2010: Pathology of male reproductive organs


Pathology of male reproductive organs 
Robert A. Foster 

Department of Pathobiology, Ontario Veterinary College, University of Guelph 
Guelph, Ontario, Canada 

 
General introduction 
 Diseases and conditions of the male reproductive system are traditionally approached from the 
perspective of anatomical location, beginning with the scrotal contents, at the site of production of 
spermatozoa, and ending with the penis and prepuce.  This parallels a problems based approach as 
diseases tend to involve the scrotum and contents, the accessory genital glands and/or the penis and 
prepuce.  If you are interested in one particular species only, the information for other species is still 
relevant because a disease in one is usually identical to that in another!  
 The Veterinary Reproductive Pathology website (www.uoguelph.ca/~rfoster/repropath/repro.htm) 
provides additional information for the dog and cat, as do recently updated pathology textbooks.1,2 
 The Nomina Anatomica Veterinaria3 (NAV), which establishes the names in anatomy, lists names 
of reproductive structures. Some differ from commonly used terms.  The latest texts in reproductive 
pathology use the NAV terminology and this overview will use the English version of the Latin name. 
 
Keywords:  Male, reproductive, pathology 
 
Scrotal contents 
Introduction 
 The testes are often considered the center of the ‘male reproductive universe’.  Not every disease 
of the scrotal contents involves the testes, however.  Orchitis is a common clinical diagnosis, but this term 
can be misleading because inflammation of the testes is a rare event. The inflammation is usually of the 
vaginal tunics and epididymis.  Often times the reaction is to spermatozoa that have leaked into the 
tissues.  The ability of spermatozoa to stimulate a florid inflammatory reaction is overlooked, but is the 
most important factor when considering prognosis. The testis is recognized as having immune privilege.  
The development of germ cells occurs long after immune tolerance develops and a constitutive production 
of anti-inflammatory cytokines in the testis is now recognized.  These are directed by local androgens to 
inhibit proinflammatory cytokines.4  An alteration of this balance results in immune and inflammatory 
reactions in the testis. 
 
Spermatic granuloma 
 The inflammatory and immunologic response to spermatozoa is of critical importance in many 
diseases and conditions of the male reproductive tract.  Any condition that causes leakage of spermatozoa 
or spermatozoal antigens into the extratubular compartment is potentially complicated by this reaction.  
Spermatozoa incite a granulomatous and pyogranulomatous reaction known as a spermatic granuloma.  
Macroscopically, these have an appearance similar to pus.  Spermatozoa have a cell wall similar in 
composition to keratin as they have many sulfur bonds.  Spermatozoa produce a foreign body type 
reaction and the large number of them and their keratin-like composition means that degradation is a slow 
process.  In addition, immune responses are florid with many immunoglobulin producing cells and CD4- 
and CD8-expressing lymphocytes appear.  Upregulation of major compatibility complex (MHC) I in 
epithelial cells also occurs.5  The reaction leads to chronic inflammation and fibrosis, and continued 
disruption and obstruction of tubes and tubules.  Spermiostasis, spermatocele and/or further spermatic 
granulomas are the consequence. 
 
Diseases of the vaginal tunics 
 Primary diseases of the vaginal tunics are rare.  Secondary involvement after epididymitis (see 
below) is a much more frequent finding.  In domesticated species the most well known primary cause of 
inflammation of the vaginal tunics is feline infectious peritonitis (FIP).  Scrotal swelling in the cat is a 

531



presenting sign that should alert the practitioner to consider FIP.6  Periorchitis is also seen in traumatic 
events, such as fight wounds in cats, which allow introduction of bacterial pathogens into the vaginal 
recess.  This recess is continuous with the peritoneum; any disease affecting the peritoneum can and will 
affect this area. 
 Hydrocele or non-inflammatory fluid within the cavity of the vaginal tunics occurs in ascites in 
all species and in bulls in conditions of suboptimal nutrition.7 
 
Disease of the testis and epididymis 
 The testes produce spermatozoa and hormones such as testosterone and inhibin.  While early 
research focused on the hypothalamic–pituitary–testicular axis, there is an enormous body of work on 
local regulation and cellular crosstalk in the testis.  Perhaps more complex is the regulation of testicular 
development and descent as it involves many different hormones, growth factors (including insulin-like 
growth factors [IGF]) and the interaction of systemic and local factors and their receptors.  Not all are 
well understood. 
 The regulation of the blood-testis barrier and the effects of inflammation, focusing on the 
molecular aspects was reviewed recently.8-10  Germ cell, Sertoli cell and interstitial endocrine cell function 
is closely interrelated and there is considerable crosstalk among them.11  Control of programmed cell 
death and apoptosis is now identified as a critical process in testicular physiology and pathophysiology.12  
It is a normal process that limits potential spermatogenesis by about 25 to 75%.  Gonadotrophins and 
intratesticular androgens act as survival factors, whereas external events such as elevated temperature 
increase apoptosis of spermatocytes. 
  
 Small testes.  Small testes mean reduced production of spermatozoa because testicular weight and 
volume (to name a few) are correlated with daily sperm output.  Scrotal circumference in the bull is 
highly correlated with daily sperm output, but there are few good measures used in the other species.  
Scrotal circumference can be used in the ram and buck, but the lack of accessible testes for this 
measurement in the other species means that we must rely on comparing the testes with objects of the 
same shape and known volume—orchidometers.  Testicular size is seldom a selection criterion in non-
ruminants. 
 It is almost impossible to differentiate the cause of small testes in older animals unless the testes 
have been examined previously.  Primary testicular hypoplasia and testicular atrophy cannot be accurately 
differentiated, in part, because hypoplastic testes undergo degeneration.  When animals are examined at 
puberty, one’s confidence in diagnosing hypoplasia is much higher.  In general, a hypoplastic testis has a 
small hypoplastic epididymis attached.  The epididymis is usually disproportionately larger in testicular 
atrophy. 
 The two main processes resulting in small testes are therefore a failure to develop and a reduction 
in size.  Failure to develop is a ‘disorder of sexual development’ (DSD)and therefore hypoplasia.  A 
reduction in size is atrophy. 
  
