all glands become very swollen, firm and
nodular. If left untreated, the problem may disappear on its own without any
complication in most cases. Treatment with prostaglandins or antiprolactinic is not
effective, while removal of ovaries or administration of aglepristone can be
curative. When mammary hypertrophy occurs following progestogen
administration, signs typically do not subside immediately following neutering or
withdrawal of progestin therapy (Gorlinger et al 2002). In such cases, surgical
removal of persisting nodules should be considered in order to perform histology
and rule out presence of neoplasia. Recently, it was shown that the condition is
responsive to targeted endocrine therapy with progesterone antagonists i.e.
progesterone receptor blockers such as aglepristone (Wehrend et al 2001, Gorlinger
et al 2002, Meisl et al., 2003), which may be an option also for cats treated with
long-acting progestogens. Although dose regimens for aglepristone in cats have not
been reported, anecdotal treatments with 15 mg/kg are known to be effective as
abortifacients or in case of a pyometra. Dosages for mammary hypertrophy may
need to be higher or prolonged in time depending on whether it is a spontaneous
disease or if it is due to progestogen administration. Recently, Muphung et al
(2009) studied the effect of aglepristone in a group of queens treated with a high
dose of medroxyprogesterone acetate (MPA - 50 mg) followed by 2 injections of 10
mg/kg aglepristone 3 weeks later. Based on histology and immunohistochemistry,
no evidence of an effect of aglepristone on the mammary gland of treated queens
was present. Lack of effect might be due to the very high dose of MPA used, to the
rather low dose of aglepristone (10 mg/kg instead of 15 mg/kg), to the short
treatment with aglepristone (only 2 injections) or to the long interval between MPA
and aglepristone treatments.
SYMPATHOMIMETIC DRUGS
The clinical effect of drugs in this category is enhancement of urethral closure
through the release of endogenous norepinephrine and direct stimulation of adrenergic receptors in the bladder neck and urethra. Thanks to such action, -

agonists can be used for the treatment of urinary incontinence and retrograde
ejaculation.
Urinary Incontinence
see the paper on Medical treatment of urinary incontinence
Retrograde ejaculation
The canine bladder neck has a rich cholinergic and adrenergic innervation.
Cholinergic stimulation produces gradual contraction of the neck as well as of the
whole bladder (occurring during micturition), while adrenergic stimulation occurring
at ejaculation causes contraction of the neck and relaxation of the body of the
bladder. Improper functioning of the bladder neck at ejaculation may cause the
sperm rich fraction to flow retrogradely into the bladder following the path of least
resistance. Retrograde ejaculation has been reported in the dog (Romagnoli and
Majolino, 2008). Sympathomimetic agents such as ephedrine, pseudoephedrine
hydrochloride, phenylpropanolamine and imipramine are generally used (alone or in
combination) to treat human retrograde ejaculation. Treatment protocols employing
sympathomimetic drugs reported in the dog include phenylpropanolamine (3 mg/kg
per os) and pseudoephedrine hydrochloride (3-5 mg/kg per os) to be administered 3,
1 and 0.5 hours prior to breeding/semen collection).
Side effects of -agonists are rare in the average dog, and include anorexia, weight
loss, hyperxcitability, restlessness, tachicardia, skin eruption. Some human
preparations of -agonists are combined with antihistaminic drugs (chlorphenamine,
pheniramine, mepiramine, dyphenylpyraline etc.) which may cause dryness of the
oral mucosa as well as drowsiness, and some others include also caffeine. Although
the clinical effects of these combinations in small animals is unknown, side effects of
antihistaminic drugs and of caffeine should not be a cause of concern except in dogs
with cardiac problems. Phenylpropanolamine is available in several European
countries as a veterinary product, as an oral preparation for incontinent bitches
(Propalin, Vetoquinol).
ESTROGENS
Estrogens have always been considered as potentially dangerous drugs because of
their role in inducing mammary neoplasia and bone marrow aplasia in women as well
as in bitches. However, only long-acting synthetic compounds such as
diethylstilbestrol, estradiol, estrone and other esther compounds are characterized by
such dangerous action because of their prolonged nuclear occupance time in estrogen
receptors of target tissues. Short-acting estrogenic compounds such as estriol,
characterized by short nuclear occupance time and minimal metabolism following
absorption (estriol does not bind to sex-hormone binding globulin) prevent
development of full (late) estrogenic effects such as endometrial hyperplasia,
pyometra and bone marrow suppression.

Urinary incontinence
see the paper on Medical treatment of canine urinary incontinence
Unwanted pregnancy
Several estrogenic compounds have been used for this purpose, but for most of them
the risk of side effects has discouraged their clinical application. Only estradiol
benzoate, when given at low doses has proven to be fairly efficacious and relatively
safe. A compound with estradiol benzoate is marketed for veterinary use in mismated
bitches in several European countries, which is to be administered at the dose of 10
mcg/kg SC on day 3, 5 and 7 post breeding. No short-term side effects have been
reported following this protocol. In a retrospective study done in the UK the
incidence of pyometra in the 4 months after the administration of low doses of
estradiol benzoate was 8.7%, whereas the incidence of that condition in a practice
situation was estimated to be < 2.0% (Whitehead, 2008).
BIBLIOGRAPHY and SUGGESTED READINGS
1. American Association of Pediatrics Committee on Drugs The transfer of
drugs and other chemicals into human breast milk. Pediatrics 108:776-789,
2001
2. Bowen RA, Olson, PN, Behrendt, MD, Wheeler, SL., Husted, PW and Nett,
TM. Efficacy and toxicity of estrogens commonly used to terminate canine
pregnancy. J Am Vet Med Assoc 186: 783-788 1985
3. Briggs GG, Freeman RK, Yaffe SJ In: Drugs in Pregnancy and lactation: a
reference guide to fetal and neonatal risk with access code. Lippincott Williams
& Wilkins, New York. 2006
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Reproduction
CLINICAL USE OF GNRH AGONISTS IN SMALL ANIMAL
REPRODUCTION2
Prof. Stefano Romagnoli, DVM, MS, Ph.D, Dipl. ECAR
Department of Animal Medicine, Production and Health,
University of Padova, Agripolis, Legnaro, 35020 (PD)
stefano.romagnoli@unipd.it

Despite their vital role for reproduction, endogenous sex steroids may have negative
effects on fertility and general health.Cyclical stimulation of mammary glands or
endometrium with endogenous estrogens and progesterone is known to predispose the
female to develop conditions such as mammary tumors and endometritis/pyometra.
Androgens are known to predispose male dogs to prostatic hypertrophy as well as
contribute to the growth of prostatic carcinoma and perianal gland tumors. Therefore
gonadectomy has always been advocated as a mean to avoid the risk of developing
uterine or mammary diseases in females and prostatic or perianal diseases in males.
However, both spaying and castration are irreversible modifications which in some
countries are considered not acceptable on cultural or psychological grounds. Also,
surgical neutering carries the risk of increased incidence of health problems such as
urinary incontinence, obesity, change of temperament, dermatological problems (Society
for Theriogenology, 2012).
A recent development in the field of control of the reproductive cycle in carnivores is the
use of gonadotropin-releasing hormone (GnRH) and especially its long acting agonists.
Gonadorelin is a synthetic form of GnRH, while compounds such as buserelin,
deslorelin, goserelin, triptorelin, leuprorelin and nafarelin are synthetic analogues which
are available as human as well as veterinary compounds. For instance, leuprorelin (also
known as leuprolide acetate), triptorelin and goserelin are almost exclusively available
as human drugs, nafarelin is currently studied for its potential use/s in controlling
reproduction in small animals while deslorelin is already marketed for veterinary use in
most western countries as a 2.1 mg, 4.7 mg and 9.4 mg implant; the 2.1 mg implant is
marketed for use in horses (Ovuplant), but its extra-label use in dogs is rather
common, while the 4.7 (Suprelorin) and 9.4 (Suprelorin 12) mg implants are
currently marketed in Europe and Oceania for the control of fertility and aggressiveness
in male dogs but their extra-label use in cats is currently being evaluated. This paper
will review current and potential clinical applications of GnRH agonists in small animal
reproduction.

Excerpts of this paper are taken from the article Clinical usage of GnRH agonists in small animal reproduction from Romagnoli
S, accepted for publication on the journal Clinical Theriogenology

POTENTIAL CLINICAL APPLICATIONS OF GnRH AGONISTS


GnRH agonists act by initially over-stimulating and subsequently down-regulating
GnRH receptors at the gonadotropes in the pituitary, thereby suppressing the function of
the HPG axis. Such a suppressing action on the release of luteinizing hormone (LH) and
follicle stimulating hormone (FSH) leads to an arrest of secretion of gonadal steroids as
well as their by-products. Such blockade of steroidogenesis can be used in dogs and
cats for a variety of indications in prepuberal and adult animals. Some clinical
applications have already been tested and demonstrated useful and effective, while
others are just the result of work in progress or have not been put into practice yet but
are theoretically feasible based on the results of experimental studies.
INDICATIONS FOR PREPUBERAL ANIMALS
Postponement of puberty
Subcutaneous administration of an early GnRH agonist to prepubertal male and female
dogs daily for 23 months partially or completely suppressed dehydroepiandrosterone
(DHEA), andostenedione, T, dihydrotestosterone, 5- androstanes and estrogens in
males, and DHEA and estrogens in females (Lacoste et al., 1989a). Treatment caused a
reduction in testicular and prostatic volume, absence of secondary follicles in the ovary
and atrophy of pituitary LH-secreting cells in both sexes. After a recovery period of 14
months both male and female dogs showed puberty and their fertility was normal
thereafter (Lacoste et al., 1989a). Azagly-nafarelin at the dose of 18 mg in a single depot
device was administered subcutaneously to 10 prepuberal beagle bitches and left in situ
for 1 year. None of the bitches came in heat or ovulated while the 10 control bitches
came in heat regularly during the study period (Rubion et al., 2004). There was no
difference in body weight and growth rate between treated and control animals, and
puberty in treated bitches resumed randomly and in a non-synchronized manner after the
device was removed (Rubion et al., 2004).
GnRH agonists can be used to postpone puberty in cats. We administered a 4.7 mg
deslorelin implant to 12 domestic shorthair European cats, 9 females and 3 males of 1.43.1 kg body weight and 3-9 months of age (Romagnoli et al., 2010). None of the cats
had shown signs of puberty prior to the start of the study, and penile spikes were not
present in any of the 3 male cats. Cats were given a GnRH stimulation test (two blood
samplings before and one hr after IV of 50 g gonadorelin) prior to study onset, and
blood samples for steroid hormone assay were collected monthly for 24 months. 3/9
queens showed signs of estrus one week following implantation, but estrus signs
gradually subdued and did not appear again until the end of the study. Serum T
increased in the 3 tomcats on the post-GnRH sample to adult levels, but penile spikes
never appeared and none of the 3 toms ever showed postpuberal behaviour until the end
of the study (Romagnoli et al., 2010). Similar results in prepuberal queens were
obtained by Risso et al. (2012) when comparing the effect of the 4.7 mg deslorelin
implant in 15 treated and 15 control 4-month old queens followed for a maximum of 18
months with physical exams and vaginal cytology. Average age at puberty was 281+21

and 178+11 days in treated and control queens, respectively, while there was no
difference in weight at the end of the study. One treated queen showed clinical and
ultrasonographical signs of pyometra 92 days after implantation and was immediately
spayed.
GnRH agonists are evidently capable of suppressing the hypothalamic-pituitary-gonadal
axis of prepuberal dogs and cats leading to postponement of puberty for a prolonged
period of time. In dogs, use of deslorelin in young animals shows an age-dependent
response, with pups of 4 months showing no estrus following implantation while all
pups implanted after 7 months of age will show puberty within a short time. Only
prepubertal administration is capable of avoiding implantation-induced oestrus response
(Trigg et al., 2004). However, detailed information on onset of susceptibility to
exogenous GnRH around the time of puberty is not available for dogs and cats. We have
observed vaginal cheratinization and a rise in testosterone in prepubertal queens and
tomcats, respectively, following administration of a 4.7 mg deslorelin implant; however,
these signs were not followed by puberty, which was instead delayed by the implant.
Use of GnRH agonists can be considered as a safe method to postpone puberty in dogs
and queens, while more data are necessary in tomcats to draw the same conclusion
(although a similar effect is likely to occur).
Indications for adult females
Contraception
The gonadal block consequent to the suppression of the HPG axis achieved with a
GnRH agonist causes onset of anestrus in the bitch. An implant of goserelin acetate
(Goserelin acetate, Zeneca, Milan, Italy), administered SC at the dose of 60 g/kg every
21 days for 12 months suppressed cyclicity in 9 adult bitches reducing circulating levels
of estradiol and P4 (Lombardi et al., 1999). Treatment of adult bitches with 3, 6 or 12
mg deslorelin (Suprelorin, Peptech Animal Health, Australia) suppressed heat for
periods varying between 10 (3.0 mg dose) and 20 (6 or 12 mg doses) months (Trigg et
al., 2001). Administration of deslorelin during anestrus or in the early stages of
proestrus will inevitably be followed by induction of estrus within 4-8 days after
implantation (Trigg et al., 2001, Romagnoli et al., 2009), while administration in
diestrus is not generally followed by heat induction (Romagnoli et al., 2009). However,
although a serum P4 concentration of 5 ng/ml is reported as a potential threshold above
which estrus is not induced (Trigg et al., 2001), Fontaine et al. (2010) have observed
estrus induction in 4/28 bitches treated in diestrus. When a GnRH agonist is
administered to an anestrous bitch the initial response of the HPG axis is a strong
secretion of FSH and LH, followed by oestrus, ovulation and development of corpora
lutea. Therefore, if breeding occurs during such an induced phase conception will
follow, but the ensuing pregnancy will only progress until shortly after day 30 because
of the down-regulation of gonadotropins leading to luteal failure (Wright et al., 2001;
Romagnoli et al., 2009). Normal pregnancy followed by parturition may occur if a bitch
is administered a GnRH implant during the second half of gestation, as it may take up to

4 weeks to cause down-regulation, thereby leaving enough time for normal whelping of
live fetuses to occur. The 9.4 mg deslorelin implant has been used in a few bitches,
with interval treatment-return to heat of 11 months (Romagnoli et al., 2009).
In order to avoid inducing estrus following treatment with deslorelin, Wright et al.
(2001) treated anestrous bitches with daily injections of megestrol acetate at 1.0 or 2.0
mg/kg for 2-3 weeks prior to placement of the implant; four/5 bitches treated with 1.0
mg/kg megestrol showed heat, while 0/10 bitches treated with 2.0 mg/kg showed heat
with duration of suppression varying between individuals. When the same 2.0 mg/kg
dosage of megestrol was administered orally for 8 days starting 4 days prior to
placement of a 10 mg deslorelin implant, only 1/10 bitches showed a post-estrus heat
response while 4/10 bitches presented a mild vulvar enlargement (Corrada et al., 2006).
When administered to adult queens at the dose of 4.7 or 6.0 mg, an implant of deslorelin
initially stimulates in most queens follicular growth and oestradiol secretion, after which
no further evidence of estrus is observed for periods of 4-14 (Munson et al., 2001) or up
to 18-26 months (Pisu and Romagnoli, 2012). In Munsons study (Munson et al., 2001)
5/10 treated queens had small estrogen increases after 7.5-14 months at which time they
were administered a second deslorelin implant, while in our study we did not show any
such increase (Pisu and Romagnoli, 2012). It is not known whether deslorelin-treated
queens may ovulate if bred, what is their incidence of spontaneous ovulation and what,
if any, is their incidence of premature luteal failure. General health and social behaviour
remain unchanged throughout the study period, and introduction of a male did not
reverse the deslorelin-induced cycle suppression (Munson et al., 2001). Similar results
were obtained also in female ferrets (Prohaczik et al., 2003).
Oestrus induction
Administration of deslorelin in anestrous bitches at the dose of 1.05 mg, 2.1 mg or
4.7 mg will induce resumption of cyclicity within 2-9 days (Kutzler et al., 2001;
2002; Volkmann et al., 2006a; Kutzler et al., 2009; Romagnoli et al., 2009; Fontaine
et al., 2011). Interval from onset of proestrus until ovulation and onset of
cytological diestrus may be shorter in bitches induced with deslorelin than in
spontaneous cycles (Volkmann et al., 2006a; Kutzler et al., 2009: Fontaine et al.,
2011). Leaving the implant in situ exposes treated bitches to the risk of pregnancy
loss occurring around mid-gestation due to premature arrest of luteal function
(Volkmann et al., 2006a; Kutzler et al., 2009; Fontaine et a., 2011). Administration
of 150 IU human chorionic gonadotropin (hCG) at day 42 post-LH does not solve
this problem as after an initial stimulatory effect on serum P4 a drastic decline is
observed over the next few days (Volkman et al., 2006b). When using a 1.05 mg
implant (half of an Ovuplant) premature luteal failure is less likely to occur but
some suppression of luteal function is still observed (Volkman et al., 2006b).
Incidence of suppression of luteal function can be diminished (or its effects
attenuated) by early removal of the deslorelin implant, provided that it is placed in

