Clinical Response and Side Effects Associated with Testosterone Cypionate for Urinary Incontinence in Male Dogs

Abstract

Urethral sphincter mechanism incompetence (USMI) is reported much more seldom in male dogs than in female dogs. The few existing reports evaluating the efficacy of medical therapy in controlling USMI in males have demonstrated limited success. In this case series, we report the effect of testosterone cypionate, given at a median dose of 1.5 mg/kg intramuscularly every 4 wk, in eight male dogs with USMI. Response was evaluated through the review of medical records and telephone interviews with the clients. Based on owners' assessments, a good to excellent response was reported in three of eight dogs (38%), a slight response was reported in one of eight dogs (12%), and a poor response was reported in four of eight dogs (50%). Adverse effects were not reported, and benefit was judged sufficient to continue therapy in two cases. The results reported in this case series suggest that testosterone cypionate might be an effective and safe treatment option for male dogs with USMI.

Full text

CASE SERIES
Clinical Response and Side Effects Associated
with Testosterone Cypionate for Urinary
Incontinence in Male Dogs
Jean-Se
´bastien Palerme, DVM, MSc, DACVIM, Allison Mazepa, DVM, DACVIM, Rae G. Hutchins, DVM, DACVIM,
Vincent Ziglioli, DVM, DACVIM, Shelly L. Vaden, DVM, PhD, DACVIM
ABSTRACT
Urethral sphincter mechanism incompetence (USMI) is reported much more seldom in male dogs than in female dogs. The
few existing reports evaluating the efficacy of medical therapy in controlling USMI in males have demonstrated limited suc-
cess. In this case series, we report the effect of testosterone cypionate, given at a median dose of 1.5 mg/kg intramuscularly
every 4 wk, in eight male dogs with USMI. Response was evaluated through the review of medical records and telephone
interviews with the clients. Based on owners’assessments, a good to excellent response was reported in three of eight
dogs (38%), a slight response was reported in one of eight dogs (12%), and a poor response was reported in four of eight
dogs (50%). Adverse effects were not reported, and benefit was judged sufficient to continue therapy in two cases. The
results reported in this case series suggest that testosterone cypionate might be an effective and safe treatment option for
male dogs with USMI. (J Am Anim Hosp Assoc 2017; 53:285–290. DOI 10.5326/JAAHA-MS-6588)
Introduction
Urinary incontinence is common in dogs and is a frequent reason
that owners bring their dogs to a veterinarian. Urethral sphincter
mechanism incompetence (USMI) is the most common cause of
urinary incontinence in adult female dogs and is estimated to affect
between 5 and 20% of spayed female dogs.
1–5
Though the true
prevalence of USMI in the total male canine population remains
unknown, one report of urinary incontinence in dogs found that
adult male dogs accounted for only 9 of 320 cases.
3
The etiology and
pathogenesis of this condition in male dogs have not been deter-
mined; however, comparison with continent dogs has identified
many risk factors, including a shorter urethral length, caudal
bladder position, and castration.
6–8
Urethral sphincter mechanism
incompetence in male dogs is defined as involuntary leakage of
urine due to decreased urethral tone after the exclusion of other
causes, such as prostatic disease, bladder or urethral calculi, bladder
or urethral neoplasia, lower urinary tract infections, ectopic ureters,
and neurologic dysfunction. The gold standard for the diagnosis of
USMI in both male and female dogs is urethral pressure profil-
ometry. However, since this technique has limited availability, his-
tory, clinical signs, physical exam, imaging of the urinary system,
urinalysis, and urine culture typically make the diagnosis in both
sexes.
The options for management of USMI in male dogs are limited.
Medical management with phenylpropanolamine (PPA), estrogens,
or anticholinergic drugs has been reported; however, the overall
reported response to these agents is poor. Although a prospective
study evaluating urinary incontinence in dogs found that seven of
From Iowa State University College of Veterinary Medicine, Ames, Iowa (J-S.P.);
Blue Pearl, Eden Prairie, Minnesota (A.M.); Veterinary Specialty Hospital
of the Carolinas, Cary, North Carolina (R.G.H.); Upstate Veterinary
Specialists, Greenville, South Carolina (V.Z.); and North Carolina
State University College of Veterinary Medicine, Raleigh, North Carolina
(S.L.V.).