 Disorders of sexual development.  Testicular hypoplasia exists when the testis remains smaller 
than expected after puberty.  It occurs as an ‘uncomplicated’ or primary condition in normally descended 
testes, in cryptorchidism, and in conjunction with other disorders of sexual development such as 
chromosomal anomalies (detailed below). 
  
 Hypoplasia.  The failure of one or both testes to grow to a normal size results because of a 
reduction in the amount of the seminiferous epithelium (lining).13  There is little written about the 
molecular mechanisms involved in hypoplasia in domestic animals.  It is known to be a genetic disease in 
many species.  Primary hypoplasia can be either unilateral or bilateral.  An affected testis is 
macroscopically similar to normal testis in almost every way—except size.  Hypoplasia is the potential 
end-result of a large number of different abnormalities that may operate at a systemic or local level (in the 
case of unilateral disease).  We are seldom able to identify a cause.  It is surprising how little is written 

532



about testicular hypoplasia except in the context of cryptorchidism!  This is despite a large percentage of 
bulls (up to 56% of Belgian Blue bulls) with a scrotal circumference that is too small,14 and many dogs 
have histological evidence of hypoplasia.15 
 The reduction in the area of seminiferous epithelium is the result of either some small tubules in 
the presence of normal ones, or all tubules are small.  Theoretically there could be a reduction in the 
number of tubules, the length of tubules, or the diameter of the tubules, or one or more combinations of 
these.  Germ cells may be absent or present but fail to produce enough spermatozoa.  Germ cells may 
have failed to migrate to the genital ridge in utero, failed to migrate in sufficient numbers, failed to 
survive, have arrested development, undergo excessive apoptosis or undergo degeneration at some stage 
of spermatogenesis.  Hypoplastic testes with a total lack of germ cells are very small and fail to enlarge 
from their size at birth.  Although we are aware of these possibilities, we often lack the tools and finances 
to determine the molecular mechanisms involved.  
 A deficiency of gonadotrophins is associated with hypoplasia (hypogonadotrophic 
hypogonadism) in humans and mice, but studies in domesticated mammals indicate a normal13 or 
increased serum concentration of follicle stimulating hormone and luteinizing hormone.  Testosterone 
concentration was lower than normal in some bulls with hypoplasia or degeneration while in sheep, 
testosterone and inhibin concentrations may be normal. 
 Kay, et al.16 reported concurrent branching of the testicular artery on the same side as a 
hypoplastic testis, regardless of side affected.  This abnormal blood supply could be responsible in some 
cases.  This should result in uniform change in the testis—it does not explain those cases where there is a 
mixture of hypoplastic and normal tubules.  This phenomenon should be investigated further. 
 Recently Borel, et al.17 identified a bull they considered to suffer from testicular hypoplasia and 
demonstrated BVD antigen in germ cells, Sertoli cells and blood vessel walls, but not in interstitial 
endocrine cells.  The photographs demonstrated testicular atrophy and degeneration, but the history of 
‘hypogonadism’ suggests this case may be one of hypoplasia with secondary atrophy.  A cause and effect 
was not established.  The involvement of BVD in testicular hypoplasia should also be investigated.  At 
the genetic level, hypoplasia is known or suspected to be hereditary in the dog, bull, ram, and buck.  The 
exact genetic abnormality is often not established. 
  
 Cryptorchidism.  There is much written about cryptorchidism because of the human disease and 
because it is so common in our domestic animals.  It is now classified as a DSD (XY SRY+ with testis).  
There is much discussion about the stages of testicular descent, but there appears to be a consensus 
emerging (reviewed by Amann and Veeramachaneni18 and Hughes and Acerini19).  There are three phases 
of testicular descent:  abdominal translocation, transinguinal migration and inguinoscrotal migration.  The 
first phase involves anchoring of the testis to the inguinal ring by the gubernaculum and relaxation of the 
cranial suspensory ligament, and this may be controlled by insulin-like peptide 3 (INSL3) and 
testosterone.  Growth and therefore enlargement of the fetus, results in caudal migration.  The second 
phase involves opening of the inguinal ring by an enlarged gubernaculum and intraabdominal pressure.  
The third phase takes the testis from the subcutaneous location into the scrotum, and is an interaction of 
androgen, calcitonin gene related protein and the genitofemoral nerve.  The exact mechanisms are yet to 
be elucidated, but they will no doubt be complex and involve an interrelationship of systemic and local 
factors.  The usual locations of the retained testis are adjacent to the inguinal ring, within the inguinal 
ring, and beneath the inguinal ring in a subcutaneous location, representing failure of one of the phases of 
migration.  Cryptorchidism is the potential end result of genetic, hormonal, structural or other 
abnormalities.  For the genetic causes, a polygenic recessive-hereditary basis has been established or 
suggested in all species.  Recent molecular techniques have identified a mutation in the INSL3 receptor 
RXFP2 that is strongly associated with the disease in humans.20  Exposure to endocrine disruptors 
interfering with hormonal actions, are blamed for some cases.  Structural abnormalities such as gonadal 
splenic fusion are recognized causes.  Flock outbreaks in sheep suggest environmental causes can operate 
as well.  Diagnosis and therapeutic intervention to modify or control testicular descent, based on 

533



correcting the exact abnormality, is currently a theoretical possibility only.  Because of prolonged 
exposure to increased temperature, the cryptorchid testis is hypoplastic and will eventually degenerate. 
  
 Chromosomal disorders of sexual development.  Animals with chromosomal abnormalities that 
affect sexual development result in dysgenesis, hypoplasia and or cryptorchidism.  There are many recent 
reviews of disorders affecting sexual development, with the most recent being from Meyers Wallen.21  
The terminology of DSD includes hermaphrodism, intersex, and ambiguous development.  This overview 
uses the recommendations of Hughes22 in naming DSD.  Briefly the DSD are categorized according to the 
genotype, presence of the SRY gene, the gonadal type and phenotype.  For example, at the chromosomal 
level, XXY SRY positive testicular DSD (Klinefelter’s-like syndrome) is recognized.  Affected cats, bulls, 
dogs, pigs, horses and sheep have an XXY genotype or a mosaicism with XXY chromosomes.  The most 
famous of these is the male tortoiseshell or calico cat.  XX SRY negative testicular DSD occurs in goats of 
the Saanen breed with the gene for polledness and in dogs.  A variety of other DSD have been identified 
as being associated with hypoplasia and or cryptorchidism including the persistent Müllerian duct 
syndrome (XY SRY positive testicular DSD) in schnauzers and bassets. 
  