easily accessible places such as the vestibular mucosa, the medial side of the leg or
the post-umbilical region (Kutzler et al., 2009; Walter et al., 2011, Fontaine et al.,
2011). Implant removal can be performed either as soon as a vulvar discharge is
observed (Walter et al., 2011), at the time of the LH peak (Kutzler et al., 2009) or at
ovulation (Fontaine et al., 2011). Although comparative evaluations of different
removal times have not been performed, if one considers reproductive parameters of
various studies no clear advantage has been identified in this respect. In bitches
induced to cycle with deslorelin ovulation rate3, conception rate4 pregnancy rate5 and
rate of premature luteal regression6 were studied by:
a) comparing treated and control bitches using a 1.05 mg (half of an Ovuplant) or
the entire 2.1 mg implant administered into the vestibular mucosa (VM) (Volkman
et al., 2006a) = ovulation rate was not calculated, all other parameters did not
differ.
b) comparing the VM vs the SC (between the shoulder blades) administration using
the 2.1 mg implant (Kutzler et al., 2009) = conception rate was either equal or
significantly better and a clear trend for a better pregnancy rate and a lower rate of
premature luteal regression were evident for VM (66.7% and 16.7%, respectively)
vs SC bitches (37.5% and 37.5%, respectively). A control, non-treated group was
not used for this study.
c) comparing treated and control bitches using the 4.7 mg implant (Walter et al.,
2011) = ovulation and pregnancy rates were similar to controls; conception rate
was not investigated; all bitches underwent ovariohysterectomy at day 9-19 postovulation, therefore it was not possible to assess occurrence and rate of premature
luteal failure.
d) comparing bitches treated in early vs late anestrus using the 4.7 mg implant
(Fontaine et al., 2011). Ovulation and pregnancy rates were significantly better
for bitches treated in late anestrus. Luteal failure was diagnosed in 3 bitches, and
the only bitch whose owner did not agree to a supporting P4 treatment aborted on
day 58 after ovulation. A control, non-treated group was not used for this study.
Deslorelin is certainly an effective drug for oestrus induction in bitches: in the studies of
Fontaine et al. (2010; 2011), bitches treated in late anestrus showed heat within 4.2+1.4
days in 97% of cases, ovulation occurred in 83% of cases and quite constantly 12+3
days after treatment, and pregnancy rate was approximately 70%. However, prolonged
pituitary downregulation causing luteal failure despite early removal or using half
dosing remains an unresolved issue. Likewise, prolonged heats and anovulatory cycles
have been observed (Volkman et al., 2006a; Romagnoli et al., 2009; Fontaine et al.,
2010; 2011, Arlt et al., 2011). As the interval between implant insertion and ovulation is
generally short, it has been suggested to remove the implant no later than 15 days post3

Ovulation rate: n of bitches ovulating divided by the total n of bitches


Conception rate: n of foetuses divided by the n of corpora lutea
5
Pregnancy rate: n of pregnant bitches divided by the total n of bitches
6
Rate of premature luteal regression: n of bitches in which serum P4 drops to basal levels during pregnancy divided
by the total n of bitches
4

treatment (e.g. even if the bitch has not ovulated yet) in order to avoid unnecessary
ovarian stimulation (Fontaine et al., 2011).
Prevention of mammary tumor metastatic disease
The role of gonadal steroids in the development of mammary tumors is well established.
Neoplastic transformation of normal cells is thought to be effected by an initiator,
after which abnormal growth is stimulated by a promoter. The mitogenic action of
estrogens on canine mammary epithelium has been described (Battistacci et al., 1974;
Hellmen, 1993). Estrogens are considered potential initiators of neoplastic growth in
different species, often in conjunction with other hormones. For instance, the
initiating role is played by estrogens and prolactin in the rat and mouse, by estrogen
plus a placental factor and perhaps a novel pituitary hormone in monkeys and humans.
In the bitch, the action of gonadal steroids, especially P4, can create a highly
proliferative environment in which an important initiating role is probably played by
growth hormone (Mol et al., 1997). Under the influence of endogenous or exogenous
P4, GH can be secreted by the canine pituitary, and if the progestational stimulus is
prolonged GH can be secreted by the mammary gland as well. Therefore, gonadal
steroids can have a direct as well as an indirect stimulatory action on the canine
mammary gland through the production of their needed co-factor, GH.
Normal and neoplastic mammary tissue features receptors for estrogen, P4, epidermal
growth factors and prolactin. The amount of such hormonal receptors decreases
proportionately to the increase in the degree of differentiation of neoplastic mammary
tissue, with malignant mammary tumors having less hormonal receptors than benign
mammary tumors (Rutteman and Misdorp, 1993). The use of GnRH agonists has
proven effective both in rats with hormone-dependent dimethylbenzanthracene-induced
mammary tumors as well as in pre-menopausal women suffering from advanced breast
cancer (Bakker et al., 1989; Bajetta et al., 1994). A recent study looked at the effect of
goserelin in bitches with spontaneous hormone-dependent mammary neoplasia
(Lombardi et al., 1999). Following assessment of presence of estrogen/P4 receptors on
a biopsy of mammary tissue, 18 bitches with hormone-dependent lobular/invasive
mammary carcinoma were selected and assigned to a control (no drug) or treated
(goserelin) group. The 9 treated bitches received an implant of goserelin acetate
(Goserelin acetate, Zeneca, Milan, Italy), administered SC at the dose of 60 g/kg every
21 days for 12 months. Goserelin treatment reduced circulating levels of estradiol and
P4 and reduced the size of mammary tumors after 3 months in all treated bitches, with
88% of them showing a relapse-free survival time of 2 years (Lombardi et al., 1999).
Although these results await confirmation, the use of GnRH agonists for the treatment of
canine mammary tumors looks promising provided that clinical cases can be selected on
the basis of tumor type and presence of steroid receptors.

Treatment of post-spaying urinary incontinence


The involuntary loss of urine which may occur following spaying in the bitch has a
multifactorial origin, as demonstrated by the fact that no single treatment (whether
medical or surgical) achieves 100% efficacy. The chronic gonadotropin elevation which
inevitably occurs after neutering (because of absence of gonadal steroid negative
feedback) has been considered as a potential cause of urinary incontinence in castrated
bitches. The hypothesis that a down-regulation of gonadotropins using GnRH agonists
may improve or fully cure urinary incontinence was initially considered valid following
clinical trials in which ovariectomized bitches refractory to the use of -agonists who
were successfully treated with a GnRH agonist (leuprorelin, buserelin, triptorelin or
deslorelin) (Reichler et al., 2003). Because of the initial increase in FSH-LH release,
some protocols included also administration of -agonist treatment for the first 3 weeks
(Reichler et al. 2006). Results have been quite positive with periods of continence
varying from 1 to some months following a single treatment with different GnRH
agonists (reviewed by Arnold et al., 2009). Although chronic administration of a GnRH
analogue decreases plasma LH and FSH to basal values, in incontinent bitches there is
little if any correlation between the effect on gonadotropin levels and the response to
treatment (Reichler et al., 2004). Serum concentration of gonadotropins appears to be
involved, directly or indirectly with the pathophysiology of canine post-spaying urinary
incontinence, with a greater role played by FSH. However, the exact pathophysiology
of this condition has not been clarified yet.
Administration of deslorelin has no significant effect on urodynamic parameters, even
when bitches respond positively to the treatment, but rather seems to modulate bladder
function allowing for a larger bladder filling volume at the same bladder pressure
(Reichler et al., 2006a; 2006b). Current clinical information suggests that when treated
with a 4.7 mg deslorelin implant, previously incontinent bitches will show
approximately a 50% recovery rate, with another 10-20% of bitches showing incomplete
response characterized by a reduction in the frequency of incontinence episodes and/or
an improvement in the response to pharmacological treatment with - agonists or estriol
(Arnold et al., 2009). We have also used the 9.4 mg implant in a few cases, with
periods of continence being prolonged up to almost a year (data not shown). In a pilot
study that we conducted in Brazil on efficacy of a 4.7 mg deslorelin implant for treating
canine post-spaying urinary incontinence, 3/6 incontinent bitches were fully continent
for 6 months following treatment, and a considerable improvement (continence of 1-3
months) was observed in the other 3 bitches (data not shown).
Indications for adult males
Contraception
In male dogs, the use of a GnRH agonist will cause a reversible blockade of fertility.
Early studies (Lacoste et al., 1989b) showed that a controlled-release microsphere
formulation providing a daily release of 100-200 mg of a LH-RH agonist causes a
temporary increase in plasma T concentration during the first few days (from 1.5 to 43.5

ng/ml) followed by a decrease to castration levels for a prolonged time. Similar results
were later obtained with implants of 6.6 mg buserelin (Riesenbeck et al., 2002), 18.5 mg
azagly-nafarelin (Ludwig et al., 2006), or 4.7 mg deslorelin (Romagnoli et al., 2005;
Junaidi et al., 2007) . Dogs treated with implants of 6.0 mg deslorelin typically show
initially an acute increase in concentration of LH and T, with both hormones becoming
undetectable after about two weeks (Junaidi et al., 2009a); histologically, disruption of
seminiferous tubules and epithelial atrophy are evident as early as day 16 and 41,
respectively (Junaidi et al., 2009b); clinically, they start becoming infertile within a 6week period and resume normal fertility only after several months (Riesenbeck et al.,
2002). A chronic treatment with a 4.7 mg deslorelin implant causes a progressive loss
of pituitary responsiveness to GnRH over a period of 4 weeks with a lack of response to
stimulation of the HPG with GnRH or LH already evident at 3 weeks and being
complete at 40 days post implantation (Junaidi et al., 2007). The decrease in testicular
size may vary from a 20-30% reduction during the first few months up to 50-60% at 6
months post-treatment (Riesenbeck et al., 2002; Romagnoli et al., 2005; Ludwig et al.,
2006).
In male dogs treated with a deslorelin implant, complete sterility is thought to occur
within a 2-month period (Riesenbeck et al., 2002). We recently looked at semen quality
in 6 adult dogs treated with a 4.7 mg deslorelin implant (Romagnoli et al., 2012).
Complete sterility (based on presence of <10 million of progressively motile sperms
(PMS) and semen volume <0.5 cc) was achieved between 23 and 84 days posttreatment, with 2 dogs being still fertile around 55-60 days post-treatment and beyond.
Also, semen motility and total count actually improved during the first month posttreatment, while semen morphology was unaffected throughout the study, although all
dogs eventually became aspermic. As libido might increase during the first few weeks
post-treatment, clients should be advised about the initial improvement in fertility
parameters as well as of the time needed for deslorelin to achieve complete efficacy.
Once the implant is not functioning any longer, testicular size starts to increase after a
few weeks, T concentrations return back to normal in about 7-8 weeks and testicular
volume is back to normal in about 6 months (Ludwig et al., 2006). Considering the
normal canine spermatogenic cycle of approximately 9 week duration, male dogs treated
with deslorelin will likely prolong their temporary sterile phase for an as long as 9
weeks on top of whatever is the period of recovery, depending on their testicular
conditions at the end of deslorelin treatment.
Reduction of aggressiveness and libido
The decrease in serum T concentration which follows down-regulation of the HPG axis
will cause individual animals to become less aggressive. We observed a decrease in
aggressiveness based on subjective assessment of number and degree of cage fights
while studying serum T secretion in shelter dogs treated with a 4.7 mg deslorelin
implants (Romagnoli et al., 2005). In our clinical experience, the 4.7 mg deslorelin

implant is effective is reducing libido and aggressiveness in male dogs, although


occasional failures are encountered; these are probably due to the fact both these aspects
of a dogs temperament are not fully dependant on serum T concentration, but there is
also a role of experience in their development.
Treatment of androgen-dependent diseases
Benign prostatic hyperplasia (BPH) is the most common canine prostatic disorder, with
more than 50% of intact dogs developing histologic evidence of BPH after 5 years of
age. Hyperplasia is probably due to an altered androgen:estrogen ratio, and requires the
presence of the testes to start and continue to develop. Dihydrotestosterone (DHT)
within the prostate gland probably serves as the main hormonal mediator for
hyperplasia. Castration is commonly considered the best treatment as the drastic
decrease in androgen secretion causes a 70% decrease in prostatic size (due to atrophy)
within 9 weeks (Barsanti e Finco, 1995; Barsanti, 1997). Following administration of a
GnRH agonist, prostatic size decreases in parallel with the decrease of T (Lacoste et al.,
1989b; Ponglowhapan et al., 2002; Riesenbeck et al., 2002; Ludwig et al., 2006). When
5 adult dogs were implanted with deslorelin at a dose of 0.5-1.0 mg/kg body weight,
their prostatic volume decreased more than 50% from week 6 through week 44 when
compared to control dogs, and serum T concentrations decreased 90% from week 8
through 32 of treatment when compared to controls (Ponglowhapan et al., 2002).
Similar results on prostatic growth were observed following treatment with a 6.6 mg
buserelin implant, with disappearance of prostatic cyst and prostate returning to
approximate pre-implantation volume by week 48 (Riesenbeck et al., 2002). We have
observed disappearance of conspicuous (>17 mm diameter) prostatic cysts following
treatment with a 4.7 mg deslorelin implant (Sontas et al., 2010) as well as of larger
(20x25 mm) prostatic cysts in 6 adult male dogs with clinical signs of benign prostatic
hypertrophy with a 4.7 mg deslorelin acetate administered every 6 months (unpublished
observation). An improvement of the clinical situation of all treated dogs was observed
without any additional pharmacological treatment already at the first follow-up visit (1
month after implant administration) and no further sign of prostatic disease has been
observed subsequently in all dogs without any other type of pharmacological treatment
being administered (unpublished observation).
Perianal gland neoplasia is observed in adult male dogs, with adenomas developing
about 4.5 times more commonly than carcinomas. Perianal gland adenomas are
considered a hormone-dependent disease for which castration (without excision of the
gland) can be a successful treatment as it promotes regression without recurrence
(Wilson and Hayes, 1979). We have treated two dogs with perianal gland disease, a 7.1
kg, 16-year old Dachshund Teckel and a 21.5 kg, 12-year old mongrel dog. Both had
clinical signs of perianal gland disease characterized by presence of a round, irregular 24 cm diameter mass which had developed over the last 1-2 months. In both cases,
administration of an implant of 4.7 mg deslorelin acetate was sufficient to cause a long

lasting regression of the perianal mass without any additional treatment (Romagnoli,
unpublished data)
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Reproduction
CLINICAL APPROACH TO INFERTILITY IN THE BITCH
Prof. Stefano Romagnoli, DVM, MS, Ph.D, Dipl. ECAR
Department of Animal Medicine, Production and Health,
University of Padova, Agripolis, Legnaro,
35020 (PD)stefano.romagnoli@unipd.it

Canine infertility can be due to wrong breeding management, reproductive cycle


disorders, non-infectious uterine disease, poor semen quality, failure of the male to
achieve a complete breeding, infectious disease of the reproductive tract, or ovarian

disease; also, non-reproductive or systemic causes may also limit fertility, such as
hypothyroidism, or advanced age of the bitch. From a practical standpoint, fertility
means achieving conception, then establishing a pregnancy through implantation
and carrying the pregnancy to term. As things can go wrong in each one of these
phases, this paper will briefly review the most common factors influencing
conception, the establishment of pregnancy as well as the successful carrying of a
pregnancy to term in canines.
FACTORS INFLUENCING CONCEPTION AND PREGNANCY IN THE
BITCH
Errors in breeding management, anovulatory cycles and ovarian/uterine problems
are frequently encountered as a cause of infertility in bitches of all ages, while poor
semen quality is often a feature of adult to older male dogs. The most common
factors influencing conception and the establishment of a normal canine pregnancy
are listed in order of incidence in Table n 1.
Cause
of
Conception
or Underlying cause
Pregnancy Failure
Breeding Management
Breeding early or late
Reproductive cycle disorders and Anestrus, short cycles, failure to ovulate,
ovarian diseases
ovarian cysts or tumors
Non-infectious uterine Disease
Cystic endometrial hyperplasia, pyometra
Poor Semen Quality
Prostate disease, testicular disease or
degeneration
Failure to Achieve a Normal Lack of experience,no coital lock, poor female
Mating
receptivity
Infectious
disease
of
the Br. canis, Herpes Virus canis, bacterial
reproductive tract
infections
Non-infectious
causes
of Endocrine disease, chromosomal abnormalities,
embryonic-fetal death
improper use of drugs
Table n 1: The most common factors influencing conception and the establishment
of pregnancy in dogs. Factors are listed in order of incidence.
A complete database of information (Table n 2) should be recorded for all previous
seasons for which information is available. Information collected through history
can be used by the clinician to decide whether or not the bitch is cycling normally,
whether or not she was bred/inseminated at the appropriate time and whether or not
reproductive disease is present. Each of the questions on table n 2 addresses a
specific issue which may be relevant for understanding the cause of failure to
conceive.
Breeding management

As most bitches ovulate on day 12 of their season, there is a widespread tendency


of owners to assume that day 12 is the ideal breeding day for all bitches. As a
matter of fact, some bitches ovulate early (such as on day 8, or 6 or even 4 from the
onset of proestrus) while others may ovulate as late as on day 17, 19 or 22-24. One
should never assume that a given bitch will ovulate on day 12 unless proven. Also,
incidence of early or late ovulation is probably higher in the those bitches who are
taken to the veterinarian with a presenting complaint of infertility with respect to
the normal canine population; bitches ovulating on day 12 from the onset of
proestrus will always conceive at the first mating and therefore will almost never be
taken to the veterinarian because of fertility problems. Managing a canine breeding
requires the client taking the bitch to the veterinary clinic as soon as the first signs
of proestrus are displayed (vulvar discharge, male attractiveness) for a first check,
and then coming back every 2-3 days to monitor how quickly the female is
progressing towards ovulation through vaginal smears and serum progesterone
assays. Vaginoscopy and ovarian ultrasound can be very helpful clinical tools in
identifying and monitoring the ovulation process. When the first day of ovulation
is identified, there are still a few days to achieve a breeding, thanks to longevity of
canine oocytes (4-5 days following ovulation).
Performing vaginal citology as well as checking the bitchs behavior to look for
onset of male receptivity are the 2 most practical ways of determining the best time
for breeding. Owners should be instructed to bring their bitch to a male dog to
check her behavior regularly as soon as possible after proestrus onset as well as to
have a vaginal smear taken from the veterinarian every 2-3 days. Breeding should
be performed as soon as the bitch stand and/or as soon as her smear is fully
cornified, in order not to miss early ovulators. However, behavior does not always
correlate with vaginal citology: some bitches will not stand to be mounted even
though their smear is fully cornified.

