Reprod Dom Anim 49 (Suppl. 2), 8–15 (2014); doi: 10.1111/rda.
12297
ISSN 0936–6768
Pharmacological Treatment for Common Prostatic Conditions in Dogs – Benign
Prostatic Hyperplasia and Prostatitis: an Update
W Ni_zanski1, X Levy2, M Ochota1 and J Pasikowska1
1
Department of Reproduction, Faculty of Veterinary Medicine, Wrocaw University of Environmental and Life Sciences, Wrocaw, Poland; 2CRECS,
Isle Jourdain Gers, France
Contents
The two most frequent prostatic diseases in dogs are benign
prostatic hyperplasia (BPH) and prostatitis. Prostatitis
requires prolonged antibiotic treatment. In acute prostatitis,
the blood–prostate barrier is broken, thus facilitating the
penetration of antibiotics, whereas in chronic prostatitis,
the barrier prevents the penetration of many drugs into the
gland. The selection of antibiotic agents is based on
the sensitivity test and the drug’s ability to penetrate into
the gland. Many protocols for the treatment of BPH are
available. In non-breeding dogs, surgical and optionally
pharmacological castration by means of GnRH agonists may
be performed. In breeding dogs, drugs retaining fertility are
used. Recently, androgen receptor antagonistic treatment
with osaterone acetate has been applied. Other drugs used
for BPH treatment include progestagens, oestrogens, anti-
oestrogens and 5a-reductase inhibitors. Some of these com-
pounds may provoke severe side effects. The efficiency of
GnRH antagonists used for the treatment of prostatic
diseases, such as neoplasia and BPH, in humans has been
recently investigated in dogs. This androgen deprivation
therapy (ADT) is devoid of an initial exacerbation of
androgen-dependent symptoms, which is typical for GnRH
agonistic treatment. In many cases, BPH and prostatitis must
be treated simultaneously as these conditions may develop in
combination.
Introduction
The prostate gland is the only accessory sexual gland in
dogs. As in humans, pathological conditions of the
prostate gland are common in the canine species and
originate from infection, alterations of hormone supply
or abnormal embryonic development of genital organs.
Generally, their incidence increases with age and may be
related to a physiological androgen-dependent hyperde-
velopment of the glandular and stromal tissue (Verste-
gen 2008). The normal prostatic secretion exerts
bactericidal effects during sexual rest, thereby prevent-
ing infection ascending via the urethra. Pathological
alterations of the glandular tissue may result in changes
in the prostatic fluid composition and in the loss of its
physiological role. Secretion of the prostate normally
contributes to the volume of the dog ejaculate (>90%).
Pathologies of the prostate gland in dogs include
inflammatory conditions, such as septic and aseptic
acute and chronic prostatitis, conditions with endocrine
background like prostatic hyperplasia, prostatic meta-
plasia and other conditions, that is, intra-/paraprostatic
cysts, and prostatic neoplasia (Johnston et al. 2001;
Verstegen 2008). The two most frequent prostatic
diseases in dogs are benign prostatic hyperplasia
(BPH) and prostatitis.
Benign Prostatic Hyperplasia
Benign prostatic hyperplasia (BPH) is one of the most
important problems in intact male dogs and thus of
similar importance as in humans. BPH may occur as
benign glandular hyperplasia or as benign complex
hyperplasia (or cystic hyperplasia). The aetiology of
BPH is still unclear in many aspects. Administration of
androgens in combination with oestrogens to orchidec-
tomized dogs induced prostatic hyperplasia, with an
increase in the number of transiently proliferating (TP)/
amplifying cells and a hyperplastic luminal epithelium
(Mahapokai et al. 2000; Lai 2009). Relative increase in
TP/amplifying cells in hormonally induced BPH in the
dog is considered to be in line with a stem cell-derived
proliferation. Androgen-independent basal cells and
TP/amplifying cells are much more abundant in the
prostate of older males than in younger dogs, and this
may contribute to the enhanced risk of development of
BPH with increasing age (Mahapokai et al. 2000; Lai
2009). Usually, BPH in the dog is uniform and diffuse. It
involves the glandular epithelial cells in the entire gland.
The degree of stromal involvement is lesser. In humans,
BPH is nodular and complex, with the involvement of
both the stroma and the epithelium. The expression of
5a-reductase (converting testosterone to dihydrotestos-
terone) in the prostatic epithelium is higher in the dog
than in man, when compared to stroma. It may explain
why the hyperplasia is mainly epithelial in dogs and
stromal in humans (Tunn et al. 1988). It should be
noted that there is another hypothesis suggesting that
oestrogens induce stromal growth in human BPH and
induce prostatic metaplasia in dogs (Collins et al. 1994;
Ho et al. 2008). BPH may also be found in dogs with
prostatic carcinoma, but there is no histopathological or
immunohistochemical (Lai et al. 2008) relationship
between the two pathologic entities, and with the pre-
malignant HG-PIN (high-grade prostatic intraepithelial
neoplasia) lesions (Madewell et al. 2004).