 Testicular atrophy and degeneration.  Testicular atrophy is defined as the macroscopic reduction 
in size of the testis after it has attained its post-pubertal size.  Degeneration is the histological term.  The 
germinal epithelium reduces in amount and eventually all spermatogenesis stops.  There is often 
spermiostasis, and mineralization of the tubular content.  Spermatic granulomas may develop.  
 Testicular degeneration usually occurs because of external influences (cf. hypoplasia) that 
interfere with any of the three main cell types of the testis—Sertoli cells, interstitial endocrine cells and 
germ cells.  There is a seemingly endless list of potential causes (Table 1).  The close interrelationship of 
the Sertoli cells, interstitial endocrine cells and germ cells means that insults to any one or several of them 
eventually affect them all.  The manifestation in the testis is not always bilateral or uniform and in some 
species has a distinct pattern.  The testes of bulls frequently degenerate from the ventrum, and rams from 
the dorsum.  Mineralization, a common sign of degeneration, may involve whole or part of one 
seminiferous tubule, or whole regions. Testicular biopsies could miss affected areas. 
 Maintenance of normal testicular function requires a normal hypothalamic pituitary gonadal axis, 
and maintenance of the normal paracrine and autocrine functions of the testis.8  Any factor that interrupts 
the endocrine control (such as endocrine disruptors), or interferes with the cytokine milieu will alter 
spermatogenesis and or induce apoptosis.  At the cellular level, the basic mechanisms of degeneration are 
similar to that of other cells and tissues.  The more we learn about the mechanisms involved in other 
tissues, the more will be identified in the testis.23  For example, a recent review highlighted the effect of 
oxidative stress on cells of the testis.24 

  
 Neoplasms.  Testicular neoplasms are most commonly found in the dog.  There is no satisfactory 
explanation for this, but intact dogs are allowed to live as long as they are able, and they tend to be 
watched closely.  Male cats tend to be castrated early and fewer of those that are intact live to old age.  
Neoplasms arise in all species sporadically and, with the exception of the dog, it is possible to predict the 
histologic type of neoplasm based on species and age.  Seminoma is the common tumor of the aged, and 
teratoma is more common in young horses.  Cats, rams and bucks get neoplasms rarely, and both 
seminoma and Sertoli cell tumor are reported.  Bulls are more likely to have interstitial cell tumors, but 
Sertoli cell tumors are also reported. 
 Three main testicular neoplasms of dogs are the Sertoli cell tumor, the interstitial cell tumor and 
the seminoma.  These are reviewed in detail at www.uoguelph.ca/~rfoster/repropath/repro.htm.  Multiple 
types of neoplasia may be found in one testis.  Most primary testicular neoplasms in dogs are benign.  
Exceptions are extremely rare.  Identification of metastasis is the only way to determine that the neoplasm 
is malignant; there are no good cytological or histologic markers.  Recently, an unusual presentation of 
testicular tumors was reported.25  These occurred in dogs that were previously castrated, and the tumors 

534



developed in the spermatic cord and incision site.  Sertoli cell tumors were most common in dogs and 
interstitial cell tumors in cats.  Implantation of testicular tissue during surgery is believed to be the cause. 
 Most neoplasms cause enlargement of the testis.  In general, seminomas are white, soft and 
usually bulge on cut section.  Sertoli cell tumors tend to contain a lot of fibrous tissue so they are white in 
color and are firm.  The interstitial cell tumor is soft, tan or yellow in color, and often contains areas of 
hemorrhage.  
 Sertoli cell tumors, but rarely interstitial cell tumors, can produce a hyperestrogenism-like 
syndrome and feminization.  This is usually manifested by attractiveness to other male dogs, 
gynecomastia, and alopecia.  Some develop bone marrow aplasia.  Affected animals return to normal after 
removal of the neoplasm.  The signs are not always associated with estrogen production and not all dogs 
will have increased serum estrogen concentrations.  In these instances inhibin secretion by the neoplastic 
Sertoli cells inhibits the secretion of follicle stimulating hormone and luteinizing hormone by the 
pituitary, which in turn, inhibits testosterone production.  The imbalance between testosterone and 
estrogen is responsible for the relative increase in estrogen and feminization.  Extratesticular signs are 
much more common when the neoplasm is larger, and therefore is more common in cryptorchid dogs.  It 
is also in these dogs that an unfortunate sequel of testicular torsion can occur. 
  
 Testicular torsion..With the exception of stallions, torsion of the testis is very rare unless there is 
incomplete descent.  A testicular neoplasm is often also present to provide sufficient weight to maintain 
the torsion.  The usual clinical presentation is acute abdominal pain, and the offending mass is blackened 
due to venous infarction and is sometimes indistinguishable as testis.  Spontaneous torsion of the 
cryptorchid testis of boars is seen commonly at slaughter. 
 There are many publications about testicular torsion in humans and rodent models.  Torsion 
results in testicular ischemia, and reperfusion results in the release of proinflammatory cytokines by 
testicular macrophages, Sertoli cells, interstitial endocrine cells, and germ cells and they bind to receptors 
on the same cell types thus having autocrine and paracrine effects.26  Oxidative injury also occurs24,27 and 
is very important. 
  