THE INFORMATION
ON:
Date of onset of
proestrual bleeding
Date of onset of first
receptivity
Breeding/s: dates,
out/inside tie, AI, fresh
vs frozen semen
Date of first refusal of
mating
Male fertility, age,
semen colture
Brucella canis antibody
status (bitch & dog)
Pregnancy status at 28
days
Previous normal
whelping/s, litter/s
Previous signs of false
pregnancy
Previous reproductive
disease
Previous nonreproductive disease

IS IMPORTANT FOR:
Estimating ovulation (in most bitches occurs on day
12 after onset of proestrus)
Estimating ovulation (in most bitches occurs 2 days
after start of receptivity)
Estimating on potential fertility as breedings with
outside tie may not be fertile; frozen semen must be
placed into the uterus 2 days after ovulation
Correlation with onset of cytological diestrus, which
is helpful to estimate ovulation
Assessing male responsibility: prostatic disease
(common in adult-older dogs) and
orchitis/epididymitis may alter semen quality
Evaluating presence of B. canis role in infertility
(Important in countries where it has been isolated)
Assessing whether conception took place

Assessing whether fertility was previously present or


if it may be a congenital problem
Ruling in/out ovulation (false pregnancy occurs only
after ovulation)
Assessing whether or not previous pathologic
conditions of the reproductive tract may affect fertility
Assessing whether clinical signs of other system may
have relevance on fertility (kennel cough may be due
to herpes virus)
Previous hormonal
Assessing potential negative effect of of previous
therapy
administration of progestogens
Table n 2 Questions to be asked when collecting reproductive history for
cases of canine female infertility and reasons for their importance.
Provided that vaginal abnormalities (strictures, bands of tissue, hymen) are ruled
out, serum P4 as well as using different male dogs (to rule out male preference) are
helpful in such cases, although some bitches become receptive to mating only in
mid to late estrus. Ovulation should always be timed using serum P4 assay every 23 days and the bitch should be bred when a high P4 value is observed (>5.0 ng/ml).
Vaginal cytology should also be used to confirm serum P4 data (serum P4 kits
which use a semi-quantitative colorimetric system are only 80% accurate) during
and (most importantly) after breeding until the first day of cytological diestrus (D1)
is identified, which occurs 6-8 days after ovulation. Vaginal endoscopy is also a
helpful tool to stage the estrous cycle. Estradiol stimulation causes vaginal mucosa
to become edematous, therefore during proestrus and early estrus vaginal folds

appear round and swollen with some blood-tinged fluid in between them. As soon
as follicular estrogen production stops fluid is resorbed from the vaginal mucosal
lining and therefore vaginal folds suddenly become wrinkled (a process called
crenulation). As the wrinkling process is associated with a decrease in estradiol
rather than an increase in progesterone, the crenulation is only an indirect indicator
of ovulation. Therefore, vaginal endoscopy is a good way of identifying and
monitoring the estradiol curve, but cannot be used to identify ovulation directly:
serum progesterone remains a vital indicator in this respect.
Reproductive cycle disorders and ovarian diseases
Prolonged lack of heat or anestrus is sometimes observed especially in older bitches.
Frequent cycling (3-4 heats/year) is also observed in bitches of all ages, and has
been associated with infertility, although the mechanism involved is not yet clear.
Anovulatory cycles occur fairly frequently (although there is not enough
information on their incidence) both at puberty as well as in the adult bitch. When a
bitch experiences an anovulatory cycle, her reproductive behavior is generally
normal, i.e. she attracts male dogs, has a normal vulvar discharge and accepts
breeding. Ovarian disease (ovarian cysts or ovarian tumors) are a rare cause of
infertility in bitches due to the fact that incidence of ovarian cysts or tumors is
higher in adult to older bitches (the older the bitch the less likely she is to be used
for reproduction). The most common presenting complaint of ovarian cyst or tumor
is prolonged heat due to a high estrogen production. Ovarian cysts and tumors have
occasionally been reported in bitches as young as 2-3 years of age.
Non-infectious uterine disease
Uterine pathology is a common cause of failure to conceive both in bitches and
queens. The bitch experiences 2 estrous cycles/year, with spontaneous ovulation,
development of corpora lutea and progesterone secretion for about 2 months. The
progesterone stimulation on the uterine lining (the endometrium) causes
accumulation of secretion of endometrial glands with formation of cystic structures
(cystic endometrial hyperplasia = CEH). Such cystic structures are very important
for feeding the embryos, and if the female is not pregnant they normally regress
towards the end the luteal phase (also called progestational phase or diestrus),
leaving the endometrium free to regenerate and be ready for the next chance for a
pregnancy. If the female is rarely if ever mated, these cystic structures will
eventually persist, thereby making large sections of the endometrium unsuitable for
the establishment of pregnancy. Uterine disease is not believed to be a problem in
breeding establishments where bitches are bred and conceive on a regular basis, as
pregnancy may have a protective effect on the endometrium. Unlike breeding
bitches, the average intact bitch kept as a pet may experience problems in becoming
pregnant if bred only as an adult dog, due to the deterioration of her uterine lining.
Endocrine diseases such as inadequate production of progesterone or thyroid
hormones during pregnancy may cause abortion. Also, diabetes, adrenal

insufficiency and other endocrine diseases may affect foetal viability. The improper
use of drugs may also have an adverse effect on pregnancy. Chromosomal
abnormalities are widely described as a cause of embryonic/fetal death in the dog.
Collecting a whole blood sample and submitting it to a laboratory for karyotype
should never be overlooked when dealing with an abortion case. Luteal
insufficiency is a recognized cause of failure to carry a pregnancy to term in the
bitch.
Poor semen quality
Dogs ejaculate 500-2000 million spermatozoa diluted in 2-50 cc of seminal plasma.
Quantity of spermatozoa as well as of seminal plasma varies according to body
weight and testicular size, with Yorkshire terriers and Great Danes producing an
average of 2-3 and 20-30 cc of ejaculate, respectively. Semen quality depends on
quantity of spermatozoa present, their motility and morphology. Assessing semen
quality is an easy task which can be performed in any veterinary clinic, provided
that the male dog is accustomed to the technique or a bitch in heat is available to
help him concentrate on ejaculation. Semen collection is generally performed with
manual stimulation of the dogs penis through an artificial vagina (a latex cone
connected to a plastic tube) or just wearing a latex glove in one hand and a smooth
glass or plastic container in the other hand. Once collected, the semen must be kept
in a warm environment (holding the tube in ones hands is enough) while it is being
checked for motility (under a light microscope at 100X), morphology (under light
microscope at 200-400X following staining with any cytological stain such as Diff
Quick, haematoxylin-eosin or Leishman blue) and number of spermatozoa (using a
haemocytometer such as a Niebauer chamber, Thomas chamber or Makler
chamber). Poor semen quality can be found in adult to older male dogs, especially
if suffering from prostate disease or following orchitis/epidydimitis or scrotal
trauma. Poor semen quality can be due to also to inbreeding causing early testicular
degeneration.
Failure to achieve a normal mating
Young stud dogs at their first attempts at breeding may sometime apparently look
not capable of mounting properly, e.g. they may approach the female from her flank
or from her head, or may spend a considerable amount of time pelvic thrusting
without achieving an intromission. Although this should be considered part of the
normal process of learning reproductive behaviour in young animals, it is
considered abnormal when displayed by adult male dogs. Sometimes a male dog
may achieve an incomplete intromission in which the bulbus glandis will engorge
outside of the vulva. When this occurs, ejaculation may take place more caudally in
the vestibule instead of in the most cranial aspect of the vagina, with a consequent
loss of semen due to a retrograde flow of spermatozoa outside the vulva or to a
higher degeneration rate of spermatozoa due to the acidic pH of the vagina. Not

achieving an inside tie in the dog may be due to lack of experience, disease of the
penis or lack of libido. When collecting history for a case of infertility it is
important to check whether or not a coital lock or an inside tie (penis engorged
and temporarily blocked into the vagina) occurred. Although outside-tie breedings
may be fertile, an outside tie should always be ruled out when investigating causes
of canine infertility. Partial or complete failure to accept breeding can also prevent
normal mating to occur. If the bitch does not accept to be bred she might not be at
the proper time for breeding, might have a vaginal septum or persistent hymen or a
vaginal mass (hyperplasia, neoplasia) which causes her to feel pain at penetration or
might have a behavioural problem (mate preference).
Infectious disease of the reproductive tract
Infectious diseases of the canine reproductive tract which can be responsible for
infertility include bacterial infection such as brucellosis due to Brucella canis (rarely
Brucella abortus or suis), infection due to salmonella species, streptococci and E.
coli; viral diseases such as herpes virus, distemper, parvovirus 1 and 2, and to the
parasites Toxoplasma gondii and Neospora caninum. Incidence may vary
depending on the country and the area/s within each country. Brucella canis and
herpes virus are highly contagious. Other bacterial infections (salmonella,
streptococcus, E. coli) and toxoplasmosis are less contagious and tend to be a
feature of the individual bitch. Not much is known about the role of Neospora
caninum in canine abortion. Herpes virus has always been known as a cause of
abortion. A herpes virus vaccine has recently been introduced in Europe, to be used
in pregnant bitches. The vaccine is supposed to be used repeatedly in pregnant
bitches, initially during early pregnancy followed by a booster injection during the
last third of pregnancy. The company claims that such a use is improving fertility in
bitches which, if confirmed, would further substantiate the role of canine herpes
virus as a cause of failure to conceive.

CLINICAL APPROACH to INFERTILITY in the BITCH


The clinical approach to canine infertility varies depending on the suspected cause.
Poor breeding management
have the bitch come back at the beginning of her season, and plan every other day
vaginal cytology from day 1 of her proestrus, and serum progesterone assay every
other day from the first day in which the smear becomes approximately 50%
cornified.
Reproductive cycle disorders and ovarian dieases
Ovarian cysts/neoplasia can be investigated with ultrasonography; canine
preovulatory follicles are about 6-8 mm diameter, and any ovarian follicle of >1.0

mm and/or persisting for more than 2-3 days should be considered abnormal; canine
ovarian cysts respond poorly to GnRH, but a course of 3-5 day treatment with 3-5
injections/day should be enacted; the dose is 1/10 of the dose for treating ovarian
cysts in dairy cows. Anovulatory cycles can be diagnosed by lack of progesterone
secretion after the end of estrus; there is no information on treatment for this
conditions, but it generally does not occurs twice in a row. Bitches in prolonged
anestrus can be treated with a 2-4 week course of cabergoline at the regular antigalactogenic dose (5 mcg/kg) once daily; the treatment should be stopped once a
bloody vulvar discharge is observed indicating the onset of proestrus.
Non-infectious uterine disease
The clinical approach to hypoluteoidism includes assessing maternal and fetal
conditions, ruling out other possible causes of abortion and repeatedly measuring
serum progesterone (P4) concentrations. In a bitch with a history of infertility due to
a suspected luteal insufficiency, P4 monitoring should start 5-to-7 days after the last
breeding and should be done once/week. Treatment includes administration of a
natural or synthetic P4 compound to support pregnancy as long as needed. The use
of synthetic P4 compounds prior to day 30 of gestation should be avoided since it
may induce malformation of the genital system of female foetuses. Protocols used in
bitches with luteal insufficiency include daily administration of Allyl-trenbolone,
0.088 mg/kg, orally, Medroxyprogesterone acetate (0.1 mg/kg), orally, or natural
progesterone 200 mg BID orally. Treatment should be withdrawn no later than
gestation day 60, as a prolonged P4 administration may inhibit the mechanism of
parturition. However, there is not enough data to advice a specific time interval prior
to the expected date of whelping during which P4 administration should be
withdrawn, and treated bitches very often end up in having a C-Section. Progestin
administration during pregnancy may negatively affect the canine lactation.
Poor semen quality
There is little if any treatment that can be done to improve semen quality in male,
unless this is due to a treatable contingent cause (such as orchitis/epidydimitis,
prostatic condition, fever, systemic disease). When low semen quality is due to
aging or precocious testicular atrophy, there is no treatment which can reverse the
condition. In oligozoospermic dogs improvements in semen quality are anecdotally
reported using PGF2a 0.1 mg/kg 15 minutes prior to semen collection, or using
gonadorelin 3.3 mcg/kg IM once weekly for 4 months (Hess, 2006), or a GnRH
agonist (Kawakami, et al., 1998).
Failure to achieve a normal mating
Once wrong breeding management is ruled out, the vagina should be examined
digitally, then using endoscopy and, if nothing is observed, using a retrograde
vaginography. Minor vaginal/vestibular restrictions (fairly common) can be
resolved manually by gentle manipulation, while partial persistent hymen often

resolves on its won at parturition. More relevant anomalies (large septa, complete
hymen, vaginal neoplasia or hyperplasia) should be dealt with on a case-by-case
basis, surgically if necessary. Mate preference or behavioural problems can be
solved using artificial insemination.
Infectious disease of the reproductive tract
Infectious diseases causing abortion will be dealt with in the chapter on
Complications in canine pregnancy. Bitches infected with Herpes Virus should be
vaccinated with the Herpes Vaccine twice (once 10 days after mating and again 6
weeks later). Bitches infected with Brucella canis should be eliminated from the
breeding kennel, and best ovariohysterectomized. Bitches suffering from any other
type of infection during the previous cycle should be checked early in proestrus
performing bacteriology of the cranial vagina, and treated with specific antibiotics
until ovulation.
BIBLIOGRAPHY and SUGGESTED READINGS
1. Gorlinger S, Galac S, Kooistra HS, Okkens AC, 2005 - Hypoluteoidism in a
bitch. Theriogenology 64, 213219.
2. Hess M Documented and anecdotal effects of certain pharmaceutical agents
used to enhance semen quality in the dog. Theriogenology 66:613-617, 2006
3. Kawakami E, Hori T, Tsutsui T. Changes in plasma LH and testosterone
levels and semen quality after a single injection of hCG in two dogs with
spermatogenic dysfunction. J Vet Med Sci 1998;60:7657
4. Kustritz MVR, 2001: Use of supplemental progesterone in management of
canine pregnancy. In: Concannon PW, England GCW, Verstegen J. (eds),
Recent advances in small animal reproduction, International Veterinary
Information Service (www.ivis.org). Document No. A1220.0401
5. Fieni F, Martal J, Marnet PG, Siliart B, Bernard F, Riou M, Bruyas JF,
Tainturier D Hormonal variation in bitches after early or mid-pregnancy
termination with aglepristone. J Reprod Fert Suppl 57: 243-248
6. Feldman RW, Nelson EC Infertility, associated breeding disorders and
disorders of sexual development. In: Feldman and Nelson, Canie and
Feline Endocrinology and Reproduction. 3rd edition, WB Saunders, 2004,
pp 868-900
7. Johnston SD An algorithm for clinical approach to infertility in bitches.
In: Proceedings of the Annual Meeting, Society for Theriogenology,
Denver, Colorado, September 1984, pp 25-32
8. Johnston SD, Root-Kustritz MV, Olson PNS Clinical approach to canine
infertility. In: Canine and Feline Theriogenology. Editors SD Johnston, MV
Root-Kustritz and Olson PNS, WB Saunders 2001, pp 245-274
9. Meyers-Wallen VN - Unusual and abnormal canine estrous cycles.
Theriogenology 68, 1205-1210. 2007

