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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
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
Bromocriptine
Metergoline
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
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
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
4. Fieni F, Dumon C, Tainturier D, Bruyas JF Clinical protocol for pregnancy
termination in bitches using prostaglandin F2. J Reprod Fert Suppl 51: 245250, 1997
5. Fieni F, Martal J, Marnet PG, Siliart B, Bernard F, Riou M, Bruyas JF,
Tainturier D Hormonal variations in bitches after early or mid-pregnancy
termination with aglepristone (RU534). J Reprod Fert Suppl 57: 243-248, 2001
6. Galac S, Kooistra HS, Butinar J, Bevers MM, Dieleman SJ, Voorhout G,
Okkens AC Termination of mid-gestation pregnancy in bitches with
aglepristone, a progesterone receptor antagonist. Theriogenology 53: 941-950,
2000
7. Gentile S Infant safety with antipsychotic therapy in breast-feeding: a
systemic review. J Clin Pschiatry 69:666-673, 2008
8. Johnston SD, Root-Kustritz MV and Olson PN Periparturient disorders in the
bitch. In: Canine and Feline Theriogenology. SD Johnston, MV Root-Kustritz
and PN Olson Eds. WB Saunders Co, 2001, pp 129-145
9. Kutzler MA Canine postpartum disorders. In: Kirks Current Veterinary
Therapy XIV. J Bonagura and D Twedt Eds, WB Saunders 2009, pp 999-
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
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
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.
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
lasting regression of the perianal mass without any additional treatment (Romagnoli,
unpublished data)
BIBLIOGRAPHY and SUGGESTED READINGS
1. Arlt SP, Spankowsky S, Heuwieser W - Follicular cysts and prolonged oestrus in a
female dog after administration of a deslorelin implant. New Zealand Veterinary
Journal, 59:2, 87-91
2. Arnold S, Hubler M., Reichler I Urinary incontinence in spayed bitches. New
insights into the pathophysiology and options for medical treatment. Reprod Dom
Anim 44 (Suppl 2): 190-192, 2009
3. Bajetta E, Celio L, Zilembo N, Bono A, Galluzzo D, Zampino MG, Longhi A,
Ferrari L, Buzzoni R: 1994. Ovarian function suppression with the
gonadotrophin-releasing hormone analogue goserelin in premenopausal advanced
breast cancer. Tumori 80: 28-32
4. Bakker GH, Setyono-Han B, Portengen H, De Jong FH, Foekens J, Klin JGM:
1989. Endocrine and antitumor effects of combined treatment with an
antiprogestin and antiestrogen or luteinizing-hormone releasing hormone agonist
in female rats bearing mammary tumor. Endocrinology 125: 1593-1598
5. Barsanti JA, Finco DR Medical management of canine prostatic hyperplasia.
In: Bonagura JD, Kirk RW: Current Veterinary Therapy XII, Philadelphia. WB
Saunders, 1995, pp 1033-1034
6. Barsanti JA Diseases of the prostate gland. In: Proceedings, Annual meeting of
the Society for Theriogenology, Montreal, Canada, September 1997, pp 72-80
7. Battistacci M, Calandra ML: 1974. Quantitative measurement of metabolites of
the tryptophane-niacin pathway in healthy bitches and those affected with
mammary dysplasia and neoplasia. Nuova Vet 50:246-252
8. Bertschinger HJ, Asa CS, Calle PP, Long JA, Bauman K, De Matteo K, Jochle W,
Trigg TE, Human A Control of reproduction and sex related behaviour in exotic
wild carnivores with the GnRH analogue deslorelin: preliminary observations. J
Repro Fertil Suppl 57, 275-283, 2001
9. Corrada Y, Hermo G, De la Sota PE, Garca P, Trigg T, Gobello C A short term
progestin treatment prevents estrus induction by a GnRH agonist implant in
anestrous bitches. Proceedings 5th Biannual EVSSAR congress, Budapest,
Hungary, 7-9 April 2006, p 278
10.De Kretser DM, Meinhardt A, Meehan T, Phillips DJ, OBryan MK, Loveland
KA: 2000. The roles of inhibin and related peptides in gonadal functions. Mol
Cell Endocrinol 161: 43-46
11.Feldman EC, Nelson RW: 2004. Hyperadrenocorticism (Cushings syndrome).
In: Canine and feline endocrinology and reproduction. Eds EC Feldman, RW
Nelson. WB Saunders. 3rd Edition. Pp 206-291
12.Fontaine E, Mir F, Vannier F, Fontbonne A, Albouy M - Use of GnRH Agonist
Implants for Medical Prevention of Estrus in the Bitch. 4th ACC&D International
Symposium on Non-Surgical Contraceptive Methods of Pet Population Control,
25.Lacoste D, Labrie F, Dub D, Blanger A, Tice T, Gilley RM, Pladger KL: 1989b.
Reversible inhibition of testicular androgen secretion by 3-. 5- and 6-month
controlled-release microsphere formulations of the LH-RH agonist D-Trp, desGly-NH LH-RH ehtylamide in the dog. J Steroid Biochem 33 (5):1007-1001
26.Lombardi P, Florio S, Paganini U, Crispino A, Avallone L: 1999. Ovarian
Function suppression with a GnRH analogue (Goserelin) in hormone-dependent
canine mammary cancer. J Vet Pharmacol Therap 22: 56-61
27.Ludwig C, Desmoulins PO, Flochlay-Sigognault A, Driancourt MA, Hoffman B:
2006. Treatment with a subcutaneous GnRH agonist-containing implant downregulates the hypothalamo-pituitary gonadal axis of male dogs. Proceedings 5th
Congress European Veterinary Society for Small Animal Reproduction, Budapest,
Hungary, 7-9 April, pp 317
28.Majdic G, McNeilly AS, Sharpe RM, Evans LR, Groome NP, Saunders TK: 1997.