Correspondence: jpalerme@iastate.edu (J-S.P.)
DES (diethylstilbestrol); PPA (phenylpropanolamine); USMI (urethral
sphincter mechanism incompetence)
ª2017 by American Animal Hospital Association JAAHA.ORG 285

eight male dogs included in the study had resolution of incontinence
as well as significant increases of their urethral pressure profile values
following oral PPA administration, a larger retrospective analysis of
43 male dogs treated with various drugs for USMI found that only
7 dogs (16%) had an excellent response to medical therapy, and
28 (65%) had a poor response.
6,9
Small case series have been published
describing surgical techniques used in the management of USMI in
male dogs. While prostatopexy was only successful in one of nine
dogs reported in one case series, urinary continence was restored in
three of seven dogs that underwent the relocation of an intrapelvic
bladder neck to an intra-abdominal position.
10,11
Likewise, two of
four males that received a single intraurethral polytetrafluoro-
ethylene injection became continent.
4
More recently, the use of
artificial urethral sphincter devices has been reported in dogs.
12
Although only three male dogs were included in this study, their
continence scores increased significantly when compared to pre-
surgical scores.
Testosterone administration is an alternative medical therapy
that has been used in male dogs with urinary incontinence. The
management of a small number of castrated dogs with methyl-
testosterone was attempted in one retrospective study.
6
The drug was
reported to be ineffective, with a “poor”response in four of five
dogs and a “good”response in one dog. Though testosterone
cypionate
a
, a testosterone ester, is recommended as a medical
therapy for male USMI in many veterinary textbooks, its successful
use in an incontinent male dog is only reported in a single case
report.
13–15
Testosterone has potential adverse effects, including
prostatic hyperplasia and behavioral aggression caused by excessive
androgenic action. The frequency of the development of adverse
effects in male dogs receiving this medication for management of
urinary incontinence has not been reported. Therefore, the objective
of this case series was to report the clinical efficacy and adverse
effects of testosterone cypionate administered to a small group of
castrated male dogs with incontinence presumed to be caused by
acquired USMI.
Materials and Methods
Case Selection Criteria
Neutered male dogs with a clinical diagnosis of urinary incontinence
made between 2003 and 2012 were identified by searching the
medical records of the North Carolina State Veterinary Hospital.
Dogs were included in this series if they were administered testos-
terone cypionate for presumed USMI, the medical record was
available for review, and the owners completed a follow-up telephone
questionnaire. Intact male dogs were excluded from the study in
order to minimize the likelihood of including dogs with prostatic
disease as a cause of urinary incontinence. Dogs were also excluded
from this study if there was ultrasonographic and/or bacteriological
evidence of a cause of urinary incontinence other than USMI, such as
the presence of ectopic ureters, tumor of the lower urinary system,
prostatic disease, or a urinary tract infection, or if the owner was not
available to complete the follow-up questionnaire. Finally, dogs that
were receiving other concurrent medications for incontinence were
also excluded from the study.
Medical Record Review
Patient medical records were retrospectively reviewed. Signalment,
history pertaining to the onset and characteristics of urinary in-
continence, results of routine urine analyses (urinalysis and aerobic
urine culture), and imaging studies were recorded. A diagnosis of
USMI was made based on a history of involuntary leakage of urine
noted by the owner with the exclusion of other known causes of
incontinence, including prostatic disease, bladder or urethral calculi,
bladder or urethral neoplasia, lower urinary tract infections, ectopic
ureters, and neurologic dysfunction. Urethral pressure profilometry
was not performed in any of the dogs and was not used as an in-
clusion criterion. The dose, dosing interval, as well as number of
administrations of testosterone cypionate were recorded. Patient
medical records were also reviewed for any information regarding
other treatments initiated for urinary incontinence and the clinical
response to these treatments.
Follow-Up Questionnaire
Owners were asked to complete a telephone questionnaire assessing
the response to treatment with testosterone cypionate in their dog.
This was performed at one time point during the study. Owners were
asked to report any adverse effects noted during the administration of
testosterone cypionate, as well as time to clinical remission and length
of response to testosterone cypionate, if noted. Additionally, owners
were asked to score from 1 to 4 their satisfaction with their dog’s
response to testosterone cypionate, with (1) indicating complete
dissatisfaction due to no response (poor), (2) indicating only slight
response (fair), (3) indicating the animal was now continent most of
the time (good), and (4) indicating very satisfied due to complete
continence (excellent).