10.Thomas PGA, Perkins NR History taking and diagnostic assessment of


the subfertile bitch. Austr Vet Pract 23:34-43, 1993
11.Tibold A and J Thuroczy - Progesterone, oestradiol, FSH and LH
concentrations in serum of progesterone-treated pregnant bitches with
suspected luteal insufficiency. Reprod Domest Anim. 2009 Jul; 44 Suppl
2:129-32.
12.Ramsey I, Herrtage M - Distinguishing normal, sick and hypothyroid
dogs using total thyroxine and thyrotropin concentrations. Canine Practice
22:43-44, 1997
13.Reimers TJ Endocrine testing for infertility in the bitch. In: Kirk RW ed,
Current Vet Therapy VIII, WB Saunders, 1983, 922-925

Reproduction
COMPLICATIONS IN CANINE PREGNANCY AND THEIR CLINICAL
APPROACH
Prof. Stefano Romagnoli, DVM, MS, Ph.D, Dipl. ECAR
Department of Animal Medicine, Production and Health,
University of Padova, Agripolis, Legnaro, 35020 (PD)
stefano.romagnoli@unipd.it

In the bitch as in most other species death of conceptus can occur at any stage of
pregnancy, resulting in partial or total resorption, partial or total abortion or
retention of foetuses which can become mummified or be colonized by bacteria
causing a pyometra. The type of outcome depends on what has caused
embryonic/fetal death, the stage of pregnancy and fetal/maternal
immunocompetence. Abortion is often difficult to diagnose as the bitch rarely
shows well defined clinical signs (often no signs at all or just a short lasting malaise
or anorexia) but it can in rare instances become a life-threatening situation leading
to shock. A relevant clinical problem is the lack of an early pregnancy test which
would allow to monitor embryonic well-being and diagnose embryonic death. Also,
the availability of a histopathological diagnosis on aborted fetuses is frequently
hampered by lack of owner collaboration as well as by the fact that bitches often
devour or hide dead fetuses. Aborted fetuses and/or placentae (the more the better)
should refrigerated at 4C and shipped to the diagnostic laboratory within 24 hours
of death.
Incidence of canine embryonic resorption or spontaneous abortion is not well
defined. On laparotomy it has been observed a 5-13% difference between n of
corpora lutea and n of fetal vesicles. On ultrasound embryonic death is
characterized by lack of vesicle growth, reduction of volume of the embryo mass,
loss of vesicular roundness, reduction of volume and ecogenicity of embryonic
fluids. Death of one or more embryos may not be detrimental to survival of the
other embryos even on the same uterine horn. Clinical signs at this stage are
frequently absent. Abortion is characterized more frequently than resorption by
general clinical signs (from very mild signs to one or more fo the followings:
anorexia, fever, depression, vomition, abdominal pain, shock) especially if not all
dead fetuses are expelled. Fetal mummification can occur in absence of bacterial
contamination, which is - again - often not accompanied by clinical signs, with
mummified fetuses occasionally found unexpectedly during a laparotomy or a
survey abdominal radiograph.

Death of conceptus can be due to developmental defect,maternal


endocrine/metabolic imbalance, infectious disease of the reproductive tract, trauma,
improper use of drugs.
Developmental defects
Karyotype abnormalities reported in the bitch which may be responsible for death of
the conceptus include monosomy and trisomy of the X chromosome, translocations
and chimerism. It is generally believed that chromosomal anomalies are very rare
as a cause of embryo/fetal death, but there is a paucity of data due to the fact that it
is often difficult to find a laboratory which performs karyotyping, and the test in
itself can be quite expensive. The true incidence of this phenomenon in the canine
could be higher than expected, and most researchers agree that the reduction in
fertility observed in highly inbred populations is due to developmental defects. In
case of a spontaneous abortion, karyotyping should always be performed. Incidence
of congenital anomalies and spontaneous abortion is directly proportional to the
degree of inbreeding.
Maternal endocrine imbalance
Hypothyroidism
Thyroid insufficiency, a relatively frequent endocrine disease in women, is
associated with an increased risk of spontaneous abortion. Hypothyroidism is also
relatively common in dogs and a relationship with low fertility in the canine,
although still not yet confirmed, is strongly suggested. As in women, canine T3, T4
and thyroid binding globlulin are higher during pregnancy. Spontaneous abortion
in dogs could be related to hypothyroidism. Hypothyroid bitches should be
considered to be at a higher risk of spontaneous abortion. Bitches with a history of
abortion should have their thyroid function checked, and the thyroid function of
those undergoing thyroid treatment should also be carefully evaluated during
gestation.
Luteal insufficiency
In women luteal insufficiency (which is characterized by short cycles, low serum
progesterone concentration during the luteal phase and insufficient endometrial
development) is reported as a cause of spontaneous abortion. Luteal insufficiency
(or hypoluteoidism) occurs also in otherwise normal women and can be successfully
treated with a repositol progesterone treatment. Progesterone is the key hormone for
endometrial development, uterine secretions, endometrial growth, establishment and
maintenance of placental attachments, inhibition of uterine motility, elimination of
leukocyte responsiveness in the uterus and development of mammary glands
(Kustritz, 2001; Feldman and Nelson, 2004). In polyestrous species, P4
concentrations can be used to rule out a pregnancy. However, this cannot be done in
the dog as P4 concentrations are similar in both pregnant and non-pregnant bitches
(Concannon et al., 1975).

Diagnosis
The diagnosis of luteal insufficiency is based on the demonstration of a very low
progesterone concentration during pregnancy in the absence of any other sign of
disease. This bears clinical relevance as it should be noted that a low serum
progesterone concentration in a bitch with an impending or recently occurred
abortion, may not necessarily mean that abortion is due to a primary luteal
insufficiency (Kustritz, 2001). Fetal distress may cause a decrease in progesterone
concentration as a normal physiologic response (Johnston et al., 2001). Therefore, it
is important to rule out bacterial or inflammatory conditions of the uterus which
may cause a decline in the progesterone level by stimulating the release of
prostaglandin from the endometrium. Furthermore, also, non-infectious causes (such
as the genetic abnormalities of the pups, systemic diseases of the bitch or trauma)
should be ruled out (Kustritz, 2001).
In order to confirm a diagnosis and administer a treatment,serum/plasma
progesterone concentrations should be measured with a RIA or chemiluminence
since the degree of accuracy of semi-quantitive in-house assays is not reliable for a
diagnosis of luteal insufficiency (Kustritz, 2001; Grlinger et al., 2005). Bitches
with a history of abortion or failure to conceive after several matings should be
closely monitored after onset of proestrus. Vaginal cytology as well as serial LH and
progesterone measurements should be performed to determine accurate timing of
the ovulation and to confirm luteal insufficiency. However, dystocia, pyometra or
septicemia may occur during treatment if miscarriage is due to a fetal abnormalities,
placentitis or intrauterine infection. Because of this reason, it is imperative that
diagnosis of luteal insufficiency is confirmed before treatment. Unfortunately there
is a lack of information on what is the serum progesterone concentration for each
stage of the canine pregnancy. Table n 1 shows a compilation of serum
progesterone concentrations throughout the canine pregnancy based on differrent
studies.

Days
Study
Smith
and
McDon
ald,
1974
Concan
non et
al.,
1975
Onclin
and
Versteg
en,
1997

LH
Ov
Surg ulat 2-14
e
ion

20-30
ng/ml
(Day
10)

1.41.8
ng/m
l

17-22
ng/ml
(Day
10)

1.82.0
ng/m
l

Concan
non,
2000

16-18
(implanta 18-25
tion)
35-40
ng/ml

40-50
ng/ml
(Days
20-25)

20-26
ng/ml
(Day
25)

30 ng/ml
(Day 16)

25- 3535 45

4555

55-65

2540
ng/
ml

1020
ng/
ml

5
ng/ml
(Day
65)

0,70,9
ng/ml

1.52.0
ng/ml
(Day
64)

315
ng/
ml
Day
s
5060

2ng/
ml
Day
65

1530
ng/
ml
-

33-38 ng/ml

15-80 ng/ml
Days 15-30

Table n 1. Different values of P4 concentrations during various stages of canine


pregnancy. Datas are standardized and counted from ovulation (compiled and
extrapolated from Smith and McDonald, 1974; Concannon et al., 1975; Onclin and
Verstegen, 1997; Concannon, 2000)
Treatment
Luteal insufficiency has been treated by supplementation with a suitable
progesterone or progestagen chosen based on the stage of pregnancy (Kustritz,
2001; Grlinger et al., 2005). Progestagens are compounds which act like
progesterone in preparing or maintaining the female reproductive tract for
implantation and pregnancy, and are commonly used for the treatment of

behavioural disorders or for the control of reproduction in small animals


(Romagnoli and Concannon, 2003). The progestational properties of many such
compounds have been well documented in all species, including the bitch (Goyings
et al., 1977, Purswell, 1991; Eilts, 1992; Von Berky and Townsend, 1993; Eilts et
al., 1994).
Prior to the progesterone/progestogen supplementation, it is crucial to verify
presence of live fetuses by ultrasonography. Progesterone supplementation in a
pregnant bitch with non-viable fetus may inhibit uterine contractions and abortion
(Memon and Mickelsen, 2000; Kustritz, 2001) whereas it may induce
masculinization of female fetuses if administered during organogenesis, which in
the bitch is complete around day 25 post-ovulation, as observed by Curtis and Grant
(1964) in a Boxer bitch treated with norethindrone during pregnancy 4 weeks after
the last mating. Accurately staging pregnancy is very important for deciding which
compound to use and when to withdraw the treatment since the half-life of each
progestagen is different. Long acting progestagens such as medroxyprogesterone
acetate or proligestone have longer half-lives whereas others such as megestrol
acetate or natural progesterone have a faster metabolism (Loose-Mitchell and
Stancel, 2001). A long-acting compound may prevent parturition causing the birth of
stillborn pups and even maternal health problems if administered in late pregnancy,
whereas ending a treatment too early may result in the birth of immature pups.
Therefore, the period of pregnancy should be determined prior to the treatment by
ultrasonography, radiography or progesterone measurements.
A few natural/synthetic progesterone compounds have been used with success in the
treatment of hypoluteoidism, such as progesterone at the dose of 2 mg/kg
intramuscularly on days 50 and 53 of pregnancy, ally-trenbolone, at the dose of
0.088 mg/kg/day (from mid-term on, following ovariectomy) and
medroxyprogesterone acetate, orally, q24 hours, at a dose of 0.1 mg/kg, between
days 42-58 of pregnancy (Purswell, 1991; Eilts et al. 1994; Grlinger et al., 2005).
We have used 1-2 (depending on body weight) progesterone capsules (a human
progesterone compound) at the oral dose of 200 mg/capsule. The problem with
administration of natural/synthetic progesterone compounds during the canine
pregnancy is that it is very difficult to establish when to stop treatment in order to
allow normal parturition to occur: in most cases of luteal insufficiency treated
bitches end up in having a C-section as parturition does not start on day 63 after
ovulation. In some cases lactation has been observed to be delayed of a few days
following natural/synthetic progesterone treatment in late pregnancy; this is
probably due to the fact that the postpartum increase in prolactin concentration
requires a drop in progesterone.
Diabetes Mellitus
In women, pregnant hyperglycemia is potentiated by a placental insulinase (a
mechanism which has not been investigated in the bitch), leading to hypoglycemia

which may (especially in diabetic patients) cause intrauterine death. Hypoglycemia


during pregnancy in humans can cause hypoglycemic coma around the 12th week
and diabetic coma around the 20th week (because of an increased need of insulin).
In women, a worsening of diabetic conditions during pregnancy carries an increased
risk of hypertension, eclampsia, urinary tract infections and placental detachment.
Glycaemia-related pregnancy disorders share some similarities in the canine and
humans species. In the bitch (as in women and in a few other species) a serum
progesterone rise is followed by a rise in serum growth hormone (GH)
concentration. Such an increased GH concentration (due to progesterone-induced
activation of GH-secreting foci in the mammary glands ) causes insulin resistance
and hyperglycemia. In the pregnant bitch insulin requirements increase during
pregnancy because of the rise in serum progesterone and the consequent rise in
serum GH. Insulin requirements also have a peak at parturition and then subdue in
the postpartum period.
The increased risk of neonatal mortality in diabetic bitches is due to an increased
risk of fetal malformations, respiratory diseases as well as neonatal hypoglycemia.
Diabetic bitches have been reported to whelp macrosomic foetuses (causing an
increased risk of dystocia), which could be due to an increased secretion of fetal
insulin in response to the increased glucose availability in the maternal circulation.
Conversely, in the pregnant bitch use of a diet with low caloric content is associated
with smaller litter size
Diabetic ketoacidosis (DKA) has been reported in the bitch. In dogs, the aetiology
of the condition is unknown however progesterone, estradiol, growth hormone and
placental cytokines are believed to be involved in the pathogenesis of the disease
(Johnson 2008). In a retrospective study by Fall et al. (2008), a breed predisposition
toward Nordic Spitz breeds to GDM has been reported due to the number of dogs
involved (11 of 13). We recently observed a case of DKA in a 6-year old pregnant
Yorkshire Terrier bitch was presented on the 62nd day after mating with a history of
two-days vomiting and coughing and a two-weeks history of polyuria and
polydipsia. Complete blood count, serum biochemistry, and urinalysis revealed
hyperglycaemia, ketonemia, ketonuria and metabolic acidosis. Gestational diabetes
mellitus was diagnosed. Following an emergency treatment with fluid therapy,
prophylactic antibiotics and regular insulin, the bitch whelped six healthy normal
puppies. Two weeks later, the bitch was clinically normal (Armenise et al., 2011).
Hypo-Hypercorticalism
Both disfunctions, although rare in pregnant women (because affected patients have
anovulatory cycles), are characterized by a high incidence of fetal death when
treatment is not performed during pregnancy. Although no information is available
in the dog concerning incidence of fetal death in bitches with hypo- or

hypercorticalism (also because these dogs are not generally bred), adrenal pathology
should always be ruled out when considering a case of fetal death.

Infectious diseases of the reproductive tract


Brucella canis
Like all other brucella infections, Brucella canis infection causes endometritis,
placentitis and late abortion in the female, epididymitis in the male. Following
infection (characterized by mild clinical signs) B. canis proliferates in lymphnodes,
spleen, bone marrow and Peyer patches, after which it invades the reproductive tract
(uterus, epididymis, prostate). Pregnant bitches will either abort between 30 and 57
days gestation (showing prolonged bloody vulvar discharge) or have a high
postnatal mortality. Fertility of breeding kennels may fall from 90% to 30% during
the first year after an epidemic. Diagnosis is achieved through isolation of B. canis
from the blood (leukocyte fraction) aborted fetuses, vulvar discharge, seminal fluid
and various lesions of dogs with clinically evident disease. The Rapid Slide
Agglutination Test is sensitive but not very specific, therefore all positive
individuals must be rechecked with the Tube Agglutination Test, immunodiffusion,
complement fixation or PCR. Treatment consists of associations of antibiotics
(tetracycline + streptomicine, minocycline + streptomicine or oxitetracycline and
streptomicine) but it is long and efficacy is not 100%. Following complete
recovery a dog may become infected again. Because of costs, length and degree of
efficacy of treatments, in the US it is recommended that affected dogs of breeding
establishments are euthanized. B. canis infection has been reported in France in
1996.
Herpes Virus canis
(CHV) - CHV is a DNA-virus whose growth is stimulated at temperature (T) of 3537 C, and inhibited at T > 39C. It generally causes disease only in immunocompromised individuals in which it is responsible for late abortion, neonatal
septicemia and urogenital as well as respiratory (kennel cough) diseases. In adults
dogs the virus replicates at the point of entry (genital or respiratory system) causing
a mild disease (kennel cough or vaginitis) while pregnant bitches may abort
showing signs of placentitis and fetal/neonatal infection. Fetuses may contract the
infection while passing through the birth canal. The immaturity of the
thermoregulatory mechanism of canine neonates creates optimal condition for the
development of CHV. CHV causes a weak and short-lasting immunologic response
after which, similarly to other herpes viruses becomes latent in sensory ganglia. Tlymphocytes are very important for the hosts defense mechanism, therefore
whenever their function is depressed (i.e. during a parvovirus infection, an
immunosuppressive treatment, pregnancy, the perinatal period, or during stress)
CHV may become clinically evident.