Generally, it may be stated that BPH develops due to
a constant influence of the testosterone metabolite
dihydrotestosterone (DHT) on the glandular tissue.
DHT is the active compound inducing proliferation and
enlargement of glandular cells (Grino et al. 1990).
Testosterone affects the expression of genes mediating
testosterone metabolism and genes mediating the effect
of those metabolites on the prostate (Shidaifat and Lin
2012). The terms ‘prostatic hyperplasia’ and ‘prostatic
hypertrophy’, both used in scientific literature and in
practice, properly describe the nature of the condition
(Krawiec and Heflin 1992; Smith 2008). In contrast to
© 2014 Blackwell Verlag GmbH
Pharmacological Treatment of Prostate
prostatic neoplasia, enlargement of the entire gland is
usually more uniform in BPH. Vascularization of the
hypertrophic/hyperplastic glandular tissue increases and
may result in vascular leakage or haemorrhage into the
gland (Verstegen 2008). Consequently, blood is excreted
through the secretory ducts into the urethra. This blood
may also be present in the semen, as observed in many
cases in the third ejaculate fraction by its opaque and
red or brown appearance. Enlargement of the gland
induced by DHT may result in pain, claudication and
defecation problems. Increase in the intraglandular
pressure may impair the passage of secretion from the
gland, and local increase in pressure in the distorted
glandular tissue may result in the accumulation of the
fluid within some of the excretory ducts. Formation of
intra- or extraglandular cysts may be observed. As the
gland is surrounded by a firm capsule, increased
intraglandular pressure may also cause compression of
the urethra and dysuria (Lopate 2010). It should be
noted that contrary to humans, dysuria is an infrequent
sign of BPH in dogs. Impairment of the function and
distorsion of the glandular structure are the obvious
reasons for the frequent simultaneous development of
prostatitis and BPH.
Prostatic diseases (mostly BPH) in intact dogs
account for 6.2% of all diseases in male dogs of 4 years
of age or younger, 17.5% in those of 4–7 years of age,
32.8% in 7- to 10-year-old dogs and 43.5% in dogs
≥10 years of age (Krawiec and Heflin 1992; Tsutsui
et al. 2000).
On the other hand, 80% of the intact dogs have gross
or microscopic evidence of BPH by 5 years of age (Berry
et al. 1986; Sirinarumitr et al. 2001). Senile involution
of the prostate gland begins in older animals, approx-
imately 11 years of age (O’Shea 1962). As 90% of dogs
aged ≥9 years showed BPH, the condition was consid-
ered to be a physiological change in intact male dogs
(Tsutsui et al. 2000). Mild prostatic hyperplasia is
thought to be normal in animals older than 5–7 years
and is only considered as a disease if BPH-related
clinical signs, such as constipation, haematuria, dysuria,
semen abnormities and dorsal curvature or claudication
of hind limbs, are present (Verstegen 2008).
Based on the clinical signs observed and subjectively
reported by dog owners, Zambelli et al. (2012) devel-
oped and statistically validated a model to assign an
objective score for canine BPH severity, the so-called
BPH symptom index, as an aid to evaluate the necessity,
kind and effectiveness of treatment.
Prostatitis
Prostatitis is the second most common pathological
condition of the canine prostate. In contrast to BPH,
inflammation of the prostate gland is observed in males
independent of age. It is reported more frequently in
intact than in orchidectomized males, indicating an
underlying influence of androgen stimulation. It was
reported that an inflammatory response was induced in
the dog’s prostate gland after androgen administration
(Mahapokai et al. 2000). Hormonal treatment of male
dogs with androgens plus oestrogens induced prostatic
hyperplasia, followed by extensive multifocal mononu-
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9
clear inflammation. This inflammatory response was
more pronounced than that in dogs treated with
androgens alone (reviewed by Lai 2009).
Chronic prostatitis is more common than acute.
Septic prostatitis is a prevalent condition in dogs,
whereas aseptic prostatitis, mostly seen in humans, is
extremely rare (Barsanti and Finco 1979). Predisposing
factors for prostatic infection may be BPH, prostatic
cysts, squamous metaplasia and neoplasia. Simulta-
neous development of BPH and infectious prostatitis is
commonly observed and consequently needs combined
treatment for the two conditions.
Infections of the prostate gland may be caused by
single aerobic, Gram-positive or Gram-negative bacte-
ria, such as E. coli, Streptococcus spp., Staphylococcus
spp., Klebsiella spp., Pseudomonas spp., Pasteurella
spp., Mycoplasma spp., Ureaplasma spp. and other
microorganisms. Infections with anaerobic bacteria are
unlikely (Barsanti and Finco 1979; Krawiec and Heflin
1992; Johnston et al. 2001; Verstegen 2008).