Results
Eleven neutered males were identified for inclusion in the study.
During the same period studied, a total of 123 spayed female dogs
were seen at our institution for USMI. Of the 11 male dogs, two
owners could not be contacted for the completion of the follow-up
questionnaire, and one dog was found to be receiving concurrent
treatment with both PPA and testosterone cypionate. Eight dogs were
included in the series (Table 1). Median follow up, as defined as the
286 JAAHA | 53:5 Sep/Oct 2017

period between the beginning of testosterone therapy and the phone
interview, was 25.5 mo (range: 2–67 mo). The median age of the
dogs was 7.5 yr. The median age of castration for the eight dogs for
which it was known was 1.5 yr (range: 6 mo to 3 yr). Urinary in-
continence in all dogs was first noted at a median age of 3.5 yr
(range: 6 mo to 8 yr) and occurred during rest and recumbency in
seven of eight dogs. The remaining dog dribbled urine continuously,
especially during or following activity. Five of eight dogs had re-
ceived previous medical treatment for urinary incontinence in-
cluding diethylstilbestrol (DES) and PPA. Of these five dogs, all had
either failed to respond to medical management or had initially
responded but then incontinence recurred.
Physical exam failed to identify an underlying cause for the
urinary incontinence of the dogs included in the study. Rectal ex-
aminations were recorded for six of eight dogs in the study and were
unremarkable. Neurologic examinations, performed in all dogs, were
unremarkable. Urinalyses and aerobic cultures were available for all
cases. Median urine specific gravity was 1.025 (range: 1.010–1.044). In
no cases were pyuria, hematuria, cylinduria, or bacteriuria reported.
One case (dog 1) had glucosuria detected and was identified as being
diabetic, based on concurrent hyperglycemia and increased fructos-
amine value. Significant bacterial growth (Proteus mirabilis) was iso-
lated from the urine of one dog (dog 3); urine from all other dogs did
not yield bacterial growth after 48 hr of aerobic culture. Urinary tract
infection was not judged to be the cause of incontinence in dog 3
based on the fact that incontinence persisted after treatment with
amoxicillin-clavulanic acid selected on the basis of microbial culture
and sensitivity. The urinary tract of each dog was assessed by ultra-
sound, positive contrast cystourethrogram, and cystoscopy in seven,
three, and two cases, respectively (Table 1). Relevant imaging findings
such as a dilated urethra, evidence of cystitis, and prostatomegaly
were identified in two, one, and one cases, respectively.
The median dose of testosterone cypionate was 1.8 mg/kg
(range: 1.0–2.2 mg/kg) administered intramuscularly for a median
TABLE 1
Patient Data, Imaging, and Previous Treatments for Incontinence
Dog Breed
Age at
Presentation (yr)
Age at
Onset (yr)
Type of
Incontinence Imaging Performed Imaging Findings
Previous Treatment
(Dose)
Response to
Previous
Treatment
1 Poodle 10 0.5 Continuous
urine
dribbling
Ultrasound NSF PPA (2.3 mg/kg/day) Relapse
2 Greater Swiss
mountain dog
9 3 Intermittent,
during
recumbence
Ultrasound Possible
prostatomegaly
and possible
urinary
bladder wall
thickening
PPA (2 mg/kg/day) None
3 Border terrier 9 3 Intermittent,
during
recumbence
Not performed N/A DES (1 mg/wk) Relapse
4 Golden retriever 4 4 Intermittent,
during
recumbence
Ultrasound, CCU,
Cystourethroscopy
Segmental
urethral dilation
PPA (3.3 mg/kg/day) None
5 Bernese
mountain dog
6 6 Intermittent,
during
recumbence
Ultrasound NSF PPA (1.4 mg/kg/day) None
6 Mixed-breed
dog
4 3 Intermittent,
during
recumbence
Ultrasound, CCU,
Cystourethroscopy
NSF None N/A
7 Labrador
retriever
9 8 Intermittent,
during
recumbence
Ultrasound NSF None N/A
8 Poodle 2 2 Continuous
urine
dribbling
Ultrasound,
CT scan, CCU
Dilation of the
proximal urethra
with strictures of the
membranous and
penile urethra
None N/A
CCU, contrast cystourethrogram; CT, computed tomography; DES, diethylstilbestrol; N/A, not available; NSF, no significant findings; PPA, Phenylpropanolamine.