Diagnosis of CHV has been historically difficult because of problems in isolating


techniques and low serum titers during the clinical disease. The use of PCR
techniques has solved almost all diagnostic problems. However, a negative PCR
response may not mean that the animal does not harbor the virus while a positive
PCR response is 100% accurate. In a longitudinal study (Ronsse et al., 2005) some
seropositive bitches became seronegative during the trial on one or more occasions,
with antibody titers showing the lowest levels in diestrus PCR is best performed on
samples of fresh blood/semen or body fluid (vaginal/bronchial flushings). Samples
of semen or vaginal flushings must be shipped to the diagnostic laboratory in liquid
nitrogen. There is no specific treatment. Anti-viral drugs used in human medicine
have not been tested in small animals. It is very important to keep neonates in a
warm environment and have them suckle at least 4 times/day. The highest risk of
infection occurs during the 3 weeks prior to and the 3 weeks after parturition. The
same female may abort more than once, but generally colostral antibodies will
protect puppies as long as they are kept in warm environment. Differential
diagnosis of CHV include infectious hepatitis, acute toxoplasmosis, B. canis
infection.
CHV is presumed to be enzootic in the canine population (as well as in other
species). Because of the virus being poorly immunogenic (typical antibody titers
range from 1:1 to 1:2), testing at a single time point will not always give reliable
results on the infection status of the animal. In order to identify presence of CHV in
a kennel, is is preferable to sample several dogs at the same time or the same dog
repeatedly on consecutive days. Diestrus should be avaoided as a sampling time,
while sampling should be performed at times when clinical signs of reproductive
disease are present. The overall prevalence of CHV in the canine population is
likely to be underestimated. Risk factors for presence of CHV in a breeding kennel
are a history of kennel cough, the use of external dogs for reproduction, poor level
of hygiene, large kennel size and increasing age of the dogs present (Ronsse et al.,
2005). A vaccine for CHV has been commercially available in Europe for several
years. Because of the latency of CHV and because of the risk of underestimating
its prevalence, use of the CHV-vaccine in pregnant bitches is currently
recommended at 10 days after mating and again 6 weeks later. Using this protocol
in a vaccination trial, Poulet et al (2001) reported higher pregnancy rates (82% vs
68%) in vaccinated vs untreated bitches.
Other pathogens
Mycoplasma/Ureaplasma are part of the normal bacteria of the canine reproductive
tract but can cause disease following experimental inoculation. Their incidence and
role in canine infertilit are unknown, also for the difficulties in isolating and
culturing techniques. Other pathogens reported as a cause of abortion or found in

aborted fetuses include E. coli, T. gondii, Campylobacter, b-haemolitic


streptococcus, Chlamydia spp. and salmonella.
Trauma
Death of conceptus can be caused by a direct uterine trauma or indirect trauma to
the mother or by an abdominal surgery, all of which may cause death of conceptus
either directly (trauma on the conceptus) or undirectly through an early placental
detachment. In pregnant women laparotomy may cause abortion especially if
surgery is on the uterus or on contiguous organs. Although such a risk is possible
in pregnant bitches as well, one should have checked fetal viability prior to the
trauma as this may also precipitate an already compromised situation. A surgical
procedure has been reported in which some canine fetuses are removed and the
remaining one are carried normally to term through administration of progesterone
IM 2 days pior to surgery (Lowry, 1975).
Drugs
The most delicate period of the canine pregnancy is the first month during which
organogenesis takes place. Prior to day 20-22 following ovulation (when
implantantion occurs and placental development starts) canine embryos are
surrounded by uterine milk, a protein endometrial secretion which is in
homeostatic equilibrium with the blood compartment, i.e. any substance that arrives
in the bloodstream reaches the endometrium. Therefore, use of any substance
during this time carries the potential risk of harming embryonic development even
though there is no risk associated for the mother. After placental development
fetuses become more resistant to toxic insults as most substance cannot reach the
placental circulation unless they are present in high concentration and for a long
time in the bloodstream. However, any drug that reaches the canine fetal circulation
must be metabolised by the fetal kidney (in carnivores the fetal liver is not
metabolically active) which in itself might threaten fetal survival. Aspirin,
dexamethasone, bromocriptine, carbaryl, estradiol benzoate and cypionate,
prostaglandin F2a and antiestrogen drugs are widely described as capable of causing
embryonic/fetal death in the dog. The effect of various drugs on the canine
pregnancy is reported in details by Papich (1989).
Clinical approach to a complicated pregnancy
Whenever a pregnant bitch or queen is presented with a condition suggestive of
impending abortion, she should first receive a thorough clinical exam with particular
attention to signs such as large quantity of mucoid vaginal discharge (clear to
yellowish mucus may be due to the cervical plug), purulent or hemorrhagic vulvar
discharge, nesting behavior, restlessness, sudden decrease of abdominal volume,
decreased appetite, high fever, depression. If any one of these signs is present, a
uterine ultrasound should be performed in order to assess fetal conditions and
heartbeat. A blood sample should be drawn for hematology and serum biochemistry

including progesterone and prolactin assay, and a bacteriological exam and


antibiotic sensitivity testing should be done on a sample of vulvar discharge.
Treatment with progesterone should be discussed with the owner if serum
progesterone concentrations are below 15 ng/ml during the second half of
pregnancy, and instituted if progesterone is <10 ng/ml. In case of progesterone
supplementation, the owner should also be warned about the risk of having to
perform a C-section, as well as having to artificially rearing the pups for the first
few days of their lives as maternal milk production may be reduced or absent after
parturition.
BIBLIOGRAPHY and SUGGESTED READINGS
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of estradiol-17 and progesterone in the bitch during the estrous cycle, in
normal pregnancy and after dexamethasone treatment. Journal of
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3. Bassu, G. (2003) How I treat infertility in the bitch: clinical case. In:
Proceedings EVSSAR 2003, 80-86
4. Concannon, P., Tsutsui, T., Shille, V. (2001) Embryo development, hormonal
requirements and maternal responses during canine pregnancy. Journal of
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5. Concannon, P.W. (1980) Effects of hypophysectomy and of LH
administration on luteal phase plasma progesterone levels in the beagle bitch.
Journal of Reproduction and Fertility, 58, 407-410
6. Concannon, P.W. (2000) Canine Pregnancy: predicting parturition and timing
events of gestation. In: Recent advances in small animal reproduction.
Concannon PW, England G, Verstegen J, eds. It: International Veterinary
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8. Concannon, P.W., McCann, J.P., Temple, M. (1989) Biology and
endocrinology of ovulation, pregnancy and parturition in the dog. Journal of
Reproduction and Fertility Supplement, 39, 3-25
9. Concannon, P.W., Powers, M.E., Holder, W., Hansel, W. (1977) Pregnancy
and parturition in the bitch. Biology of Reproduction, 16, 517-526
10.Curtis, E.M. and Grant, R.P. (1964) Masculinization of female pups by
progestogens. Journal of the American Veterinary Medical Association, 144,
395-398
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(1975) Blood plasma concentrations of progesterone and estradiol in the dog

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78, 554-564
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(1994) The use ofally-trenbolone as a progestational agent to maintain
pregnancy in ovariectomized bitches. Theriogenology, 42, 1237-1245
14.Estill, C.T. (1998) Theriogenology question of the month: Hypoluteoidism in
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15.Evermann F - Diagnosis of herpetic infections. In: Current Veterinary
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pagg 1313
16.Fall T, Johansson Kreuger S, Juberget A, Bergstrm A, Hedhammar A. (2008)
Gestational diabetes mellitus in 13 dogs. Journal of Veterinary Internal
Medicine;22(6): 1296-300
17.Goormaghtigh, N. (1927) Le corps jaune de la chienne gravide; contribution a
letude de metabolisme des lipoides. Archives de Biologie, 37, 46-120
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in a bitch. Theriogenology, 64, 213-219
19.Irons, P.C., Nthling J.O., Volkmann, D.H. (1997) Failure of luteolysis leads
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Johnston, S.D., Kustritz M.V.R., Olson, P.N.S. eds. Canine and Feline
Theriogenology, W.B. Saunders Company, Philadelphia, Pennsylvania, USA,
66-104
22.Kustritz, M.V.R. (2001) Use of supplemental progesterone in management of
canine pregnancy. In: Recent advances in small animal reproduction.
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Veterinary Information Service (www.ivis.org). Document No. A1220.0401.
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in the dog. Theriogenology, 64 (3), 755-765.
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parturition and the periparturient period. In: Ettinger, S.J., Feldman, E.D.
(eds). Textbook of Veterinary Internal Medicine. W.B Saunders Company,
Philadelphia, Pennsylvania 19106, USA,
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Veterinary Therapy X. Small Animal Practice. Editore RW Kirk, WB
Saunders 1989, pagg 1317

27.Onclin, K. and Verstegen, J.P. (1997) Secretion patterns of plasma prolactin


and progesterone in pregnant compared with nonpregnant dioestrous beagle
bitches. Journal of Reproduction and Fertility Supplement, 51, 203-208
28.Onclin, K., Murphy, B., Verstegen, J.P. (2002) Comparisons of estradiol, LH
and FSH patterns in pregnant and nonpregnant beagle bitches.
Theriogenology, 57, 1957-1972
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Small Animal Practice. Editore RW Kirk, WB Saunders 1989, pagg 1291
30.Poulet H, Guigal PM, Soulier M, Leroy V, Fayet G, Minke J et al Protection
of puppies against canine herpesvirus by vaccinations of the dams. Vet Rec
148:691-695, 2001
31.Purswell, B.J. (1991) Management of apparent luteal insufficiency in a bitch.
Journal of the American Veterinary Medical Association, 199(7), 902-903
32.Romagnoli, S. and Concannon, P.W. (2003) Clinical use of progestins in
bitches and queens: a review. In: Recent advances in small animal
reproduction. Concannon PW, England G, Verstegen J, eds. Ithaca:
International Veterinary Information Service (www.ivis.org). Document No.
A1206.0903.
33.Romagnoli S, Johnston SD - Vulvar discharge. In: Small Animal Medicine.
Editore DG Allen, Lippincott, Philadelphia 1991, pagg 763-789.
34.Ronsee V, Verstegen J, Thiry E, Onclin K, Aeberle C, Brunet S, Poulet H Canine herpesvirus-1 (CHV-1): clinical, serological and virological patterns
in breeding colonies. Theriogenology 64:61-74, 2005
35.Schlotthauer CT, Wakim KG - Ectopic pregnancy in a dog. JAVMA 127:213,
1955
36.Shille VM - Management of reproductive disorders in the bitch and queen. In:
Current Veterinary Therapy IX. Small Animal Practice. Editore RW Kirk, WB
Saunders 1986, pagg 1225
37.Smith, M.S. and McDonald, L.E. (1974) Serum levels of luteinizing hormone
and progesterone during the estrous cycle, pseudopregnancy and pregnancy in
the dog. Endocrinology, 94(2), 404-412
38.Sokolowski, J.H. (1971) The effects of ovariectomy on pregnancy
maintenance in the bitch. Labaratory Animal Science, 21(5), 696-699

Reproduction
MEDICAL TREATMENT OF CANINE URINARY INCONTINENCE
Prof. Stefano Romagnoli, DVM, MS, Ph.D, Dipl. ECAR
Department of Animal Medicine, Production and Health,
University of Padova, Agripolis, Legnaro, 35020 (PD)
stefano.romagnoli@unipd.it

Urinary incontinence (UI) is the involuntary loss of urine during the filling phase of
the bladder which typically occurs during recumbency and/or standing. Dogs of any
age or sex may present with UI but the problem is more prevalent in spayed females
accounting for about 75% of adult cases. UI is sometimes observed in prepubertal
dogs due to congenital conditions. UI became more common in Europe and the
United States during the second half of the last century as gonadectomy was more
frequently used to control canine overpopulation. The most common reason for
developing urinary incontinence in adult animals is urethral sphincter mechanism
incompetence (USMI) - a reduced urethral closure due to weakening of the urethral
sphincter that commonly develops after spaying and is thought to be due to lack of
estrogenic stimulation. This presentation will review therapeutic management for
canine urinary incontinence.
A summary of the most common causes of congenital vs acquired urinary
incontinence in the dog are summarized in Table n 1. Performing ovariectomy or
ovariohysterectomy increases the risk of developing urinary incontinence, as
evidence by the incidence of urinary incontinence in spayed bitches to be between 6
and 20% (Holt, 1985; Arnold, 1992). A long-term study performed on a high
number of bitches in the UK revealed a yearly incidence rate of 1.74% in spayed vs
0.2% in entire bitches, with a relative risk of becoming incontinent for spayed
bitches of 7.8 times higher than entire ones (Thrusfield et al., 1998). In a recent
study performed in the US in which almost a thousand female dogs where followed
up for about 6 years after having been spayed prepuberally, incidence of urinary
incontinence was 1.19%; spaying before 3 months of age gave a relative risk of
urinary incontinence 3.46 times greater than spaying after 3 months of age, which is
equivalent to an incidence of 5% when spaying occurs before puberty, and of 12%
when spaying occurs before 3 months of age (Spain et al., 2004).
Pathophysiology of incontinence
Urinary incontinence seems to be more common in medium to large weight dogs,
with breeds such as boxers, dobermanns, giant schnauzers, bobtails, Siberian
huskies, golden retrievers, Irish setters, rottweilers, Weimaraners and their crossbreds being particularly represented both among male and female dogs (Holt, 1985;

Holt and Thrusfield, 1993; Arnold, 1992; Arnold, 1999; Weber et al., 1997; Nickel
et al., 1998; Thrusfield et al., 1998; Nickel et al., 1999; White, 2001).
Gonadectomy in female dogs causes a steady increase in pituitary secretion of
luteinizing hormone (LH) and follicle stimulating hormone (FSH), as well as a
progressive lowering of serum estrogen concentrations. While the role of increased
LH and FSH in UI is still not clear, it has been clearly established that decreased
estrogen secretion can cause:
Cause of
CONGENITAL
urinary incontinence
their incidence (in
young dogs)
Ectopic ureter
Congenital anomalies
of the urethral
sphincter
Congenital anomalies
of other structures of
the urogenital system
(bladder hypoplasia,
intersex conditions,
persistence of urachus,
congenital neurologic
diseases etc.)