Treatment for Prostatitis
Acute prostatitis with severe, profound inflammation
resulting in pain, glandular enlargement, urination/
defecation failure, fever and leucocytosis requires an
aggressive therapy. Intravenous administration of fluids,
such as electrolyte solutions, and non-steroidal anti-
inflammatory drugs (NSAIDs) are usually used. In
acute prostatitis, the blood–prostate barrier is broken
(Barsanti and Finco 1979), resulting in an easy pene-
tration of antibiotics and other drugs into the gland
independent of pH and oil solubility of the active
compound. Therefore, the antibiotic agent should be
chosen on the basis of a sensitivity test. Usually, the
specimen is collected by prostatic wash (details of
diagnosis are presented in the manuscript of Levy et al.
2014). Initially, before the result of the sensitivity test is
obtained, an antibiotic of broad spectrum should be
administered (Memon 2007; Verstegen 2008; Lopate
2010).
In chronic prostatitis, the blood–prostate barrier
prevents the penetration of many drugs into the gland.
The selection of antibiotic is performed based on the
sensitivity test (details of diagnosis are presented in the
manuscript of Levy et al. 2014) and the drug’s penetra-
tion ability into the gland. Only weak alkaline antibi-
otics, with high pKa (acid dissociation constant) and
high lipid solubility, are able to diffuse into the prostatic
parenchyma. The effectiveness of trimethoprim, clinda-
mycin, chloramphenicol and erythromycin has been
proven. Zwitterionic antibiotics such as the fluoroqui-
nolones enro-, cipro-, marbofloxacin are also effective as
they have multiple pKa (Barsanti and Finco 1979;
Dorfman et al. 1995; Johnston et al. 2001).
As many cases of prostatitis develop in consequence
of BPH, simultaneous treatment for both conditions is
needed. BPH treatment using antiandrogenic pharma-
cological agents or testosterone deprivation by surgical
castration may be considered as supportive therapy
for prostatitis (Cowan et al. 1991; Johnston et al.
2001). Orchidectomy is usually performed according
to general surgical procedures. In chronic prostatitis,
10
antibiotics are applied for at least 4–5 weeks. In some
cases, 8–12 weeks of treatment is necessary (Barsanti
and Finco 1979; Verstegen 2008). Potential side
effects of a long-term antibiotic treatment include
bacterial resistance, liver dysfunction, renal dysfunc-
tion, anaemia (high risk for chloramphenicol,
fluoroquinolones), arthropathy (fluoroquinolones) and
some possible complications of trimethoprim adminis-
tration, such as hypothyroidism, urolith formation or
keratoconjunctivitis sicca (Rubin 1990; Johnston et al.
2001).
Treatment for BPH
Treatment for BPH includes the suppression/prevention
of androgen synthesis or action. The treatment of choice
in dogs not intended for breeding is surgical castration.
Involution of the gland is complete 6–12 weeks after
gonadectomy, but the clinical signs of the condition may
disappear earlier.
In breeding dogs, treatment with pharmacological
compounds inhibiting the production or activity of
androgens may be preferred in order to maintain
fertility. This should not be applied in cases of prostatic
and testicular neoplasia, prostatic cysts of large dimen-
sions or severe clinical signs related to extreme enlarge-
ment of the prostate. It is necessary to exclude testicular
tumours before the antiandrogen therapy is introduced.
It is very likely that testicular tumours produce oestro-
gens. In oestrogen-dependent conditions, such as pros-
tatic metaplasia, the antiandrogen therapy would be
ineffective and aimless. Therefore, pharmacological
treatment for BPH in cases of concomitant presence of
testicular tumours should be avoided.
Progestagens
This group of synthetic progestins presents antiandro-
genic action (Tsutsui et al. 2001; Johnson 2003). Many
such drugs have been used for decades in the past. Their
administration is still considered when short and low-
cost therapy is required. They also may be used in
combination with GnRH agonists (see below). Cur-
rently, due to the availability of new pharmacologic
agents, treatment with synthetic progestins has to be
considered regarding their potential to evoke severe side
effects. A potential influence of progestagen adminis-
tration on enhancing the production of somatotropin,
induction of a severe atrophy of the zona fasciculata and
reticularis of the adrenal gland and also its influence on
glucose and insulin balance should be considered
(Eigenmann and Eigenmann 1981; Bamberg-Thalen
and Linde-Forsbeg 1993; Johnston et al. 2001). On the
other hand, in vitro experiments confirmed the strong
glucocorticoid action of some progestins, such as
medroxyprogesterone acetate (MPA). Therefore, long-
term treatment with high doses of progestins may result
in an iatrogenic Cushing’s syndrome (Selman et al.