Use of Testosterone Cypionate in Dogs with Incontinence
JAAHA.ORG 287

dosing interval of 4.5 wk (range: 3–6 wk) (Table 2). The median
number of treatments was four (range: 2–25). Owners scored a
median satisfaction score of 1.5 (range: 1–4), with three of eight
owners reporting that their dog had either a good or excellent re-
sponse to testosterone cypionate. One of eight owners indicated a fair
response, and four of eight owners indicated a poor response. No
adverse effects were reported in any dog. In two dogs, satisfaction was
deemed sufficient to warrant the continued use of testosterone.
Discussion
In the present study, treatment with testosterone cypionate was
retrospectively evaluated in eight dogs. In five of these dogs, previous
treatments with either PPA or DES had been unsuccessful. Despite
this, testosterone cypionate resulted in good or excellent control in
only three of eight dogs based on assessment by the dogs’owners.
The most common medical therapies for USMI in female dogs are
PPA and estrogens. The success rate of PPA alone in female dogs has
been reported to be as high as 85–90%, while the response rates for
estrogens has been reported to range from 18–65%.
2,16,17
The re-
sponse rate to PPA and DES in male dogs has been reported to be
substantially lower in some studies, with complete response
reported in only 31 and 37% of male dogs, respectively.
6
Factors proposed to be important in maintaining continence in
healthy male dogs include a long proximal urethra, increased urethral
tone generated by the prostate, and, potentially, differences in fol-
licular stimulating hormone and luteinizing hormone receptors
located in the urethra and bladder.
18
The mechanism through which
testosterone cypionate improves urinary continence in males is
poorly understood. Though purely speculative, hypertrophy of the
prostate, mediated by nuclear androgen receptors, has been pro-
posed to play a role in maintaining urinary continence.
19,20
In ad-
dition, functional effects mediated through phosphodiesterase-5 as
well as a
1
-adrenergic receptors are thought to be important in
maintaining tone of the bladder and urethral smooth muscles. All of
the subjects in this study were castrated; therefore, smaller prostatic
mass might have contributed to the reduced continence in these
patients. Prostatic hypertrophy following treatment with testoster-
one cypionate, therefore, might explain the improved continence in
some of these dogs; however, prostatic size following treatment was
not recorded in the medical records.
The more traditional medical therapies used for USMI in both
males and females, PPA and DES, are oral medications that require
frequent administration to maintain continence. Diethylstilbestrol is
initially given daily and then administered once weekly to maintain
continence. Use of DES in males is uncommon because of the low
response rate as well as the serious potential side effects, including
feminization, induction of squamous prostatic metaplasia, and bone
marrow suppression. Phenylpropanolamine requires long-term oral
administration every 8–12 hr, and, even though clinical side effects
are rarely encountered, significant increases in systolic blood pres-
sures have only been reported in studies of continent research
beagles.
16, 21–23
Therefore, intramuscular administration of testos-
terone cypionate every 4 wk might offer a more convenient and safe
dosing interval for some owners. Unfortunately, due to the small
scale of our study, no conclusions could be made about the optimal
dosing or number of treatments necessary to have the highest
likelihood of a response.
Though no published data exists documenting adverse effects
associated with testosterone supplementation in dogs, various pa-
thologies including perianal adenomas, perineal hernias, and pros-
tatic hyperplasia have been associated with increased serum
testosterone levels in dogs.
24–26
In our study, no adverse effects were
reported. The median number of treatments administered was four.
It is possible that an increased rate of side effects would have been
TABLE 2
Testosterone Cypionate Dosing Schedule and Response
Dog Dose (mg/kg IM) Dosing Interval (wk) Total Number of Treatments Owner Score Response Follow-Up (mo) Outcome
1 1–2 3 2 1 Poor 8 Discontinued administration
2 1.4 4 Unknown 2 Fair 67 Discontinued administration
3 1.1 4–6 8 4 Excellent 22 Continued administration
4 2.2 4 4 1 Poor 41 Discontinued administration
5 2.2 4–6 4 1 Poor 29 Discontinued administration
6 2.2 6 3 1 Poor 39 Discontinued administration
7 1.0 6 2 3 Good 2 Discontinued administration
8 2.1 3 25 3 Good 17 Continued administration
IM, intramuscularly.