Incide
nce
45%
35%

20%

Cause of ACQUIRED
urinary incontinence and
their incidence
Incide
(in adult dogs)
nce
Ectopic ureter
5%
Weakening of the urethral
75%
sphincter (urethral sphincter
mechanism incompetence =
USMI)
Other diseases of the
20%
urogenital system (cystitis,
bladder neoplasia, ureterovaginal fistulas, prostatic
disease and consequences
of prostatic surgery,
congenital neurologic
diseases of the pelvic
region or of the urogenital
system, detrusor instability,
chronic urinary retention)

Table n 1 Causes of congenital vs acquired urinary incontinence and their


relative incidence in the canine population. Ecotpic ureter is the most common
cause in young animals, while urethral sphincter mechanism incompetence (USMI)
is the most common cause in adult neutered bitches.
o Weakening of the canine external urethral sphincter (musculus urethralis),
which lowers urethral pressure and the bladder-emptying pressure threshold
o Atrophy of the urethral mucosa
o Reduced blood flow to the urogenital system
o Reduced response of sympathetic (estrogen-sensitive) -1 adrenergic receptors
that mediate contraction of the canine external urethral sphincter.
The action of the bladder center in S1S3 may be decreased by lower
abdominal/pelvic trauma or surgery that can alter nerve supply to the urethra and
also to the pelvic diaphragm, which provides periurethral support. In male dogs

prostatic surgery is commonly associated with development of UI following


prostatectomy (incidence of 95% to 100%) and less drastic procedures, such as
placement of a penrose catether (incidence of 10%-20%). Likewise, in
ovariohysterectomized (not ovariectomized) bitches, UI that develops shortly after
surgery may be the result of an iatrogenic ureterovaginal fistula. In prepubertal
animals, one or both ureters terminating at the apex of the bladder neck, the level of
the urethra, or the cranial vagina can cause continuous dribbling of urine. Also,
pathologic development of the urogenital system in intersex conditions can cause
UI.
The physiology of micturition in the dog
The bladder wall consists of 3 layers of smooth muscle which are intermixed, an
outer and an inner longitudinal layer and a relatively thick middle circular layer.
The three sheets form the detrusor muscle, which squeezes and empty the bladder.
Near the bladder neck the internal layer, mostly oblique in the rest of the bladder,
tends to become circular thereby forming a sort of internal sphincter (Howard and
Christensen, 1979; Cullen, 1981). However, such internal sphincter is so poorly
defined that most authors question its existence (Barone, 1983; Dyce et al., 1996).
Other authors call the whole smooth muscle layer of the urethra internal sphincter
and the striated part external sphincter. In the dog, continence is thought to depend
on the tension passively exerted by the elastic elements within the bladder neck
mucosa (acting as internal sphincter) as well as on the action of the striated
urethralis muscle (acting as an external sphincter). The internal sphincter lies within
the abdominal cavity which allows any increase in intraabdominal pressure
(coughing, barking etc.) to be transmitted to the sphincter as well as to the bladder.
The lower urinary tract has somatic, sympathetic and parasympathetic motor
innervation. The somatic innervation (acting via the pudendal nerve) provides
voluntary control over the external urethral sphincter and perineal musculature.
Sympathetic innervation (arising in the dog from L1-L4 and then synapsing with the
caudal mesenteric ganglia to form the hypogastric nerve) promotes bladder filling
acting through predominantly -adrenergic receptors in the bladder (causing
relaxation), and predominantly -adrenergic receptors in the internal urethral
sphincter (causing contraction). Parasympathetic innervation is given by neurons
originating from S1-S3 to form the pelvic nerve and then synapsing in the pelvic
plexus and pelvic ganglia within the bladder wall. Parasympathetic innervation acts
through cholinergic receptors primarily on the detrusor causing its contraction
during micturition (Table n 1).
Contraction of the internal urethral sphincter during the storage phase prevents urine
leakage maintaining continence thanks to tonic -adrenergic stimulation via the
hypogastric nerve. The smooth muscle fibers of the external urethral sphincter
maintain a constant tone by responding quickly to temporary increases in bladder
pressure. The smooth muscle fibers (= internal urethral sphincter) maintain a

constant tone and contribute 50% to urehtral closure. The striated muscle (= external
urehtral sphincter) is not able to maintain a constant tone. It responds quickly and
transiently to sudden increases in bladder pressure. At the same time the detrusor
muscle is inhibited by -adrenergic stimulation which allows filling of the bladder
by maintaining a low pressure inside. Micturition is voluntarily started when
bladder capacity is reached thanks to bladder stretch receptors signalling the
brainstem micturition center. Contraction of abdominal muscles and relaxation of
perineal muscle are the first 2 steps of a series of events which include an increase
in parasympathetic stimulation to the bladder and contraction of hte detrusor,
inhibition of -adrenergic tone and stimulation of -adrenergic tone to the urethral
sphincter (Table n 1). Complete voiding is allowed by coordination of detrusor
contraction and sphincter relaxation.
CLINICAL APPROACH TO CANINE URINARY INCONTINENCE
Many clinical conditions may be the primary cause and/or contribute to the
development of clinical signs of urinary incontinence in the canine population. This
is particularly true in older animals, both males and females. A complete list of all
the conditions which may directly or indirectly be responsible for urinary
incontinence is included (Table n 3).
Wet perineum, staining of the perineal hair or urine scalding are among the most
common clinical signs,
Constant loss of urine is typical of ectopic ureters, ureterovaginal fistulas
(following ovariohysterectomy, not after ovarectomy) or severe cases with
USMI.
Dribbling of urine when recumbent or asleep is characteristic of USMI,
Intermittent dribbling suggests expulsion of urine due to autonomous contraction
of the detrusor muscle, defined as detrusor instability (most commonly caused by
bacterial urinary tract infection).
Persistent urachus in young dogs is characterized by dribbling occurring mainly
after exercise.
Dribbling after urinating only is typical of urovagina.
When collecting history it is important to assess whether or not a major abdominal
or urogenital trauma or surgery occurred in the recent past which may have caused
pelvic or pudendal nerve damage. Palpate abdomen and rectum to rule out nonneurogenic causes of urinary incontinence (calculi, neoplasia, vulvovaginal
strictures, changes in thickness of the bladder or urethral wall). Palpate the bladder
to check for bladder atony (large and flaccid bladder suggesting an emptying
disorder) or cystitis (small and tickened bladder). Also, palpation of the bladder is
important to estimate residual urine volume after voiding. Normal residual volume
is approximately 0.2-0.4 ml/kg. Attempt manual expression of urine from the
bladder: a low resistance offered by the urethra will indicate a urine storage disorder
(due to lower motor neuron or primary urethral disease).

Clinical condition
Neurologic defects
Difficulties in seeing,
moving, maintaining bilance;
generalized weakness
Increased activity at night
Weakening of the urethral
sphincter (USMI)
Anomalies of bladder tone
Decrased bladder capacity
Polyuria/Polydipsia
Urinary tract infection
Urinary obstruction (stones,
neoplasia)
Bladder/urethral neoplasia
Use of diuretics or
corticosteroids
Use of tranquillizers
Use of a-adrenergics
Use of b-adrenergics

Effect on urinary continence


Decreased cortical awareness of micturition
behaviour; insufficient detrusor activity; reflex
dyssinergy
Incapacity of reaching proper voiding areas
Nocturia
Incontinence at night, when laying or under stress
Overflow incontinence, detrusor instability
Urge incontinence, nocturia, frequent voiding of
small volumes of urine
Increased urinary volume, frequent voiding of
small volumes of urine
Irritability, urge incontinence
Irregular incontinence, due to high urine output;
detrusor atony
Incontinence at night, when laying or under stress;
obstruction
Increased urine formation
Decreased cortical awareness of micturition
behaviour
Increased urine retention
Incontinence due to high urine output

Table n 3 Clinical conditions typical of older dogs and their effect on urinary
continence (Krawice & Rubin, 1985)
Perform a complete neurological exam checking anal tone, the perineal reflex and
the bulbocavernosus reflex (all depend on an intact sacral reflex arc as well as
pudendal nerve). Perform a complete urinalysis: a dilute urine may indicate
polyuria, while evidence of bacteria or inflammatory cells in the sediment will
indicate infection. Perform urine culture and serum biochemistry which may shed
light on causes of polyuria. An excretory urography can be helpful in documenting
ectopic ureters or in evaluating the lower urinary tract when it is difficult to perform
a retrograde contrast evaluation. USMI, the most common cause of urinary
incontinence in adult neutered bitches is typically diagnosed by ruling out all other
causes of urinary incontinence such as urinary tract infection, polyuria, detrusor
instability, ureteral ectopia, lower motor neuron disease, etc. Rule out all conditions
causing increased urinary output (Cushings disease, diabetes mellitus,

corticosteroid treatment). Canine urinary incontinence is intermittent in nature, as


showed by the fact that up to a third of placebo treated bitches may show 100%
improvement during the first month (Scott et al, 2002).
TREATMENT OF CANINE URINARY INCONTINENCE
The medical treatment of urinary incontinence due to USMI involves using
sympathomimetic drugs, steroids or GnRH agonists. Both sympathomimetic as
well as estrogen (estriol) medications should be the treatment of choice in adult
animals with USMI especially when incontinence occurs after neutering. The two
classes of drugs can be used together, for the well known action of estrogens in
increasing the synthesis of receptors of -agonists, thereby improving their effect.
Try to have the bitch maintain a small bladder during periods of recumbency, i.e., by
allowing her to urinate immediately before bedtime. In many animals the efficacy
of both sympathomimetic as well as estrogen (estriol) medications tend to decrease
over time (despite increasing dosages) perhaps because of desensitisation of their
receptors. Because of the multifactorial character of this condition, no single
treatment will be 100% effective especially in a long term perspective. Also, the
combined use of sympathomimetics and estriol is anecdotally reported as efficacious
in bitches refractory to the use of either drug alone. GnRH agonists have been
proven approximately 70% effective in making the bitch fully continent or
improving the effect of sympathomimetics or estriol.
Sympathomimetic drugs
These drugs cause enhancement of urethral closure through the release of
endogenous norepinephrine and direct stimulation of -adrenergic receptors in the
bladder neck and urethra (Creed, 1983; Callahan and Creed, 1985; Richter and Ling,
1985). They typically have a rapid onset (within a few days) and high degree (7590%) of efficacy
Phenylpropanolamine
0.5-4.0 mg/kg TID
Ephedrine
1.0-4.0 mg/kg BID
Pseudoephedrine
15 (<25 kg bw)-30 mg (>25 kg) TID
Phenylephrine
0.1-0.3 mg/kg IV
Imipramin
5-15 mg/dog per os BID (1 mg/kg TID *)
In some European countries phenylpropanolamine is marketed as a veterinary
product, while in most other countries human preparations can be used to treat this
problem in dogs and cats. The dose range for most -agonist drugs varies between
1.0 and 3.0 mg/kg, orally, 1-3 times daily. The variability of tablet size (between 25
and 35 mg depending on drugs as well as countries) of human and veterinary
preparations generally dictates the final dose which should be in the range of 1.0-1.5
mg/kg twice daily for the initial treatment. Phenylpropanolamine and ephedrine are
currently regarded the most effective among the -agonist drugs (Richter and ling,
1985; Hussein et al., 1987). The onset (within a few days) and degree (approx. 80%)
of efficacy of sympathomimetic drugs are both quite high, making these compounds

certainly a good treatment whenever a urethral sphincter incompetence is present.


Treatment success in a recent blinded, placebo-controlled trial in which
phenylpropanolamine was administered at the dose of 1.0 mg/kg was 85% (full
success) plus a 15% of significant improvement, while it was 33% and 14% in
placebo treated bitches, respectively (Scott et al., 2002). The right dosage should be
established for each individual case: start with a low dose and titrate up until a good
efficacy is reached.
Steroids
Long-acting synthetic compounds such as diethylstilbestrol, estradiol, estrone and
other esther compounds are characterized by a dangerous action on bone marrow
and uterus because of their prolonged nuclear occupance time in estrogen receptors
of target tissues (Clark and Markraverich, 1984). Short acting compounds such as
estriol are known to be devoid of side effects. The following is a list of estrogens
which have been used to treat canine urinary incontinence.
17- estradiol
0.01 mg/kg MID sc/im for 3 days
Estradiol benzoate
0.01-1.0 mg MID per os
Estradiol valerate
1.0 mg/10 kg bw
Diethylstilbestrol
0.06 mg MID, tapering out to 0.01 mg
Estriol
0.5-2.0 mg
Conjugated estrogens
0.02 mg/kg
Estriol is considered a safe drug due to its short-action which is characterized by
short nuclear occupance time and minimal metabolism following absorption. Estriol
does not bind to sex-hormone binding globulin, which helps in preventing
development of full (late) estrogenic effects such as endometrial hyperplasia,
pyometra and bone marrow suppression. Estriol has been used for decades in
women in hormone replacement therapy, and is marketed as a veterinary preparation
to treat canine urinary incontinence in some european countries. Its efficacy after 42
days of 2.0 mg/day treatment was 85% in a multicentric clinical trial recently
performed on 129 bitches in 4 european countries (Mandigers and Nell, 2001).
Hematological abnormalities are not observed when using dosages of 0.5-1.0
mg/day even for years, nor have they been reported in mid-term (3 months) chronic
toxicity studies using 2.0, 6.0 and 10 mg doses (Hendriks and Janszen, 1998).
Vulvar swelling and male attractiveness is occasionally observed in bitches treated
with estriol doses of >1.5 mg/day. Some signs of estrus can be observed in bitches
administered higher dosages (Hendriks and Janszen, 1998). In one study a 10%
incidence of vulvar swelling and male attractiveness was observed in bitches treated
with the 2.0 mg estriol/day. Using a 1.0 mg MID dose for 7 consecutive days no
signs of vulvar swelling or vaginal discharge were observed. Estriol is marketed as
a veterinary preparation to treat canine urinary incontinence in some european
countries (Incurin, Intervet), and the recommended dosage is 1.0 mg/day, to be
lowered gradually to 0.5 if possible, although it can be increased up to 2.0 mg/day
for some periods of time.

GnRH agonists
see the paper on Clinical use of GnRH agonists in small animal reproduction
BIBLIOGRAPHY and SUGGESTED READINGS
1. Arnold S, Arnold P, Hubler M, Casal M, Rusch P Urinary incontinence in
spayed bitches: prevalence and breed prediposition. (Originally published in
Schweizer Arch Tierheilkunde 131:259-263, 1989, reprinted in) Eur J Comp An
Pract 2:65-68, 1992
2. Arnold S Urinary incontinence in spayed bitches. Part 1: significance, clinical
features and aetiopathology. (Originally published in Schweizer Arch
Tierheilkunde 139:271-276, 1997, reprinted in) Eur J Comp An Pract 9: 125-129,
1999
3. Callahan SM, Creed KE The effects of estrogen on spontaneous activity and
response to phenilephrine of the mammalian urethra. J Physiol 358:35-46, 1985
4. Creed KE Effect of hormones on urethral sensitivity to phenylephrine in
normal and incontinent dogs. Res Vet Sci 34:177-81, 1983
5. Clark JH, Markraverich BM The agonistic and antagonistic actions of estriol. J
Steroid Biochem 20:1005-1013, 1984
6. Hendriks S, Janszen B Safety trial in bitches with tablets containing estriol
(Incurin). In: Proceedings 1st EVSSAR Congress: Clinic and Reproduction.
Barcelona 1-3 May 1998, p 318
7. Holt PE Urinary incontinence in the bitch due to sphincter mechanism
incompetence: prevalence in referred dogs and retrospective analysis of 60 cases.
J Small An Pract 26:181-190, 1985
8. Holt PE, Thrusfield MV Association in bitches between breed, size, neutering
and docking, and acquired urinary incontinence due to urethral sphincter
mechanism. Vet Rec 133:177-180, 1993
9. Hussein MA et al. Phenilpropanolamine pharmacokinetics in dogs after IV, oral
and sustained release formulation. Biopharmaceutics and Drug Disposition
8:497-505, 1987
10.Mandigers PJI, Nell T Treatment of bitches with acquired urinary incontinence
with estriol. Vet Rec 149:764-767, 2001
11.Nickel RF, Wiegand U, Van der Brom WE Evaluation of a transpelvic sling
procedure with and without colposuspension for treatment of female dogs with
refractory urethral sphincter mechanism. Vet Surg 27:94-104, 1998
12.Nickel RF, Vink-Noteboom M, Van der Brom WE Clinical and radiographic
findings compared with urodynamic findings in neutered female dogs with
refractory urinary incontinence. Vet Rec 145:11-15, 1999
13.Reichler, I.M., Hubler, M., Jchle W., Trigg, T.E., Pich, C.A. and Arnold, S.
(2003): The effect of GnRH analogs on urinary incontinence after ablation of the
ovaries in dogs. Theriogenology 60, 1207-1216

14.Richter KP, Ling GV Clinical response and urethral pressure profile changes
after phenylpropanolamine in dogs with primary sphincter incompetence.
JAVMA 187: 605-611, 1985
15.Scott L, Leddy M, Bernay F, Davot JL Evaluation of phenylpropanolamine in
the treatment of urethral sphincter mechanism incompetence in the bitch. J Small
An Pract 43:493-496, 2002
16.Spain CV, Scarlett JM, Houpt KA Long-term risks and benefits of early-age
gonadectomy in dogs. JAVMA 224 (Feb 1):380-387, 2004
17.Thrusfield MV Association between urinary incontinence in bitches: its
incidence and relationship to neutering practices. J Small An Pract 39:559-566,
1998
18.Thrusfield MV, Holt PE, Muirhead RH Acquired urinary incontinence and
spaying in bitches. Vet Rec 116:695, 1985
19.Weber Uth, Arnold S, Hubler M, Kupper JR Surgical treatment of male dogs
with urinary incontinence due to urethral sphincter mechanism incompetence.
Vet Surg 26:51-56, 1997
20.White RN Urethropexy for the management of urethral sphincter mechanism
incompetence in the bitch. J Small An Pract 42:481-486, 2001

Reproduction
CAN
INE and FELINE PEDIATRICS
Prof. Stefano Romagnoli, DVM, MS, Ph.D, Dipl. ECAR
Department of Animal Medicine, Production and Health,
University of Padova, Agripolis, Legnaro, 35020 (PD)
stefano.romagnoli@unipd.it