Testicular expression of inhibin and active subunits and follistatin in the rat and
human foetus and neonate and during postnatal development in the rat.
Endocrinology 138:2136-2147
29.Massoud W, Paparel P, Lopez JG, Perrin P, Daumont M, Ruffion A Discovery of
a pituitary adenoma following a gonadotropin-releasing hormone agonist in a
patient with prostate cancer. Int J Urol. 2006 13(3):303-4
30.Mol JA, Selman PJ, Sprang EPM: 1997. The role of progestins, insulin-like
growth factor (IGF) and IGF-binding proteins in the normal and neoplastic
mammary gland of the bitch: a review. J Reprod Fert Suppl 51:339-344
31.Pisu MC, Romagnoli S - Impiego clinico di un impianto di deslorelin nel gatto.
Veterinaria, Anno 26 (1), February: 1-7, 2012
32.Ponglowhapan S, Lohachit C, Swangchanutai T, Trigg TE: 2002. The effect of the
GnRH agonist deslorelin on prostatic volume in dogs. Proceedings Congress
European Veterinary Society for Small Animal Reproduction, Liege, May 10-12,
p 150;
33.Reichler IM, Hubler M, Jochle W, Trigg TE, Pich CA, Arnold S: 2003. The
effect of GnRH analogues on urinary incontinence after ablation of the ovaries in
dogs. Theriogenology 60:1207-1216
34.Reichler IM, Pfeiffer E, Pich CA et al: Changes in plasma gonadotropin
concentrations and urethral closure pressure in the bitch during the 12 months
following ovariectomy. Theriogenology 2004, 62, 1391-1402
35.Reichler IM, Hung E, Jchle W, Pich CA, Roos M, Hubler M, Arnold S.
FSH and LH plasma levels in bitches with differences in risk for urinary
incontinence. Theriogenology. 2005, 63 (8):2164-80.
36.Reichler IM, Jochle W, Pich CA, Roos M, Arnold S: 2006a. Effect of a long
acting GnRH analogue or placebo on plasma LH/FSH, urethral pressure profiles
and clinical signs of urinary incontinence due to sphincter mechanism
incompetence in bitches. Theriogenology 66: 1227-1236
50. Tammela T, 2004 Endocrine treatment of prostate cancer. J Steroid Biochem Mol
Biol 92(4):287-95
51. Taniyama H, Hirayama K, Nakada K, Numagami K, Yaosaka N, Kagawa Y,
Izumisawa Y, Nakade T, Tanaka Y, Watanabe G, Taya K: 2001.
Immunohistochemical detection of inhibin-, -B, and A chains and 3hydroxysteroid dehydrogenase in canine testicular tumors and normal testes. Vet
Pathol 38:661-666
52. Trigg TE, Wright PJ, Armour AF, Williamson PE, Junaidi A, Martin GB, Doyle
AG, Walsh J: 2001. Use of a GnRH analogue implant to produce reversible longterm suppression of reproductive function in male and female domestic dogs. J
Repro Fertil Suppl 57, 255-261,
53. Trigg TE, Doyle AG, Walsh J, Theeerawat S: 2004. Advances in the use of the
GnRH agonist deslorelin in control of reproduction. 5th International Symposium
on Canine and Feline reproduction. S. Paolo, Brazil August 4-6, pp 49-51
54. Trigg TE, Doyle AG, Walsh J, Swangchan-uthai T: 2006. A review of advances in
the use of the GnRH agonist deslorelin in the control of reproduction.
Theriogenology xxxxx in press
55. Volkmann DH, Kutzler MA, Wheeler R, Krekeler N: - The use of deslorelin
implants for the synchronization of estrus in diestrus bitches. Theriogenology 66:
1497-1501, 2006a
56. Volkmann DH, Kutzler MA, Wheeler R, Krekeler N, Klewitz J, Lamb SV: 2004.
Failure of hCG to support luteal function in bitches after estrus induction using
deslorelin implants. Theriogenology 66: 1502-1506, 2006b
57. Williams MB, Hernandez J, Thompson I, 2005: Luteinizing hormone-releasing
hormone agonist effects on skeletal muscle: how hormonal therapy in prostate
cancer affects muscular strength. J Urol. 173(4):1067-71
58. Wilson GP, Hayes HM Jr: 1979. Castration for treatment of perianal gland
neoplasms in the dog. J Am Vet Med Assoc. Jun 15;174(12):1301-3.
59. Wright PJ, Verstegen JP, Onclin K, Jochle W, Armour AF, GB Martin, Trigg TE:
2001. Suppression of the oestrous response of bitches to the GnRH analogue
deslorelin by progestin. J Repro Fertil Suppl 57, 263-268
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
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
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
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.
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
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.
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
hypercorticalism (also because these dogs are not generally bred), adrenal pathology
should always be ruled out when considering a case of fetal death.
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)
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
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,
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
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)
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
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