1997). The most severe side effect of progestins is
induction/exacerbation of diabetes mellitus by inhibiting
the transport of insulin in tissues and decreasing the
number of insulin receptors. An additional possible side
effect of administration of progestagens is hypothyroid-
W Ni_za
nski, X Levy, M Ochota and J Pasikowska
ism. Diabetes mellitus and hypothyroidism occurred in
5% of the dogs treated with MPA (Bamberg-Thalen and
Linde-Forsbeg 1993). Furthermore, increased appetite
in the early weeks after the beginning of the treatment
(31%) was observed (Bamberg-Thalen and Linde-
Forsbeg 1993; Johnston et al. 2001; Verstegen 2008).
Administration of high doses of these compounds
may impair spermatogenesis, finally resulting in as-
thenozoospermia and teratozoospermia (England 1997).
Progestagens used for BPH treatment decrease the
testosterone concentration in blood without a significant
impact on libido. Furthermore, LH secretion appears to
be unaffected (Bamberg-Thalen and Linde-Forsbeg
1993; England 1997).
Among numerous progestagens, megestrol acetate
(MGA), medroxyprogesterone acetate, chlormadinone
acetate (CMA) (Murakoshi et al. 1992; Johnston et al.
2001) and delmadinone acetate (DMA) (Lange et al.
2001; Johnson 2003; Albouy et al. 2008) were used for
BPH treatment. Oral administration of MGA at a dose
of 0.5 mg/kg/day BW for 2 months reduced the pros-
tatic size within 1–2 months after the start of treatment
(Johnston et al. 2001). MPA (3–4 mg/kg BW) is injected
subcutaneously every 5 months. The decrease in the
blood level of testosterone was observed from the 5th
week of administration, inducing shrinkage of the
prostate gland within 4–6 weeks in 53%, and the
resolution of clinical signs in 84% of BPH cases (Wright
et al. 1979; Bamberg-Thalen and Linde-Forsbeg 1993).
A 5-month oral treatment with CMA (0.3 mg/kg BW)
was effective in the reduction in prostatic size, but did
not affect the testes or the pituitary function (Murakoshi
et al. 1992). No evidence of abnormal spermatogenesis
was seen in the seminiferous tubules. No changes in the
Leydig cell population were found. Administration of
CMA produced no significant treatment-related changes
in the number of LH-immunoreactive cells in the
pituitary gland (Murakoshi et al. 2001). Delmadinone
acetate was administered at 1.5 mg/kg BW SC, 39/week
for the 1st, 2nd and 4th weeks, by single SC or IM
injection of 3 mg/kg BW (Albouy et al. 2008), or IM
injection of 1 mg/kg BW (Lange et al. 2001). It did not
influence the glucose tolerance, or the somatotropin
concentration, but inhibited the function of adrenal
glands (Johnson 2003).
Inhibitors of 5a-reductase
5a-Reductase (5a-R) inhibitors prevent the conversion
of testosterone to DHT, which is the active androgen
within the prostatic tissue. Inhibition of this enzymatic
step results in a reduction in the glandular dimensions.
5a-R inhibitors may be classified into two types
according to their distinctive mechanisms of action:
competitive – represented by finasteride – and non-
competitive – represented by episteride. As shown in a
recent study in beagle dogs, both types resulted in a
decrease in DHT concentration in prostate gland tissue.
However, 5a-R inhibitors of the competitive type
reduced DHT concentration in peripheral blood to a
greater extent, resulting in an increase in the testoster-
one level in blood and the prostate gland (Zhao et al.
2013).
© 2014 Blackwell Verlag GmbH
Pharmacological Treatment of Prostate
Finasteride may be considered a therapeutic drug in
dogs. It was approved for the treatment of BPH in men
in the early 1990s (reviewed by Smith 2008). Reports on
its successful use in dogs suffering from BPH by daily
oral administration of 0.1–0.5 mg/kg BW for 16 weeks
(Sirinarumitr et al. 2001) or 1 mg/dog for 3–21 weeks
(Iguer-Ouada and Verstegen 1997; Lange et al. 2001)
are available. A significant decrease in DHT blood
concentration was observed (Nakayama et al. 1997;
Lange et al. 2001). After 5–15 weeks of treatment, it
induced a marked decrease in the size of the prostate
and a fall in its secretions. At maximum effect, the
calculated prostate volume was reduced to 30% of the
initial value (Iguer-Ouada and Verstegen 1997). Sper-
matogenesis, semen characteristics, libido, serum testos-
terone concentrations (Lange et al. 2001) and fertility
were not affected (Kamolpatana et al. 1998). As in
finasteride-treated dogs, neither changes in testicular
weight and daily sperm production/total sperm number
(Nakayama et al. 1997; Lange et al. 2001) nor side
effects were observed (Iguer-Ouada and Verstegen
1997), and fertility was unimpaired (Johnson 2003), this
compound is recommended for the treatment of BPH in
stud dogs used in breeding programmes. Administration
of finasteride over several weeks exerts long-lasting
therapeutic effects on the hyperplastic prostate gland
(Iguer-Ouada and Verstegen 1997). Finasteride is a
teratogenic compound; therefore, pregnant women
should avoid contact with this drug. Although there is
a potential risk of absorption of this drug from the
seminal fluid through the female’s genital tract, no
visible abnormalities were reported in puppies sired by
dogs treated with this drug (Iguer-Ouada and Verstegen
1997).