Small animal clinicians are often asked to evaluate neonates, especially when young
kittens or puppies have been orphaned (because their mother has died or is too ill to
care for her litter) or abandoned as strays. Neonates are very fragile patients which
require a great deal of care, knowledge of their particular needs as well as of their
peculiarities in terms of biological values different from adults.
Examining neonates - Kittens and puppies should be examined with clean hands
gently and patienty on a warm, clean surface, using gloves to perform any procedure.
The necessary equipment includes a gram scale, digital thermometer, and infant
otoscope with infant cones, a penlight, and a stethoscope with an infant bell and
diaphragm. Prior to handling the neonate observe his response to the environment as
well as his body conditions, posture, locomotion and respiraration. Record
respiration rate before handling, then measure rectal temperature and heart frequency.
Birth weight oscillates between 80-140 g (kittens and small breed puppies) up to >
400 g for large breed puppies. Neonates should gain approximately 70-130 g each
week. Kittens normally double their birthweight in 6-8 days, while puppies may take
up to 12 days. Beagle puppies suckling normally triple their bodyweight ad 15 days
of life, while those who are fed artificially only double their weight by the same time.
Orphans tend to grow more slowly (they generally increase their weight by 10-15%
every day), but all differences disappear at approximately 6-8 months of life.
Weighing neonates regularly (at birth, daily for the first week and then 2-3
times/week until weaning) is very important as any lack on increase in bodyweight is
worrisome and any weight loss > 10% should be regarded as a poor prognostic sign.
Whenever providing artificial nutrition, the anogenital reflex should be stimulated
after feeding by rubbing a cotton moistened with warm water around the perineal
area until defecation and urination occurs. Always examine carefully the neonate
from head to tail, checking teeth eruption, presence of cleft palate, status of oral and
conjunctival mucosa, anogenital distance (13-15 mm in males, 4-8 mm in females).
Palpate the abdomen to check normality of viscera and filling status of the stomach,
and look at umbilical status, presence of umbilical hernia, limb deformities, chest
wall deformities and nonpatent urogenital or rectal openings. The paws should also
be checked as the skin underneath is very delicate and easily damaged. A small

wound there can become the port of entry for bacteria causing local and then general
infection (Figure n 1)
Basic neonatal diagnostics - Critical diagnostic testing can be performed in
neonates. Some of the most important serum biochemistry values for puppies and
kittens are reported in table n 1. .Blood collection can be done from the jugular
vein using an insulin syringe with a 23-26 gauge needle (put 1-2 drops of heparin
into the syringe to avoid coagulation during collection).
Puppies
1-3 day 2 wk 4 wk
Bilirubin 0.5
0.3
0.0
e
ALT
69
15
21
AST
108
20
18
ALP
3845
236
144
GT 1111
24
3
Tot.
4.1
3.9
4.1
Proteins
Albumin 2.1
1.8
1.8
e
Choleste 136
282
328
rol
Glucose 88
129
109

8 wk Adult
0.1
0-0.4

Kittens
2 wk 4 wk Adult
0.3
0.2
0-0.2

21
22
158
1
4.6

12-94
13-56
4-107
0-7
5.4-7.4

18
18
123
1
4.4

16
17
111
2
4.8

28-91
9-42
10-77
0-4
5.8-8.0

2.5

2.1-2.3 2.1

2.3

2.3-3.0

155

103-299229

361

145

65-110 117

110

150270
63-144

Table n 1 - Serum biochemistry values for puppies and kittens during the first
few weeks of life, compared with adult values. In puppies, -GlutamilTransferase and Alkaline phosphatase (values in bold) are very high for the first
few days of life due to ingestion of large quantities of colostrum. Therefore, these
two values are important indicators that the transfer of maternal immunity occurred
properly.

With just 0.5 ml of blood a blood smear can be done, glucose can be measured
using a glucometer or reactive strips and the following tests can be performed using
a microhematocrit: packed cell volume, total proteins and a rough estimate of red
blood cells (including immature RBC) and white blood cells; also from the colour
of plasma one can assess whether or not there is presence of bilirubine, haemolysis
and lipemia. Urine and faeces canbe collected by gentle manual stimulation of the
perineal area with a moistened cotton. A physiologic anemia is observed in puppies
and kittens throughout the fist month of life.
Neonatal mortality - A fading neonate is defined as a puppy or a kitten which fails
to grow normally and/or starts losing conditions rapidly, stops nursing and dies
rapidly without any sign or showing just persistent crying. This is a frustrating
problems for veterinarians and breeders because of the difficulty in establishing a
diagnosis and providing a successful treatment. Mortality due to this syndrome
occurs mainly between 3.5 and 5.0 days of age, puppies and kittens are generally of
adequate birth weight for the breed and would be considered to have good potential
for a normal life, their mothers are in good health with unremarkable pregnancies of
normal gestation length, with no history of dystocia, poor mothering or lactational
deficit. Approximately 15-40% of puppies and kittens die between birth and 3
months of life, with the majority of these losses occurring at birth or within 4-5
weeks of age. The 2-week distinction is rather arbitrary, and most clinicians will
consider as fading puppies or kittens all those newborns that die within 12 weeks of
age. Puppy and kitten losses up to 12 months of age are due to problems acquired in
utero, at birth (birth to 2 weeks) or around weaning time (5 to 12 weeks of age).
Usually post-mortem examination reveals that body weight is below birth weight,
stomach and intestines are devoid of contents and there is generally no gross lesion
or defect.. The liver to body weight ratio changes from 1:10 to 1:20,
histopathological examination reveals no evidence of an infective etiology or other
specific lesion. No common management factor has been associated with puppy
mortality. There is a strong tendency for certain bitches within a given kennel to
have frequent fading litters, while other dams will experience no problem. Post
mortem investigation is frequently unrewarding, especially when puppies were
frozen after death (freezing causes tissue artifacts, it is best to preserve at +4 C) and
when just one puppy is examined. Chances of achieving a diagnosis increase with
the number of puppies/litters examined. Causes of death include congenital
anomalies, teratogenic defects, nutritional disease resulting from improper diets fed
to the mother or her youngs, low birth weight, trauma, neonatal isoerythrolysis (in
kittens), infectious diseases and other miscellaneous factors.
Congenital anomalies These include cleft palate, cranial deformities, agenesis of
small and large intestine, respiratory and cardiac anomalies, extensive umbilical and

diaphragmatic hernias, anomalies of the kidney and lower urinary tract,


muscoloskeletal anomalies. Anomalies of biochemical type (enzymatic pathway
failures etc.) are thought to occur in equal amount among kittens and puppies and go
largely unreported.
Teratogenic defects - No information of frequency of occurrence is available. There
are several drugs whose teratogenic and/or toxic potential to the fetus is well known
and which may contribute to the development of congenital anomalies or to fading
newborns, including drugs in the following categories: antimicrobials (amikacin,
cloramphenicol, quinolones, streptomycin, doxycycline, gentamycin, kanamycin,
metronidazol, oxytetracycline, tetracycline, tobramycin); antifungal drugs
(amphotericin B, ketoconazole, griseofulvin); antiparasitic drugs (amitraz,
levamisole, thiacetarsamide, trichlorfon); anticancer drugs (all); anestethic and
preanesthetic drugs (diazepam, halothane, methoxyflurane, pentobarbital, thiamylal,
thiopental); gastrointestinal drugs (diphenoxylate, loperamide, methoscopalamine);
cardiovascular drugs (captopril, isoproterenol, nitroprusside, propanolol, thiazide
diuretics); anticonvulsivant drugs (all); muscle relaxants (dantrolene,
methocarbamol); endocrine drugs (all except thyroid hormones).
Poor nutrition Malnutrition of a puppy or kitten may result from severe maternal
malnutrition or a lack of adequate maternal blood supply, possibly for competition
of placental space. Inadequate milk production may be associated with an
inexperienced or overly nervous mother, old, sick or malnourished mother, dystocia,
certain familial traits, systemic illness or mastitis. Inadequate milk uptake by the
neonate can also result from anything causing ill-heath or weakness, from
competition and bullying by siblings, to any environmental factor that distracts or
upsets the mother-neonate bond.
Poor nutrition during pregnancy may cause newborns to be weak because of
problems in regulating their blood glucose. Maternal starvation can reduce fetal
birth weight, decrease fetal blood glucose and increase fetal ketone levels. Bitches
fed a low carbohydrate diet during pregnancy have fewer pups who were born alive
and fewer pups who were still alive at 3 days of age. Toy breed pups are more
predisposed to fasting hypoglycemia than large breed pups. Neonates have small
livers and also lack the feedback mechanism between hepatic gluconeogenesis and
blood glucose concentration, which makes regulation of glycemia more difficult
than in the adult. Pups and kittens are also relatively insensitive to insulin and have
a poor gluconeogenic response to counter-regolatory hormones. Also, newborn
dogs have a lower rate of glucose metabolism and reduced glucose clearance.
Therefore, glucose administration can cause prolonged hyperglycemia. Glucosuria
is common in neonates until 2-8 weeks of age.

Puppies and kittens are also very susceptible to dehydration. This may result from
inadequate consumption of milk, or excessive fluid losses (usually associated with
overheating, excessively low humidity, or diarrhoea). Neonates contain relatively
more body water than adults and their water turnover rate is twice that of adults. For
instance, maintenance fluid requirements for a kitten or a small breed pup are ~130220ml/kg/24h, compared to 50-65ml/kg/24h for an adult. This is because neonates
have greater fluid losses through their skin, lungs and kidneys, which are all
immature. For this reason, administration of fluids in sick neonates or in neonates
who have not eaten for the past 2-4 hours is of utmost importance.
Low birth weight Low birth weight is strongly associated with a higher
probability of puppy and kitten losses. The cause of low birth weight has not been
clearly established: it is probably a multifactorial event as neither sex, litter size,
weight of the mother nor prematurity have been solely associated with low birth
weight in puppies and kittens. Low birth weight is also associated with a tendency
to do poorly in general and to die at a young age. Many fading puppies and kittens
that die in the first weeks of life are of normal size, but their growth is slow, and
their weight well below normal.
Trauma Death due to trauma is usually associated with dystocia, cannibalism or
maternal neglect. Cannibalism of normal, healthy neonates can occur in nervous
primiparous mothers. However, it is difficult to differentiate maternal neglect or
cannibalism of otherwise normal neonates from maternal neglect or cannibalism of
sick puppies and kittens, which should be regarded as a normal response of a mother
to a pup/kitten who is perceived to have no chance to
Neonatal isoerythrolysis Neonatal isoerythrolysis (NI) is relatively common is
certain purebred kittens. Unlike puppies, kittens have naturally occurring antibodies
against the other blood type in their plasma. Cats have 3 blood groups; Type A, B,
and AB. Type A is genetically dominant to Type B. Genetically, a Type A cat may
therefore be A/A or A/B. The rare blood type AB is inherited slightly differently, and
is recessive to Type A but dominant to Type B. AB cats are only found in breeds in
which the Type B has been identified, usually increasing in frequency as the
percentage of Type B cats increases. The frequency of Type A, B and AB blood
types varies between breeds, and also, to some extent, between countries. Generally,
most domestic short and longhaired cats (DSH/DLH) are Type A (75-100% Type A;
0-25% Type B; 0-10% Type AB). Interestingly, the Bengal breed appears to have a
particularly high number of AB cats, although actual prevalence data are not yet
available. All Type B cats have high levels of naturally occurring antibody directed
against Type A erythrocytes, while only a third of Type A cats have naturally
occurring antibody directed against Type B erythrocytes (and the amounts of
antibody are usually rather low). NI occurs when a Type B queen gives birth to a
Type A kitten. Antibodies of the IgG class (and to a lesser extent of the IgM class)

are acquired by kittens with colostrum. Kittens with blood type A have weak anti-B
antibodies, while kittens with blood type B have strong anti-A antibodies. During
the first 16 hours of life maternal antibodies are transferred to the kitten through
colostrum ingestion. If the kitten has blood type A or AB and the mother has blood
type B, colostral antibodies will lyse the kittens red blood cells. Haemolysis can be
intravascular and/or extravascular, causing severe anemia, nephropathy, multiple
organ failures as well as disseminated intravascular coagulopathy. Since all blood
type B cats have high antibody titers, even primiparous mothers can have litters with
NI. Clinical signs develop more often in blood type A or AB kittens born to blood
type B mothers. As the fetus is protected from maternal antibodies, kittens at risk
are born healthy and nurse vigorously, but will start showing clinical signs within
hours to days after colostrum ingestion. Clinical signs will include either a) sudden
death; b) progressive failure to nurse and to thrive during the first 3 days (with
presence of dark, brown-red urine caused by haemoglobinuria, icterus, anemia) with
death occurring during the first week; some kittens may survive and develop a tailtip necrosis between the first and second week of life; or c) no clinical sign except
for presence of tail-tip necrosis, positive direct Coombs test and moderate anemia.
Kittens showing signs of NI, if <24h old, should be immediately removed from
their mother to prevent further absorption of anti-A antibodies. In kittens, most
colostral antibodies are absorbed by 12-24h of age. Once removed, the kittens can
either be fostered to a Type-A queen, or fed milk replaced formula for 24 hours.
After this time it is generally safe for them to be returned to their dam. If the
anaemia is severe a blood transfusion will need to be performed. However, despite
removing the kittens as soon as clinical signs are noted, most affected kittens will
die within their first week of life.
Infectious diseases Death of puppies and kittens due to infectious disease
occur most frequently during the weaning period, and are due to either
respiratory, gastrointestinal tract or peritoneal disease. Under non-stressuful
conditions a viral/bacterial organism will cause only a self-limiting, clinically
inapparent disease, whereas if the neonate is stressed for whatever reason illness
will become manifest and puppy/kitten losses will ensue. Neonatal sepsis is
caused by bacteria such as Staphylococcus, E. coli, Klebsiella, Streptococcus,
Pseudomonas, Clostridium, Bacterioides, Pasteurella, Brucella and Salmonella.
Most of these bacteria are normally present as faecal or vaginal flora of the
mother, and in case of neonatal sepsis we have often isolated the same
microorganism from the dead puppy/kitten and from the mothers faeces. Viral
diseases which are responsabile of canine/feline neonatal death include
parvovirus, coronavirus, herpesvirus, adenovirus, calicivirus, retrovirus and
morbillivirus. Clinical signs tend to be variable depending on route of infection
and on amount of colostral antibodies received. Even when a careful vaccination
plan is implemented, conditions may occur within a breeding establishment
through which passive immunity will fail (most often for colostral deprivation)

causing neonates to become susceptible to viral infections which are thought to


be well controlled.
Miscellaneous factors Other less common factors of death in neonates include
roundworm, hookworm, coccidia and Giardia infections and fatty liver syndrome
(not unusual in toy breeds, with affected puppies showing sudden onset of
depression, anorexia, persistent crying, diarrhea, hyperpnea, hypothermia,
seizures and death within 1-6 days).
BIBLIOGRAPHY and SUGGESTED READINGS
1. Cave TA, Thompson H, Reid SWJ, Hodgson DR and Addie D (2002) Kitten
mortality in the UK: histopathological examinations (1986-2000). VR 151:
497-501
2. Chandler LM (1992) Pediatric normal blood values. Kirks Current
Veterinary Therapy XI, eds. RW Kirk and JD Bonagura, WB. Saunders,
Philadelphia. pp. 981-984
3. Hoskins JD (1995) Fluid therapy in the puppy and kitten. Kirks Current
Veterinary Therapy XII, eds. RW Kirk and JD Bonagura, WB. Saunders,
Philadelphia. pp. 34-37
4. Hotston Moore P and Sturgess CP (1998) Care of Neonates and Young
Animals. BSAVA Manual of Small Animal Reproduction & Periparturient
Care, p 153-169
5. Otto C and DT Crowe (1992), Intraosseous resuscitation techniques and
applications, in Current Veterinary Therapy XI, eds. RW Kirk and JD
Bonagura, Philadelphia: L&B Saunders, pp.107-109.
6. Sturgess CP (2006) Feline paediatric medicine. Europ J Comp Anim Pract
16(1): 83-94

Reproduction
BENIGN PROSTATIC HYPERTROPHY in the DOG
Prof. Stefano Romagnoli, DVM, MS, Ph.D, Dipl. ECAR
Department of Animal Medicine, Production and Health,
University of Padova, Agripolis, Legnaro, 35020 (PD)
stefano.romagnoli@unipd.it

In the dog, benign prostatic hyperplasia (BPH) is a process characterized by


development of cysts within the prostatic parenchyma. Presence of fluid-filled
cysts makes the prostate subject to infection from bacteria ascending the urethra
as accumulated prostatic fluid is an excellent media for bacterial growth.
Hematogenous spread of bacteria and spread from the kidneys and bladder via
urine or from the testicles and epididimys via semen can also occur. Bacterial
prostatic infection can be acute and fulminant or chronic and insidious leading to
abscessation.
Physiopathology of Canine BPH
Prostatic hyperplasia is probably due to an altered androgen:estrogen ratio, and
requires the presence of the testes to start and continue to develop.
Dihydrotestosterone (DHT) within the prostate gland probably serves as the main
hormonal mediator for hyperplasia. The hyperplastic prostate is highly
vascularized and therefore the gland bleeds easily, which explains the common
clinical sign of blood from the tip of the penis or blood in the urine. Blood loss in
the prostatic urethra can be so intense that the ejaculate may appear completely
red. Although presence of blood in the semen is typically considered to be a
cause for infertility, dogs with some blood in their ejaculates may sometimes be
fertile. The reason for BPH being a common cause of infertility in the dog is
probably due to the alteration of the biochemistry of the prostatic fluid whose
important action of nutrition of spermatozoa is decreased. Prostatitis or
abscessation are likely consequences of presence of blood in the prostate.
BPH is diagnosed based on history (bloody penile discharge, difficulties in
defecation/urination, poor semen quality and infertility, absence of
haematological/biochimical alterations), physical exam and abdominal ultrasound
(increase in prostatic size, presence of prostatic cysts), and if necessary a fine
needle aspirate. Urinalysis helps to rule out urinary tract diseases as a cause of
penile discharge (cystitis should be treated prior to onset of BPH therapy to avoid
confounding factors in the interpretation of results).