288 JAAHA | 53:5 Sep/Oct 2017

seen if the treatments had been continued for a longer period of
time. Interestingly, the owner of the dog that received the most
treatments (n¼25) did not report any adverse effects. None of the
dogs in the current study were reported to have gastrointestinal
signs or clinical signs suggestive of prostatic hypertrophy, such as
stranguria, hematuria, and/or tenesmus. Nonetheless, owners of
dogs undergoing this therapy should be cautioned to look for such
clinical signs. All the dogs in this study had subsequent testosterone
administration performed by their referring veterinarians. Conse-
quently, only three of the eight dogs were reassessed at our insti-
tution while on testosterone therapy. Of the two dogs that had rectal
exams recorded, no abnormalities were noted. In addition, no
follow-up imaging was performed to evaluate prostatic size fol-
lowing testosterone cypionate administration.
A recent human clinical trial evaluating three different testos-
terone formulations for the treatment of late-onset hypogonadism
reported the incidence of prostatic side effects after 3 mo of therapy.
27
These investigators documented no clinical signs suggestive of prostatic
hypertrophy and no statistical difference in pre- and posttreatment
prostate-specific antigen concentrations, which is a sensitive marker of
increased prostatic mass in humans. Although these data suggest that the
possible side effect of prostatic hypertrophy has little clinical relevance,
caution is warranted in extrapolating this conclusion to canine patients
until future studies involving follow-up prostatic ultrasonography have
been performed. Posttreatment complete blood counts and biochemical
profiles were not available for review in this group of dogs; therefore, the
presence of laboratory abnormalities is unknown. Humans treated with
testosterone cypionate for late-onset hypogonadism have shown no
significant hematologic abnormalities after 14 wk of therapy.
27
This case series has several limitations. The information re-
garding each patient was variable, based on completeness of the
medical record and the reliability of the owner to recall response to
treatment and overall satisfaction when contacted for follow-up. The
reliance on owners’observations rather than urodynamic data to
determine the drug’s effect is a significant drawback. Several in-
vestigators have noted a placebo effect in owners’perception of their
dogs’continence following medical intervention.
21,28
Second, this
study lacked a control group. Limited comparisons were made using
previous reports that evaluated other medical therapies for incon-
tinence (PPA and DES), but no direct comparisons between the
treatments could be made. It is possible that we are reporting a
group of dogs that was more difficult to treat since a substantial
proportion had failed to respond to standard medical therapy prior
to referral. Third, since the drug dose, dosing interval, and duration
of treatment were determined based on clinician discretion as well
as the patient’s response to the drug, there was no standardized
treatment schedule for the patients in this study. For example, one
dog received only 2 doses of testosterone cypionate, while another
received 25 doses. This might have impacted the reported efficacy as
well as the frequency and severity of side effects of the drug. Finally,
the definitive diagnosis of USMI was not made by urethral pressure
profilometry in any dog. Therefore, some of the dogs included in this
study might have been suffering from incontinence due to another
mechanism despite our best efforts to exclude those patients.
Conclusion
Though the resultsreported here are based on a small retrospective case
series, our data suggest that testosterone cypionate might be an option
in treating USMI in male dogs that are refractory or have contrain-
dications to more commonly used medications. Additionally, no severe
adverse effects were noted in this case series when testosterone cypi-
onate was dosed at 1.0–2.2 mg/kg intramuscularly every 3 to 6 wk for
up to 25 doses. Based on these data, prospective, multi-institutional
controlled studies of the effects of testosterone cypionate in male dogs
with USMI are warranted. These studies should incorporate more
rigorous assessments of the patient’s anatomy using ultrasonography
or computed tomography, urethrocystoscopy, urethral profilometry
pre- and posttestosterone cypionate administration to more objec-
tively monitor response to therapy, as well as regular monitoring of
biochemical and hematologic parameters pre- and posttherapy.
FOOTNOTES
a
DEPO-Testosterone Injection; Pfizer, New York, New York
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