 Orchitis.  Apart from bulls in areas endemic for Brucella abortus, orchitis is a rare and sporadic 
disease in domesticated animals.  The vast majority of cases in domestic species diagnosed clinically as 
orchitis are really epididymitis.  Foci of lymphocytes are occasionally seen in the testes of most species 
and suggest a subclinical disease. 
 Orchitis as the primary manifestation occurs sporadically and is reported in cats with FIP, rams 
and bucks with Corynebacterium pseudotuberculosis, pigs with Brucella suis or Burkholderia 
pseudomallei and stallions with migrating larvae of Strongylus spp. nematodes. Sporadic infection with 
other bacteria will no doubt occur from time to time.  The isolated position of the testis suggests that 
infection with the various agents is hematogenously derived, or occurs by direct traumatic penetration.  
The growth of bacteria is no doubt aided by the immune privilege of the testis. 
 Experimental studies particularly of autoimmune orchitis are numerous and have helped to 
unravel the molecular mechanisms.  The cytokines that are important in the normal regulation of the testis 
are also involved in immune and inflammatory reactions.  As well as the direct effects of effector cells on 
the testicular cells, there is upregulation of chemokines such as CCL2, 3 and 4, toll-like receptors (TLR) 
and release of proinflammatory cytokines IFNγ, IL-6 and TNFα result in germ cell apoptosis and disrupt 
spermatogenesis.8 
  
 Developmental epididymal disease.  There are many different developmental diseases that affect 
the epididymis, but only two that we will deal with specifically here.  They are segmental aplasia and 
spermatic granuloma of the epididymal head.  
 The first of these, segmental aplasia, occurs when a portion is missing.  Usually it is the tail of the 
epididymis.  As can be expected, the affected side is sterile.  Although this occurs in all species, it is 
known to have a hereditary basis in bulls. 

535



 The second disease is called spermatic granuloma of the epididymal head.  In this condition not 
all efferent ductules attach to the epididymal tube—some end blindly.  In the blind ending ductules, 
spermiostasis develops and subsequently becomes a spermatic granuloma.  This disease is recognized as 
the granulomas only occur in the region of the epididymal head.  Every case of azoospermia with normal 
testicular production of spermatozoa, based on biopsy or unilateral castration that I have investigated, had 
this condition.  I now regard the diagnosis of testicular sperm resorption as a cause of azoospermia with 
great suspicion. 
  
 Infectious epididymitis.  Bacteria cause most infections of the epididymis.  Viruses, such as 
equine arteritis virus and others are reported to induce epididymitis.  Primary infection with Brucella spp. 
in each species results in epididymitis.  B. ovis, B. canis, B. melitensis and B. suis are especially virulent 
for the epididymis.  It is assumed that the infection is systemic and the bacterium localizes in the 
epididymis. 
 Direct infection of the epididymis by penetrating injury is a rare event.  Secondary infection from 
periorchitis, or peritonitis is an occasional possibility.  Almost all species develop infection of the 
epididymis by the ascending route.  This has been studied in the ram where Actinobacillus seminus and 
Histophilus somni are common isolates.  While the exact mechanism is not known, the work of Jansen28 
in South Africa during the 1980’s indicated that preputial organisms migrate to the accessory genital 
glands (AGG) and infect the epididymis by retrograde movement.  The privileged environment of the 
lumen of the epididymal duct allows the organisms to infect the organ and incite damage.  The formation 
of spermatic granulomas means that the reproductive potential of the affected side is lost.  Complete 
return to normal is rare.  In the dog, the sequel of self-trauma of the scrotum and systemic affects of 
infection with endotoxin producing bacteria such as Escherichia coli further complicates epididymitis by 
causing systemic illness.  
 The epididymis relies on innate immune mechanisms to prevent infection.  The isolation of the 
epididymal duct and its narrow and long course must provide a challenge to ascending organisms.  The 
one-way flow of spermatozoa and strong muscular contractions are also detrimental to bacterial passage.  
Antimicrobial molecules such as TLRs are found in the rat epididymis29 and granulocyte chemotactic 
protein (GCP-2/CXCL6) is present in human epididymis,30 thus microbial pattern recognition molecules 
are present to prevent infection.  The epididymis has no natural local immune system of antigen receptors, 
recirculation of immunocytes and no local plasma cell population.  Some aggregates of lymphocytes are 
occasionally seen in otherwise normal animals.  After infection, the epididymis must develop a local 
immune system, but alas, the damage is usually so extensive, and the sequelae so severe that immunity is 
too late.  Even so, the epithelial cells have the ability to express MHC I and II and lymphocytes and 
plasma cells can be recruited after challenge.5 
 
Spermatic cord 
 The spermatic cord is composed of the deferent duct (ductus deferens), pampiniform plexus, 
muscle and nerve.  There are many diseases that affect this area.  The principal ones we will deal with are 
varicocele and inguinal hernia.  
 When palpating the region of the spermatic cord and the inguinal ring, all of the structures of this 
area can usually be identified.  The deferent duct may have indications of a previous vasectomy, the 
lymph node may be enlarged with lymphoma, and a large inguinal hernia will be palpated as a sack-like 
structure that may contain intestines.  It is particularly important in the horse to palpate the scrotum of 
animals that have colic. 
 Varicocele is a disease that particularly affects old rams.  It can be a cause of subfertility of both 
testes because of the effects of reduced blood flow that is involved with the formation of varicocele.  The 
bilateral nature of the effects suggests that a failure to thermoregulate is probably simplistic.  Varicocele 
is a common disease in humans31 where up to 15% percent of individuals are affected.  Most are on the 
left side because the left testicular vein empties into the left renal vein at a right angle, rather than 
obliquely into the caudal vena cava as occurs in the right testicular vein.  The higher pressure in the left 

536



testicular vein combined with less effective venous valves results in dilation of the vein and varicocele.  
Except in the ram, where varicocele is more common, most cases of varicocele in animals occur 
secondary to scaring or other obstruction of the testicular veins.  Varicocele is usually only recognized in 
domestic animals when thrombosis develops.  There is considerable discussion about the effects of 
varicocele on fertility.  In humans, varicocele can cause failure of testicular development and if the 
condition develops after puberty, infertility.  Infertility is thought to be the result of increased scrotal 
temperature, greater oxidative stress and reduced blood flow resulting in greater Fas ligand activity32 
which is involved in apoptosis of germ cells.  The semen of men with varicocele contains higher levels of 
oxidants and reduced levels of antioxidants compared to that of unaffected individuals.33  Intersititial cell 
dysfunction from interstitial fibrosis may also be involved. 
 