Inhibitors of steroid receptors
Osaterone acetate (OA) (17a-acetoxy-6-chloro-2-oxa-
4,6-pregnadiene-3,20-dione) has proved to be an effec-
tive and potent competitive inhibitor of testosterone
receptors. Its complex mechanism of action is quite
uncommon. It impairs the uptake of DHT in the prostate
gland and inhibits the action of the 5a-reductase.
Furthermore, OA directly decreases the DHT and
androgen nuclear receptor content in the prostate
(Takezawa et al. 1992; Tsutsui et al. 2000, 2001). OA
has a 5-fold stronger regressing effect on the prostate
gland than has chlormadinone (Tsutsui et al. 2000).
Histological and immunohistochemical study revealed
that OA does not affect the testes (seminiferous and
Leydig cells) and the pituitary LH-secreting cells.
However, slightly decreased serum testosterone levels
were found in OA-treated animals, suggesting that a
marginal antigonadotrophic effect cannot be excluded
(Murakoshi et al. 1992).
The rate of change in prostatic area (RCPA) was
abrupt and clearly visible (approximately 58.5–77.9% of
pre-treatment values) after 1 week of treatment despite
the variety of doses used (0.1, 0.2, 0.5 and 1 mg/kg BW)
(Tsutsui et al. 2000). In intact dogs, OA exhibited
biexponential disposition with a particularly long half-
life of 197.9  109.9 h. The main route of OA excretion
is faeces via the bile as glucuronide. It is worth noting
© 2014 Blackwell Verlag GmbH
11
that in dogs a significant amount of the compound is
recycled biliarily (Minato et al. 2002).
Osaterone acetate is marketed in pills containing
different amounts of the active compound according to
the dog’s body weight. Daily oral administration for
7 days results in a significant decrease in prostate gland
size. Glandular dimensions return to pre-treatment state
within 5 months after beginning of the treatment
(Tsutsui et al. 2000, 2001). For prolongation of the
therapeutic effects, the protocol may be repeated. OA
does not significantly impair the process of spermato-
genesis. The total number of spermatozoa remains
nearly unchanged, whereas a transient increase in the
percentage of morphologically abnormal sperm cells
was observed (Tsutsui et al. 2000). The volume of
prostatic fluid represented in the third ejaculate fraction
may be slightly diminished for 2–4 weeks after the start
of OA administration, in accordance with the drug-
related effects on the glandular tissue. Nevertheless, this
drug has proved to be very effective in BPH therapy.
Stud dogs treated with OA remain fertile, and it may
still be used in breeding programmes. Contrary to
progestagens (see above), almost no side effects are
observed. Our own observations revealed a transient
increase in appetite during the initial 1–3 weeks after
beginning of the treatment with OA, as well as lethargy
and mild hair loss in 3, 2 and 1 of 15 dogs, respectively.
Flutamide, a pure androgen receptor blocker, inhibits
androgen uptake and binding to the nuclear androgen
receptor. Flutamide has been positively tested as a
therapeutic drug in BPH cases. It yielded good results in
treating of this condition without negatively affecting
semen quality or libido. A 1-year oral treatment with
5 mg/kg/day did not alter libido or sperm production
(Romagnoli 2006). In most countries, flutamide is not
approved for use in veterinary medicine, although it
appears safe and effective (Memon 2007).
The use of a GnRH agonist is a modern treatment for
BPH. Similar to the actions of native GnRH, synthetic
GnRH agonists such as buserelin, nafarelin, leuprolide,
deslorelin and goserelin stimulate the production and
release of gonadotrophins from the hypophysis. How-
ever, GnRH agonists, when used in sustained doses,
reversibly inhibited the pituitary–gonadal axis after an
initial period of stimulation (‘flare-up effect’) (Trigg
et al. 2001; Gobello 2006). It should be borne in mind
that initial increase in sexual activity may be inhibited
by simultaneous administration of other drugs rapidly
suppressing the hypothalamo-pituitary-gonadal axis. In
recent years, slow-release GnRH formulations or
GnRH implants became popular in veterinary practice
for pharmacological castration of male dogs and cats.
GnRH, when steadily released from the implant, super-
imposes the physiological pulsatile GnRH release and
thereby oversaturates and down-regulates the pituitary
GnRH receptors. The resulting decrease or even lack of
FSH and LH results in an inevitable and drastic
reduction in testicular steroid synthesis (Memon 2007).