An enlarged, hypertrophic prostate may cause blood dripping from the tip of
penis, or it may grow and expand in the rectal canal, causing tenesmus and
sometimes difficult defecation. Other than the above signs, affected dogs are
usually normal and the prostate on palpation is non-painful, symmetrically
enlarged and with variable consistency. Urine may contain blood (gross or
microscopic). If hyperplasia is accompanied by urethral discharge, this is
typically haemorrhagic or clear but not purulent.
Prostatic enlargement may be also visualized on abdominal radiography as
causing dorsal displacement of the colon and cranial displacement of the bladder.
On retrograde urethrocystography the prostatic urethra may be normal or
narrowed and undulant with mucosal irregularity, and the urethroprostatic reflux
may be normal or greater than normal. On ultrasound, the prostate may appear
diffusely hyperechoic with parenchymal cavities (which means that
intraprenchymal cysts have developed). The canine prostate is best evaluated in
the sagittal and transverse planes using 5.0 or preferably 7.5 MHz scanners. An
enema should be administered prior to scanning to eliminate colonic contents
which may mimic peripheral prostatic disease. Conditions such as cysts or
abscesses are visualized easily. Other less distinct but echogenically complex
areas may indicate neoplasia or areas of infection within the gland. Although
technically a definitive diagnosis of BPH is only possible by biopsy, such an
invasive approach is not necessary to institute a therapy if clinical signs are
present, and from a practical standpoint ultrasound assessment of prostatic size
and presence of cysts is often the only thing that is necessary to identify the
problem and start dealing with it. No alteration of haematological or
biochemical parameters are commonly observed in dogs with BPH.
BPH can be difficult to differentiate in dog from other most common prostatic
disorders (prostatitis, prostatic cysts, carcinoma and adenocarcinoma) because of
the similarity of clinical findings. In men with prostatic carcinoma the use of
serum markers such as acid phosphatase (AcP) and prostate specific antigen
(PSA) has facilitated determination of the extent of disease, evaluation of
therapeutic response and detection of relapse after therapy. Information about
these markers is still controversial in the dog. Serum and seminal prostatic AcP
activities do not differ significantly between normal dogs and those with prostatic
diseases, or among dogs with different prostatic disorders; PSA is not detected in
canine serum or seminal plasma. The major secretory product of the canine
prostate is canine prostate-specific arginine esterase (CPSE) which constitutes
more than 90% of seminal proteins in this species. CPSE is a known marker of
dog prostatic secretion, although its exact role in the different disease of the
canine prostate is not yet completely understood. Even if dogs with BPH tend to
have higher serum CPSE concentrations than normal dogs, the diagnostic
usefulness of CPSE is limited because concentrations in dogs with prostatitis and
prostatic carcinoma were not significantly different from those of dogs with BPH.

CPSE is under testosterone control and, therefore, may serve as functional marker
of the androgenic state and response to antiandrogenic therapy, either by receptor
antagonists or 5-alpha-reductase inhibitors. Although further research is necessary
to define the exact role of CPSE, it seems to be a promising diagnostic tool in
nonneoplastic canine prostatic disorders.
Treatment for canine BPH
Surgical or pharmacological castration (using GnRH agonists) or the
administration of estrogens, steroidal or non-steroidal antiandrogens can be used.
Although occasionally reported as an effective treatment for BPH, estrogens carry
the potential risk of serious bone marrow side effects (anemia, leukopenia,
thrombocytopenia, pancitopenia) as well as the risk of growth of the
fibromuscular stroma of the prostate which may cause metaplasia of the prostatic
glandular epithelium and secretory stasis resulting in prostatic enlargement and
predisposition to cyst formation, bacterial infection and abscessation. Therefore,
we do not currently advice using estrogens to treat canine prostatic hyperplasia.
Estrogen receptor blocker may be used to treat BPH as they compete with
androgen receptors thereby decreasing prostatic size and weight (although the
altered ratio estrogen:testosterone is not modified which means that number and
size of prostatic cysts do not change). Recently, tamoxifen (an estrogen receptor
blocker with a mixed antagonist-agonist action) has been reported to be
efficacious and devoid of side effects in male dogs with BPH (except for a
decrease in libido and semen quality) (Corrada et al., 2004). Following 28 days
of treatment at the daily dose of 2.5 mg/day, tamoxifen causes a decrease in
testicular and prostatic size and a decrease in testosterone and libido. Tamoxifen
does not seem to have serious side effects and has been suggested recently as a
potential treatment for canine BPH, although there is no information on its longterm effect and safety and more studies are probably necessary before it can be
prescribed routinely (Corrada et al., 2004).
Castration The most effective treatment to induce regression of prostatic
hyperplasia is castration, after which prostatic size may decrease as much as 50%
in 3 weeks and 70% over 9 weeks. Orchiectomy has long been considered the
treatment of choice for those dogs whose reproductive function is not important
to the owner. As post-castration involution begins within days of surgery,
clinicians should palpate the dogs prostate 3 weeks post-operatively to make sure
the involution rate is normal thus ruling out a more serious prostatic disease such
as neoplasia or abscessation. Surgical castrations should not be performed in the
presence of prostatic infections due to the risk of scirrhous cord development.
Therefore, it would be better to administer an antibiotic treatment in case of
clinical signs of prostatitis or of presence of a > 10.000 colony forming units
(CFU) per ml of semen in a semen culture. With regard to orchiectomy, one
important thing to consider is that recent studies indicate that incidence of

prostatic carcinoma could be higher in castrated rather than in intact dogs; reasons
for this are not entirely known yet, but it is speculated that once prostatic atrophy
starts, neoplastic cells already present will increase their growth rate. For this
reason we do not currently advice owners to castrate their adult dog unless it is
strictly necessary (i.e. if there is a testicular tumor).
Steroidal antiandrogens - Steroidal antiandrogens compete with androgen
receptors and perhaps also with DHT receptors at the cellular level in target
organs. Compounds such as megestrol acetate, medroxyprogesterone acetate,
delmadinone acetate, chlormadinone acetate and ciproterone acetate are
successfully used in the dog, although for the majority of them there is only a
limited amount of experimental data on their effectiveness in the dog. Their
action causes a sort of pharmacologic castration and is rather precociously
observed during treatment, as improvement can be observed already after 7-15
days. Megestrol acetate can be used at the dose of 2.2 mg/kg per os MID for a
maximum of 2 weeks, or at the dose of. 0.55 mg/kg/day PO for 4-8 weeks.
Medroxyprogesterone acetate can be used at the dose of 3-4 mg/kg SC every 10
weeks. Chlormadinone acetate can be used at the dose of 1-2 mg/kg orally for 1
month, or as a subcutaneous implant of 5.0 mg/kg which lasts for 12 months.
Ciproterone acetate is also a progesterone derivative with a very strong
antagonistic effect on DHT receptors at the daily dose of 0.5-1.0 mg/kg per os.
Recent studies done at the University of Pisa, Italy, show a good clinical effect on
dogs suffering from prostatic disease when treated with ciproterone acetate for at
least 2-4 weeks; the drug is well tolerated and causes decreased libido and
spermatogenesis. We currently use cyproterone acetate in dogs with acute clinical
signs of BPH such as rectal compression, urethral compression or signs of
prostatitis. Cyproterone acetate has a very quick action with signs disappearing
already during the second week of treatment, therefore it is helpful whenever the
dog is suffering from signs related to BPH or when a worsening of the condition
is anticipated such as during the first 2-3 weeks following administration of a
GnRH agonist implant (see over). Its effects are rather long-lasting, with a 3-4
week course of oral administration being enough to maintain the dog for a few
months without clinical signs.
Non-steroidal antiandrogens Non-steroidal antiandrogens include finasteride,
flutamide and tamoxifen. Finasteride inhibits 5-a-reductase (the enzyme
responsible for the final transformation of testosterone into di-hydro-testosterone
or DHT) thereby lowering the concentration of DHT which is the active
metabolite at the level of target tissues, without altering serum testosterone
concentrations. This leaves spermatozoa production undisturbed, which makes
finasteride a good choice for breeders (although a chronic use may be associated
with a decrease in ejaculate volume as well as decrase in semen quality).
Finasteride is only approved for use in men, but it is well known to produce a

dose-dependent decrease in prostatic size also in dogs. It can be used at the daily
dose of 1.5 mg (approximately 1/3 of a 5.0 mg pill) for dogs <15 kg body weight,
2.5 mg (approximately half pill) for dogs of 15-30 kg body weight, and 5.0 mg
for dogs of >30 kg body weight. Finasteride is well tolerated and can be
administered for long periods of time. However, as soon as it is discontinued the
prostate will start growing again. Flutamide is a human antiandrogen which can
cause a significant decrease in prostatic size as detected by ultrasonography
within 10 days. When administered to research dogs at 5 mg/kg/day PO for 1
year, it did not alter libido or sperm production. Also flutamide is a human drug
not approved for use in veterinary medicine, although it appears safe, effective
and well tolerated in dogs. We currently use finasteride in breeding dogs both to
induce remission of clinical signs of BPH as well as to keep the condition under
control with 1-2 treatment cycles/year. Unlike cyproterone acetate, finasteride is
fairly slow to show its efficacy, as clinical signs may take up to 3-4 weeks to
disappear, and tend to appear again within a few weeks of treatment withdrawal.
GnRH Agonists see paper on Clinical Use of GnRH agonists in small animal
reproduction
How to prevent canine BPH
The best way to prevent the development of clinical BPH in the dog is to identify its
early pre-clinical signs by performing a regular monitoring of prostatic conditions
by ultrasound. On ultrasound, the hyperplastic prostate may appear diffusely
hyperechoic with parenchymal cavities. Conditions such as prostatic cysts can be
visualized easily using 5.0 or preferably 7.5 MHz scanners with sagittal and
transverse planes of scanning. If signs of BPH (such as presence of prostatic cysts
or increased prostatic size) are observed during a routine check while the dog is
asymptomatic, owners should be advised to watch for the development of clinical
signs in order to start treatment as soon as possible. The most effective treatment is
castration, following which prostatic size may decrease as much as 50% in 3 weeks
and 70% over 9 weeks. As post-castration involution begins within days of surgery,
clinicians should palpate the dogs prostate 3 weeks post-operatively to make sure
the involution rate is normal thus ruling out a more serious prostatic disease such as
neoplasia or abscessation. However, recent studies indicate that incidence of
prostatic carcinoma could be higher in castrated rather than intact adult dogs;
reasons for this are not entirely known yet, but it is speculated that once prostatic
atrophy starts, neoplastic cells already present will increase their growth rate. Also,
castration is often refused by the owner on cultural and/or psychological grounds.
When castration cannot be considered, other classes of drugs can be used. There is
little information on the value of a preventive treatment for BPH in the dog. In men,
preventive treatment is often discouraged because of the many side effects which
may be caused by alpha-1 adrenergic antagonists. However, incidence of side

effects of such drugs in the dog is unknown, and most importantly alpha-1
adrenergic antagonists are not 1st-choice drugs for canine BPH, while steroidal or
non-steroidal antiandrogens or GnRH agonists are more indicated for this purpose.
Side effects of long term treatment with steroidal antiandrogen include termporary
adrenocortical suppression and a decrease in libido and semen quality. All steroidal
antiandrogens should be avoided in breeding animals because of their potential
negative impact on fertility. However, the use of medroxyprogesterone acetate (3-4
mg/kg SC every 3 months), megestrol acetate (0.5 mg/kg per os for 2 months),
chlormadinone acetate (0.1-0.3 mg/kg/day per os for 6 months) as well as osaterone
acetate in its well known weekly treatment regimen have been associated with a
normal or acceptable fertility in male dogs and therefore might be used for limited
amounts of time in these patients:
BIBLIOGRAPHY and SUGGESTED READINGS
1. Barsanti JA, Finco DR Medical management of canine prostatic
hyperplasia. In: Bonagura JD, Kirk RW: Current Veterinary Therapy XII,
Philadelphia. WB Saunders, 1995, pag 1033-1034
2. Bell FW, Klausner JS, Hayden DW, Feeney DA, Johnston SD Clinical
and pathological features of prostatic adenocarcinoma in sexually intact
and castrated dogs: 31 cases (1970-1987) JAVMA 199:1623-1630
3. Corrada Y, Arias D, Rodriguez R, Spaini E, Fava F, Gobello C Effect of
tamoxifen citrate on reproductive parameters of male beagle dogs.
Theriogenology 61: 1327-1341, 2004
4. Court EA, Watson ADJ, Church DB, Emslie DR Effects of delmadinone
acetate on pituitary-adrenal function, glucose tolerance and growth
hormone in male dogs. Austr Vet J 76(8): 555-560, 1998
5. Frank D, Sharpe N, Scott MC, Mirro E, Hartman B, Haliwell WH
Chronic effects of flutamide in male beagle dogs. Toxicol Pathol 32:
(2):243-249, 2004
6. Gobello C., Gervasio C., Corrada Y.: Serum and seminal markers in the
diagnosis of disorders of the genital tract of the dog: a mini-review
Theriogenology, 57, pp. 1285-1291, 2002b.
7. Kojima Y, Kawakami S, Shino M Effects of chlormadinone acetate
treatment on canine prostatic hyperplasia. J Japan Vet Med Assoc 50 (12)
725-728, 1997
8. Iguer Ouada M, Verstegen JP Effect of finasteride on seminal
composition, prostate function and fertility in male dogs. J Reprod Fert
51:139-149, 1997
9. Johnston SD., Kamolpatana K., Root-Kustritz MV., Johnston GR. Prostatic
disorders in the dog. Animal Reproduction Science, 60-61: 405-415, 2000.
10.Johnston SD, Root-Kustritz MV, Olson PNS Diseases of the canine
prostate. In: Canine and Feline Theriogenology. Editors SD Johnston, MV
Root-Kustritz and Olson PNS, WB Saunders 2001, pag 337-355

11. Romagnoli S - Deslorelin in Small Animal Andrology. Proceedings, 5th

Biannual congress European Veterinary Society Small Animal


Reproduction, Budapest 7-9 April 2006, pagg 204-207
12.Sirinarumitr K., Johnston SD., Root-Kustritz MV., Johnston GR., Sarkar
DK., Memon MA. Effects of finasteride on size of the prostate gland and
semen quality in dogs with benign prostatic hypertrophy. JAVMA, 218(8):
1275-1279, 2001.
13. Teske E, Naan EC, van Dijk EM, Van Garderen E, Shcalken JA Canine
prostatic carcinoma: epidemiological evidence of an increased risk in
castrated dogs. Mol Cell Endocrinol 197: 251-255, 2002
14.Trigg TE, Wright PJ, Armour AF, Williamson PE, Junaidi A, Martin GB,
Doyle AG, Walsh J Use of a GnRH analogue implant to produce
reversible long-term suppression of reproductive function in male and
female domestic dogs. J Repro Fertil Suppl 57, 255-261, 2001
15.Tunn U., Senge T., Schenck B., Neumann F. Effects of cyproterone acetate
on experimentally induced canine prostatic hyperplasia. Urol. Int., 35: 125140, 1980.
16. Wright PJ, Stelmasiak T, Black D et al. Medroxyprogesterone acetate and
reproductive processes in male dogs. Austr Vet J 55:437-438, 1979