Accessory genital glands 
 The AGG include the ampullae, vesicular glands (seminal vesicles), prostate, and bulbourethral 
glands. They are frequently overlooked during necropsy examination, unless there are specific indicators 
of disease.  
 Diseases of the AGG are sporadic in most of the species and tend to be incidental findings. 
Disease of the prostate of the dog, and vesicular glands (seminal vesicles) of bulls, are common and 
important.  
 
Prostatic disease in the dog 
 The prostate is the only genital gland of the dog and it is prone to diseases that can be difficult to 
differentiate. The gland is relatively inaccessible and signs of prostatic disease are not always specific to 
that organ. 
  
 Prostatic hyperplasia.  The prostate gland has been the focus of much research, especially in the 
area of prostatic hyperplasia.  Canine prostates progressively enlarge with age. A prepubertal dog has a 
very small prostate, and with puberty, it increases in size to 'normal'. The size tends to reflect body size 
although the Scottish terrier is reported to have a prostate that is about four times the size of dogs of a 
similar size.34  About 63% of dogs develop progressive enlargement of the prostate with age after 
puberty.34  The gland can become large enough to cause clinical signs or fecal obstruction rather than 
urinary obstruction (as occurs in humans). The enlarged prostate hangs over the pelvic brim when the dog 
is in its normal quadrapedal position, but when the position for defecation is assumed, the prostate is 
pulled by gravity into the pelvic inlet and with an increase in intraabdominal pressure, forms a 'ball valve' 
and compresses the colon.  The increase in size is reported to be the result of increased interstitial tissue 
with the overall amount of epithelium not increasing in amount.  The lumen of glands, however, increases 
in diameter with age.35,36  Shain and Boesel37 examined the androgen receptor content of canine prostates 
and found that hyperplastic glands had a higher receptor content than normal, but there was no difference 
in the receptor content per cell and there was no increase in testosterone.  Moore,et al.38 found that 
estradiol enhanced androgen effects on the prostate by enhancing an androgen binding protein in the 
cytoplasm.  Castration of juveniles results in a failure of prostatic development and reduces the number of 
prostatic diseases to one–carcinoma (see below). 
 Squamous metaplasia will cause a prostate to be larger.  It occurs after administering estrogens 
and in Sertoli cell tumors.  In all animals, paracrine signals from the stroma define the epithelial type that 
will develop.  It will also define the arrangement of the epithelium, including whether the epithelium will 
form a gland or a cavity.  This whole interaction involves epithelial feedback and regulation (reviewed by 
Cunha, et al.39).  Steroid hormones regulate this interaction and in the normal prostate, AR is an important 
factor.  In estrogen-induced squamous metaplasia, estrogen stimulates estrogen receptor (ER)α, which is 
especially important in the stroma (the main ER of the epithelium is ERβ).  In ER knockout mice, both 
stromal ERα and epithelial ERα must be present and stimulated to induce both proliferation and 
metaplasia.  The stratified squamous cells acquire cyclooxygenase 2 activity as a result of estrogen 
stimulation.  

537



 Prostatitis.  Prostatitis is a common finding, even in asymptomatic dogs.40  It is reported to occur 
in canine brucellosis.41  Many dogs have foci of inflammatory cells in the interstitial tissues,35 suggesting 
that subclinical infection may be common.  Ten percent of dogs had these at six months but 45% had 
them at seven years of age. 
 Sequential studies of prostatitis are lacking, so much is assumed from studies in other animals.  It 
is assumed that prostatitis occurs mostly by ascending infection—organisms travel from the penis and 
prepuce via the urethra to the prostate.  The bacteria isolated from cases of prostatitis include Escherichia 
coli, Proteus, Klebsiella, Staphylococcus, and Streptococcus sp., but there is little information on 
prevalence.  Hematogenous spread and localization in the prostate is probably the way that infection with 
Brucella canis reaches the prostate, but infection from epididymitis is also possible.  There is also the 
theoretical possibility of infection of the prostate from the bladder and urine. 
 Once bacteria infect the prostate, they proliferate within the lumen of the glands, and from there 
either elicit an inflammatory response or invade.  Thus there is an acute intraacinar or glandular phase and 
later an interstitial phase.  Neutrophils and the contents of their granules contribute to the chemotactic 
factors of the bacteria to incite an inflammatory response.  Bacteria are usually Gram negative and 
therefore release endotoxin.  With time, the interstitial response will become more obvious, and 
lymphocytes and plasma cells predominate.  This interstitial phase will also be accompanied with fibrosis.  
Abscessation of the prostate is also an outcome of prostatitis.  
  
 Paraprostatic cysts and pseudocysts.  The most common 'cyst' attached and external to the 
prostate is the paraprostatic pseudocyst.  Some can be 30 cm in diameter or larger and form a space-
occupying mass in the abdomen.42  It is not known how or from what they arise.  Some cysts, particularly 
the smaller ones, are lined by epithelium and they may communicate with prostatic cysts and acini.  Many 
prostates have projections of glands from the prostate into and through the capsule—they extend between 
bundles of the discontinuous smooth muscle of the capsule.  Many paraprostatic cysts are therefore an 
extension of cysts in prostatic hyperplasia.  Other possible origins for paraprostatic cysts are the serosal 
inclusion cyst and hematomas.  Those that are in the dorsal midline region of the prostate are probably 
derived from a cystic uterus masculinus, a remnant of the paramesonephric duct.  The structure of the 
cysts make determining their origin impossible as the inner lining is seldom lined by epithelium.  The 
term pseudocyst is more precise in this instance.  The lining is often either fibrous or granulation tissue 
with an appearance similar to a 'seroma'.  The wall is usually of compressed fibrous tissue and the outer 
lining is mesothelium (serosa).  It is not unusual for the pseudocysts to have mineralization of the wall, 
although the literature is scant.43,44 
  