The decrease in blood testosterone level is accompanied
by a measurable diminution of the prostate gland
(Romagnoli 2006). In adult dogs treated with an
implant containing 0.5–1.0 mg deslorelin per kg body
weight, serum testosterone concentration had decreased
12
by 90% (relative to controls) and the prostate gland
volume had diminished by >50% at 6 weeks postim-
plant administration. A significant diminution of the
prostate gland was first observed after 37 days. From
day 22 up to day 37, sperm cell concentration and sperm
motility decreased simultaneously with increasing per-
centages of morphologically abnormal spermatozoa.
From day 37 onwards, semen collection resulted in
complete lack of seminal fluid (aspermia). When the
treatment was discontinued (no repetition of implant
administration), the prostate returned to its approxi-
mate pre-treatment volume by 48 weeks (Romagnoli
2006).
In another study, 30 mature dogs received implants
with deslorelin acetate (0.08–0.79 mg/kg) (Trigg et al.
2001). Eleven dogs were given a second implant before
or after the end of the suppression period. Testosterone
concentrations decreased to <1 ng/mL within a mean of
17 days after implant administration in all groups and
remained at this level for a period of 3 months up to
2.7 years. The duration of the inhibitory effect appeared
to be dose related. Restoration of the hypothalamo-
pituitary-gonadal axis became evident by increasing
scrotal circumference and testosterone concentrations as
well as by the improvement of semen quality and
fertility relative to pre-treatment conditions. In studies
performed in fewer dogs and with different deslorelin
doses, similar periods of effectiveness are reported.
Subcutaneous administration of implants containing 0.5
and 1 mg/kg of body weight deslorelin acetate to five
dogs significantly decreased serum testosterone values
and prostate size for 7–11 months, respectively
(Ponglowhapan et al. 2002). In seven dogs, implants
with 6.6 mg buserelin caused a decrease in testosterone
and oestradiol concentrations to basal levels within
15 days. Hormone values remained low for a mean of
7–8 months (Riesenbeck et al. 2002). Testicular and
prostatic size was reversibly reduced. No semen could be
collected on day 21 after implant administration.
Recently, colour Doppler blood flow indices indicat-
ing dog prostate perfusion after treatment with a 4.7 mg
deslorelin implant were described and compared to
initial, pre-treatment values (Polisca et al. 2013) and
values reported for BPH by G€ unzel-Apel et al. (2001).
The systolic peak velocity (SPV) and end diastolic
velocity (EDV) in prostatic and subcapsular arteries
decreased gradually from day 11 after implant admin-
istration. The reduction was significant at day 22 and
day 37 and lowest values were reached at day 52 until
the end of observation (6 months). The power Doppler
pixel intensity of both arteries showed a gradual
decrease from day 5 until day 52. Serum testosterone
concentration decreased to undetectable levels from day
11 to the end of the observation period. Furthermore, a
gradual decrease in Doppler parameters SPV, EDV,
SPV/EDV and FVI (flow velocity integral) in the
prostatic and testicular blood flow was observed after
2–3 weeks of exacerbation of sexual function (initial
‘flare-up effect’) (Ni_zanski, Pasikowska, Stanczyk 2013,
unpublished data).
GnRH agonists other than deslorelin were also
investigated for BPH treatment in dogs. Similar to
deslorelin implants, implants containing azagly nafare-
W Ni_za
nski, X Levy, M Ochota and J Pasikowska
lin induced the reduction in prostatic size by 52% after
8 weeks (Goericke-Pesch et al. 2010). Mean testicular
size was reduced at the same time by 54%. Relative
reduction in prostatic size was more marked in dogs
with BPH than in healthy ones at weeks 8 and 26 and
clinical signs of BPH disappeared rapidly after implant
administration. Currently, nafarelin is not registered for
veterinary use in Europe.
Treatment for BPH using a 4.7 mg deslorelin implant
combined with osaterone acetate 0.25–0.5 mg/kg BW
appears to be very effective, inducing an abrupt decrease
in prostate gland volume which is maintained for at
least 5 months (Ni_za nski, Pasikowska, Sta nczyk 2013,
unpublished data). Taking into account the possible
mechanisms of the initial and abrupt suppression of the
‘flare-up effect’ after GnRH agonist implantation,
progestin administration for several days also appears
as an interesting topic for further scientific exploration.
Recently, GnRH antagonists were positively tested in
the treatment for human prostate cancer, which is
hormone dependent (Lai 2009). Such drugs directly
block the pituitary GnRH receptors and thereby sup-
press the hypothalamo-pituitary-gonadal axis without
the ‘flare-up effect’ and initial rise in testosterone level
and this may be potentially useful in the treatment of
hormone-dependent conditions like canine BPH. While
the development of GnRH agonists has progressed
during recent decades, the antagonists have lagged
behind, partly because of the high cost of production.