 Prostatic neoplasia.  Prostatic carcinoma is a term with several meanings.  The convention is that 
carcinomas of the prostate are actually adenocarcinomas (from the prostate glandular tissue), and 
although this is reasonable in humans, it is not necessarily the case in dogs.  There are several types of 
carcinoma in dogs, including adenocarcinoma (presumably from the glands), transitional cell carcinoma 
(from the prostatic ducts), mixed carcinomas and squamous cell carcinomas.  There is disagreement as to 
which is the most common and this is because subclassifying carcinomas is subjective.  Prognostically, 
there is little difference as virtually every dog develops metastasis.45 
 Prostatic carcinomas occur in sexually intact and neutered dogs.46,47  Carcinomas in castrated 
dogs tend to have pulmonary metastasis when diagnosed and transitional cell differentiation is more 
common than adenocarcinoma.  Intact dogs have an equal prevalence of transitional cell and glandular 
differentiation.34,48 
 Prostatic carcinomas occur in sexually intact and neutered dogs.46,47  Tumors in castrated dogs 
tend to have pulmonary metastasis when diagnosed.  Those carcinomas with transitional cell 
differentiation tend to occur more commonly in castrated dogs whereas neutered dogs are evenly split 
between those with and those without transitional differentiation.34,48 
 The phenotype of carcinomas in the prostate was debated for many years.  Attempts to separate 
them morphologically,49 using immunohistochemistry for cytokeratin 7 and arginine esterase,50 and 

538



protein expression profiling51 were fruitless as prostatic glandular epithelium and normal bladder 
epithelium are identical in their expression.  It seems reasonable to call all carcinomas of the prostate the 
generic term 'carcinoma of the prostate' or 'prostatic carcinoma'. 
 A diagnosis of prostatic carcinoma in a dog carries an extremely poor prognosis.  Metastasis to 
the lung is most common but about 14% have metastasis to bone, especially the lumbar vertebrae and 
pelvis.45,48,52 
 There are no known causes, although there is a slightly increased risk in castrated dogs.47  As 
already indicated, castration is not protective so the systemic hormonal environment does not appear to be 
important.  Lai, et al.53 found that androgen receptors were less common in neoplastic prostatic tissue than 
in normal prostate.  Positive staining was in the cytoplasm rather than the nucleus and there were no 
detectable mutations to DNA coding for the AR.  There are numerous studies outlining the distribution of 
ERs in canine prostates, and the intranuclear receptors are found in stromal cells and in the epithelial 
cells.  Hyperplastic prostates have a similar distribution.  Grieco, et al.54,55 found a loss of ERs in the 
stromal of all prostates including those with carcinoma.  The main ER in the epithelium is ERβ.  In the 
more 'differentiated' tumors, ER was present but with less intense staining.  Staining was reduced with the 
less differentiated tumors.  The significance of this is yet to be established.  Gallardo, et al.56 examined 
AR, ER α and β, and progesterone receptor expression in prostatic specimens from dogs with prostatic 
hyperplasia, prostatitis and neoplasia.  Expression of these was less common in disease except for 
progesterone receptor, where more animals had expression in disease conditions. 
 It is widely believed that precursor lesions, such as low grade prostatic intraepithelial neoplasia, 
do not occur in dogs, although Matsuzaki, et al.57 believe they do.  High grade prostatic intraepithelial 
neoplasia however is reported in clinically normal dogs58 and in dogs with carcinoma.59,60 
 Some prostatic carcinomas have cytogenetic abnormalities and of particular interest is one with 
an abnormality similar to human prostatic carcinoma.  The carcinoma studied had trisomy of chromosome 
13, which is similar to chromosome 8 of humans and which also has cytogenetic anomalies in some 
human prostatic carcinomas.61,62 
 
Vesicular adenitis (seminal vesiculitis) in bulls 
 Vesicular adenitis occurs commonly as a subclinical disease in ruminant species.  In bulls it is 
recognized as an important clinical disease and a cause of infertility and poor freezibility of semen.  It is a 
disease of young bulls predominantly—those less than two years of age.  The pathogenesis has not been 
proven, but it is commonly believed that hematogenous infection is important.  This would certainly be 
the case with Brucella abortus or Mycoplasma bovis infection.  Abnormalities of the seminal colliculus 
are implicated also.  Ascending infection in a similar mechanism to the pathogenesis of epididymitis in 
rams28 seems to have been overlooked by many.  Arcanobacterium pyogenes and Histophilus somni are 
common isolates in North America63 but many bacteria and some mycoplasmas were recovered from 
clinical cases.64-66 
 Two forms of vesicular adenitis in the bull are recognized, an acute fibrinopurulent form where 
there are the typical signs of acute inflammation—swelling, pain on palpation and neutrophils in the 
semen.  Some bulls may have systemic signs.  A chronic interstitial form is the second type and there is a 
considerable increase in size, excessive fibrosis, firm consistency and loss of lobulation.64-66 
 
Penis and prepuce 
 Diseases of the penis and prepuce are common in all species.  Many of the congenital or 
developmental diseases are part of the DSD.  Congenitally short penis, lack of sigmoid flexure in 
ruminants, hypospadias, deviations and other obvious and less obvious anomalies may be seen from time 
to time.  The epithelium of the penis and prepuce are fused until puberty, when there is separation of the 
epithelium.  Failure of complete separation will result in a persistent membrane (called a persistent 
preputial band) or frenulum that may cause deviation of the penis when it is erect. 
 Trauma and related diseases67 occur in all species but eversion of the preputial mucosa is very 
important and common in bulls of the Bos indicus and in polled breeds of the Bos taurus species.  

539



Eversion is normal but inadequate preputial muscles and injuries to the everted epithelium are the cause.  
Trauma and desiccation lead to edema, inflammation, and persistent preputial prolapse.  Mating injuries 
occur in dogs and horses especially, and the constricting effects of hair (and ‘hair ring’) occur in cats, 
sheep and goats. 
 Forced deviation of the penis (hematoma of the penis, broken penis) is a disease of bulls mostly.  
Deviation of the penis during coitus causes the extremely high pressure generated by the coital thrust to 
result in rupture of the penis at the level of the insertion of the retractor penis muscle.  A hematoma 
develops and it may be large enough to cause hypovolemic shock.  Most are not so immediately life-
threatening and will heal with scarring and phimosis.68 
 Paraphimosis is a complication of tranquilizing horses, especially if phenothiazines are used.  It 
also occurs in debilitated horses.69  Affected horses are unable to retract the penis, and engorgement and 
trauma result.  Dogs frequently develop paraphimosis as a ‘spontaneous’ lesion. 
 Most species, but especially cats and ruminants, develop urolithiasis and the stones lodge in the 
penile urethra.  Penile necrosis, and ‘water belly’ with bladder and/or urethral rupture, occurs. 
 Inflammation and or infection of the prepuce (posthitis) mostly occur as a nonspecific event.  
Inflammation of the penis and prepuce is called balanoposthitis but should more accurately be called 
phalloposthitis except in the dogs where the head of the penis is the portion of the penis from the bulb to 
the tip; balanoposthitis is the appropriate term. 
 As with any external site, the prepuce has a normal flora that contains potential pathogens.  
Sexually transmitted organisms are usually found in the prepuce and may not be a cause of disease in 
males.  Organisms of importance include the herpesviruses, mycoplasmas and ureaplasmas of most 
species.  Specific agents include Tritrichomonas foetus, Campylobacter fetus, Corynebacterium renale 
and Ureaplasma diversum in bulls, and Eubacterium suis in pigs.  A nonspecific preputial discharge is 
seen frequently in male dogs.  Geldings tend to extrude their penis less often than stallions, and they 
urinate in their sheath.  The buildup of smegma and or the effect of urine allow secondary organisms to 
flourish. 
 Outbreaks of posthitis are recorded in wethers, and rarely in rams.  There is a combination of 
factors in this disease. The animals are usually on a high protein diet thus producing abundant urea.  The 
causative agent is Corynebacterium renale, a urease-producing organism that breaks down urea to 
ammonia.  It is believed that the ammonia causes ulceration adjacent to the preputial orifice.  Further 
damage and infection results in a severe posthitis then preputial obstruction, scarring and eventually 
death.70,71  Boars develop preputial diverticulitis with ulcers and abundant necrotic debris. 
 Canine transmissible venereal tumor (CTVT) in endemic areas is common, and diagnosis of 
masses around the prepuce can usually be made on either fine needle aspiration or incision or excisional 
biopsy.  Canine transmissible venereal tumor was the first naturally occurring neoplasm that is spread by 
the transferring of cells from an affected dog to another.  It happens to be venereally transmitted.  The 
second neoplasm to be spread in a similar fashion is the oral facial tumor of Tasmanian devils, called 
devil facial tumor disease.  They are therefore allographs.  There are several reviews written about the 
CTVT.72-74  The cells of CTVT have a chromosomal number of 57, 58 or 59.  Murgia, et al.75 used 
molecular techniques to demonstrate that neoplasms from different continents and collected decades apart 
are clonal, and, while there are two subtypes, they have a common origin.  The DNA of the CTVT is 
closely related to DNA of wolves and East Asian dog breeds.  The cells of a CTVT are able to avoid 
detection by the immune cells.  They downregulate class I molecules and there is no class II activity 
because they secrete inhibitory cytokines (TGFβ1 and IL 6).75,76  In the initial proliferative phase of 
CTVT, they express little MHC Class I or II.  After about 12 weeks in an experimental model, 
lymphocytes stimulated MHC expression and subsequent regression of the tumors.77  Most transmissible 
venereal tumors are exquisitely sensitive to vincristine.   
 Squamous cell carcinoma of the penis of the horse is a relatively common condition of older 
animals.  The head of the penis is mostly affected, and about 10% metastasize to the superficial inguinal 
lymph nodes.78,79  The cause is not known and smegma is no longer considered a likely candidate. 

540



 Young bulls commonly develop fibropapillomas.  The papilloma virus, bovine papilloma virus 
type 2, causes these exophytic lesions.  They often occur during the first mating season, and they are 
fleshy lesions that become ulcerated and cause hemorrhage and pain.80 
 

Table 1.  Some of the known causes of testicular degeneration in mammals, including rodents. 
 
Advancing age 
Chlorinated naphthalenes 
Epididymitis 
Chemicals 
     Chemotherapy 
     Halogenated compounds including 
      hexachlorophene 
Nitrogen containing compounds including 
     Benzimidazoles 
     Nitrofurans 
Heat 
Hormones 
     Dexamethasone 
     Estrogen 
     Testosterone 
     Zeranolone 
Metal compound toxicity 
Neoplasia 
     Pituitary tumors 
     Sertoli cell tumors 
     Nutritional disorders 
     Negative energy balance 
     Fatty acid deficiency 
     Hypovitaminosis A 
     Hypervitaminosis A 
     Hypovitaminosis B 
     Hypovitaminosis E 
     Hypovitaminosis C 
     Protein and amino acid deficiency 
     Zn deficiency 
Oxidative stress 
Plants 

          Locoweed (Astragalus) 
          Lysine seeds 

Radiation 
Stress/Corticosteroid therapy 
Trauma 
Ultrasound 
Viral infection 
     PRRS virus 
 

 

 