The initial two generations of GnRH antagonists
presented weak effectiveness and exhibited side effects
such as histamine release leading to anaphylactic reac-
tions. Recently, a new series of potent, acceptably long-
lasting (≤10 days) low-histamine-release third-genera-
tion GnRH antagonists were developed – cetrorelix,
abarelix, ganirelix, which are marketed and others such
as antarelix, teverelix, degarelix, ozarelix, ornirelix,
acyline (Gobello 2012). A detailed review has been
presented by Gobello (2012). An example of a drug
belonging to this group and recently intensively tested in
humans for androgen deprivation therapy (ADT) is
degarelix. Clinical trials have demonstrated that degar-
elix has a long-term efficacy similar to the GnRH
agonist leuprolide in achieving testosterone suppression
in human prostate cancer (Zattoni 2012; Hatoum et al.
2013; Rick et al. 2013). These compounds have also
been tested in animals. Garcıa Romero et al. (2009)
revealed that in male dogs a single subcutaneous
treatment with the GnRH antagonist acyline safely
and reversibly decreased serum gonadotrophin and
testosterone concentrations for 9 days. No local or
systemic side effects were detected. It was also proved
that in dogs, a single administration of this drug
prevented the pituitary–gonadal axis responding to
GnRH agonistic (buserelin) stimulation for 14 days
(Garcia Romero et al. 2012a). It should be also noted
that in cats, a single dose of acyline reversibly impaired
spermiogenesis, spermatocytogenesis and sperm motility
for 2 weeks (Garcia Romero et al. 2012b). Up to now,
GnRH antagonists have not been widely introduced
into veterinary practice mainly due to high costs of the
drug and the necessity of relatively frequent adminis-
tration.
© 2014 Blackwell Verlag GmbH
Pharmacological Treatment of Prostate
Oestrogens
Both oral and injectable oestrogen preparations, includ-
ing diethylstilbestrol (DES) and oestradiol cypionate
(ECP), have been used in the past for BPH treatment in
dogs (Smith 2008). Reduction in the prostate gland
resulted from suppression of the hypothalamo-pituitary-
gonadal axis and a subsequent decrease in blood
testosterone concentrations.
Currently, oestrogens are no longer recommended for
veterinary use due to a number of side effects. Admin-
istration of oestrogens may induce squamous epithelial
metaplasia of the prostate gland and formation of
prostatic cysts. Besides impairment of spermatogenesis,
severe bone marrow suppression which may result in
thrombocytopenia, leukopenia and fatal aplastic anae-
mia is a further aspect characterizing the obsolescence of
oestrogen treatment in male dogs (Johnson 2003;
Memon 2007).
Antioestrogens
Tamoxifen is an antioestrogenic compound. It compet-
itively blocks oestrogen receptors with a mixed antago-
nist–agonistic effect. Tamoxifen was successfully used for
the treatment of prostatic diseases in dogs. Administra-
tion of the drug in seven male beagle dogs (2.5 mg PO)
for 28 days significantly decreased peripheral testoster-
one concentrations and the prostate size accompanied by
a reduced ejaculate volume (Corrada et al. 2004).
Furthermore, a decrease in testicular size and sperm
count as well as impairment of sperm motility and
morphology was observed. All parameters returned to
pre-treatment conditions with the next spermatogenetic
cycle. No clinical or haematological side effects were
observed during 4 weeks of post-treatment follow-up
(Corrada et al. 2004). In another study, tamoxifen was
administered for 60 days (2.5–10 mg/day) to 6 dogs with
normal prostate glands and 8 dogs presenting BPH
(Gonzalez et al. 2009). At the end of the treatment, the
prostatic volume had decreased by 28.5  4.3% in BPH
males. During the following 4 months, a re-increase
in prostatic volume occurred without reaching pre-
treatment dimensions.
Another antioestrogen, the aromatase inhibitor anas-
trozole, has been comparatively investigated for BPH
treatment (Gonzalez et al. 2009), showing similar
effects. After 60-day oral administration (0.25–1 mg/
day), the prostate gland volume was reduced by
21.6  6.3% with a subsequent progressive re-increase
within the 4-month follow-up period. Compared to
tamoxifen, anastrozole produced less pronounced
decreases in libido, testicular consistency and scrotal
diameter. In dogs treated with anastrozole ejaculate
volume, sperm count, sperm motility and morphology
remained unaltered throughout the study. Administra-
tion of anastrozole, similarly to tamoxifen, seemed to be
efficient in improving prostatic echogenicity to a normal
pattern. No side effects were observed regarding hae-
matological and biochemical parameters. On the whole,
anastrozole was assessed as a safe and effective alterna-
tive for the medical management of canine BPH
(Gonzalez et al. 2009). However, the relatively short
treatment period for both drugs should be indicated.
© 2014 Blackwell Verlag GmbH
13
Taking into account the potentially oestrogenic effects
of tamoxifen and scarce clinical data on the use of
anastrozole, cautious use is advisable.
Other Drugs Tested in Humans and Dogs
Some drugs for the treatment of human lower urinary
tract symptoms (LUTS) associated with BPH have been
tested on the dog animal model. In spite of the fact that
LUTS rarely accompany canine BPH, some of these
compounds were effective in the treatment of dogs’ BPH
urinary tract symptoms. If their usefulness in dogs can
be confirmed in clinical studies, they may be considered
as optional drugs in that species.
Eplerenone, an aldosterone receptor antagonist, is
approved for the treatment of hypertension and heart
failure after a myocardial infarction in humans. In pre-
clinical studies performed in dogs, the most sensitive
and pronounced off-target effect of eplerenone was
atrophy of the prostate gland (Levin et al. 2013). Due to
the possible influence on the cardiovascular system, it
does not appear to be a prospective drug for BPH
treatment in dogs.
The selective a1A-adrenergic receptor antagonist
silodosin was approved for the treatment of LUTS
associated with BPH in humans. By antagonizing
a1A-adrenergic receptors in the prostate and urethra,
silodosin causes the relaxation of smooth muscles in
cases of LUTS (Schilit and Benzeroual 2009). In spite of
the fact that the pathomechanism of BPH in humans
and dogs is different, the potential role of such drugs in
symptomatic treatment for canine BPH might be worth
checking in future in these particular cases of BPH
resulting in LUTS.
Tadalafil is a phosphodiesterase (PDE)-5 inhibitor
recently approved in the USA for the treatment of
LUTS associated with BPH in humans. The mechanism
for the improvement of lower urinary tract disease
symptoms is probably related to alterations in nitric
oxide levels and/or reduction in pelvic atherosclerosis.
The efficiency of PDE-5 inhibitors in the above-men-
tioned indication has been demonstrated in several
randomized placebo-controlled clinical trials in humans
(Cantrell et al. 2013). The effectiveness of this drug in
the treatment of BPH cases resulting in urinary tract
problems in dogs has not been checked yet.
A non-secosteroidal vitamin D receptor (VDR) ago-
nist (CH5036249) was tested in dogs as an animal model
to evaluate its suitability for BPH treatment. The drug
showed effectiveness in therapy of a spontaneous BPH
beagle model. Growth of the prostate gland was
inhibited in two of three dogs compared with the
control group. Substantial atrophy of the glandular
epithelium was observed in all treated dogs (Taniguchi
et al. 2010). The usefulness of this compound in the
treatment of BPH accompanied by LUTS may be
considered if more complete clinical trials are
performed.
The effect of a single intraprostatic injection of
botulinum toxin type A (BT-A) into each lobe of
prostate on the volume of the gland and on semen
quality in BPH dogs (clinical, ultrasound and radio-
graphic confirmation) was investigated by Mostachio
14 W Ni_za
nski, X Levy, M Ochota and J Pasikowska

et al. (2012). The results of this experiment appear
interesting. No local complications or systemic side
effects were reported. Eight weeks after treatment, the
prostate volume reached its minimum, but the difference
from pre-treatment values was not significant. At semen
collection, all dogs showed normal libido, erection and
ejaculation. No significant differences were observed in
all any seminal parameters.
Extracts from Serenoa repens are effectively used for
curing the signs of urine retention accompanying BPH
in humans. Urine retention is very rare in connection
with canine BPH (Johnson 2003). In dogs, oral admin-
istration of the compound for 91 days had no single
effect on prostatic size, blood testosterone level, libido,
semen quality, ultrasound and X-ray images as well as
histological structures of the prostate gland, and this
may not be useful for BPH treatment in this species
(Barsanti et al. 2000).
Conclusions
Recently, many protocols of pharmacological treatment
for BPH and prostatitis in dogs have been proposed.
The most promising results in treating these usually
concomitantly observed conditions are obtained using
antibiotic agents and antiandrogenic drugs. Further
studies on the potential use of GnRH agonists should be
performed. The encouraging results of the recent
experiments performed in humans and animals using
GnRH antagonists suggests the possibility of more
common use of these compounds also in dogs. New
methods of treatment for human BPH-related symp-
toms investigated recently need further research in dogs.
Conflicts of interest
None of the authors have any conflicts of interest to declare.
Author contributions
Wojciech Ni_zanski, Małgorzata Ochota, Xavier Levy and Joanna
Pasikowska collected references and contributed to the manuscript
writing and design.

normal prostate and dogs with chronic Gonzalez G, Guendulain C, Maffrand C,

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Author’s address (for correspondence):
Wojciech Ni_za
nski, Department of Repro-
duction, Wrocław University of Environmen-
tal and Life Sciences, pl. Grunwaldzki 49,
50-366 Wrocaw, Poland. E-mails: wojtek.
nizanski@gmail.com