541



References 
1. Foster RA: Male reproductive system. In: McGavin MD, Zachary JF, editors. Pathological basis of veterinary disease. 
 Toronto: Mosby; 2006. p. 1317-1348. 
2. Foster RA, Ladds PW: The male genital system. In: Maxie MG, editor. Jubb, Kennedy and Palmer’s Pathology of 
 domestic animals. 5th ed. St. Louis: Saunders; 2007. p. 565-619. 
3. Nomina Anatomica Veterinaria 5th ed [homepage on the Internet]. Hanover:The Editorial Committee; [cited 2010 
 April 5]. Available from: http://www.wava-amav.org/Downloads/nav_2005.pdf. 
4. Fijak M, Meinhardt A: The testis in immune privilege. Immunol Rev 2006;21:66-81. 
5. Saravanamuthu V, Foster RA, Ladds PW, et al: T and B lymphocyte subsets in spermatic granuloma in the ram. Vet 
 Pathol 1991;28:482-491. 
6. Foster RA, Caswell JL, Rinckardt N: Necrotic and fibrinous interstitial orchitis in a cat with feline infectious 
 peritonitis. Can Vet J 1996;37:681-682. 
7. Abbit B, Fiske RA, Craig TM, et al: Scrotal hydrocele secondary to ascites in 28 bulls. J Am Vet Med Assoc 
 1995;207:753-756. 
8. Guazzone VA, Jacobo P, Theas MS, et al: Cytokines and chemokines in testicular inflammation: a brief review. 
 Microsc Res Tech 2009;72:620-628. 
9. Li MWM, Mruk DD, Lee WM, et al: Cytokines and junction restructuring events during spermatogenesis in the testis; 
 an emerging concept of regulation. Cytokine Growth Factor Rev 2009;20:329-338. 
10. Lui W-Y, Lee WM: Molecular mechanisms by which hormones and cytokines regulate cell junction dynamics in the 
 testis. J Mol Endocrinol 2009;43:43-51. 
11. Roser JF: Regulation of testicular function in the stallion: an intricate network of endocrine, paracrine and autocrine 
 systems. Anim Reprod Sci 2008;107:179-196. 
12. Giampietri C, Petrungaro S, Coluccia P, et al: Germ cell apoptosis control during spermatogenesis. Contraception 
 2005;72: 298-302. 
13. Rao Veeramachaneni DN, Ott RS, Heath EH, et al: Pathophysiology of small testes in beef bulls: relationship between 
 scrotal circumference, histopathologic features of testis and epididymides, seminal characteristics, and endocrine 
 profiles. Am J Vet Res 1986;47:1988-1999. 
14. Hoflack G, Van Soom A, Maes D, et al: Breeding soundness and libido examination of Belgian Blue and Holstein 
 Friesian artificial insemination bulls in Belgium and The Netherlands. Theriogenology 2006;66:207-216. 
15. Rehm S: Spontaneous testicular lesions in purpose-bred beagle dogs. Toxicol Pathol 2000;28:782-787. 
16. Kay GW, Grobbelaar JA, Hattingh J: Heritable testicular hypoplasia in Nguni (Bos indicus) bulls: vascular 
 characteristics and testosterone production. J Reprod Fertil 1992;96:537-547. 
17. Borel N, Janett F, Teankum K, et al: Testicular hypoplasia in a bull persistently infected with bovine diarrhoea 
 virus. J Comp Pathol 2007;137:169-173. 
18. Amann RP, Veeramachaneni DNR: Cryptorchidism in common eutherian mammals. Reproduction 2007;133: 541-
 561. 
19. Hughes IA, Acerini CL: Factors controlling testis descent. Eur J Endocrinol 2008;159:S75-82. 
20. Feng S, Ferlin A, Truong A, et al: INSL3/RXFP2 signaling in testicular descent in mice and men. Ann NY Acad Sci 
 2009;1160:197-204. 
21. Meyers-Wallen VN: Review and update: genomic and molecular advances in sex determination and differentiation in 
 small animals. Reprod Domest Anim 2009;44(Suppl 2):40-46. 
22. Hughes IA: Disorders of sex development: a new definition and classification. Best Pract Res Clin Endocrinol Metab 
 2008;22:119-134. 
23. Richburg JH: The relevance of spontaneous and chemically induced alterations in testicular germ cell apoptosis to 
 toxicology. Toxicol Lett 2000;112-113:79-86. 
24. Turner TT, Lysiak JJ: Oxidative stress: a common review factor in testicular dysfunction. J Androl 2008;29:488-498. 
25. Doxsee AL, Yager JA, Best SJ, et al: Extratesticular interstitial and Sertoli cell tumors in previously neutered dogs and 
 cats: a report of 17 cases. Can Vet J 2006;47:763-766. 
26. Lysiak JL: The role of tumor necrosis factor-alpha and interleukin-1 in the mammalian testis and their involvement in 
 testicular torsion and autoimmune orchitis. Reprod Biol Endocrinol 2004;2:9-19. 
27. Aitken RJ, Roman SD: Antioxidant systems and oxidative stress in the testes. Adv Exp Med Biol 2008;636:154-171. 
28. Jansen BC: The epidemiology of bacterial infection of the genitalia in rams. Onderstepoort J Vet Res 1983;50:275-282. 
29. Palladino MA, Savarese MA, Chapman JL, et al: Localization of toll-like receptors on epididymal epithelial cells and 
 spermatozoa. Am J Reprod Immunol 2008;60:541-555. 
30. Collin M, Linge HM, Bjartell A, et al: Constitutive expression of the antibacterial CXC chemokines GCP-2/CXCL6 by 
 epithelial cells of the male reproductive tract. J Reprod Immunol 2008; 79:37-43. 
31. Mohammed A, Chinegwundoh F: Testicular varicocele: an overview. Urol Int 2009;82:373-379. 
32. Del Giudice PT, Lima SB, Cenedeze MA, et al: Expression of the Fas-ligand gene in ejaculated sperm from 
 adolescents with and without varicocele. J Assist Reprod Genet 2010;27:103-109. 
33. Abd-Elmoaty MA Saleh R, Sharma R, et al: Increased levels of oxidants and reduced antioxidants in semen of infertile 
 men with varicocele. Reprod Fertil 2010; epub ahead of print. 

542



34. O'Shea JD: Studies on the canine prostate gland. 1. Factors influencing its size and weight. J Comp Pathol 
 1962;72:321- 331. 
35. James RW, Heywood R: Age-related variations in the testes and prostate of beagle dogs. Toxicology 1979;12:273-279. 
36. Lowseth LA, Gerlach RF, Gillett NA, et al: Age related changes in the prostate and testes of the beagle dog. Vet Pathol 
 1990;27:347-353. 
37. Shain SA, Boesel RW: Androgen receptor content of the normal and hyperplastic canine prostate. J Clin Invest 
 1978;61:654-660. 
38. Moore RJ, Qazak JM, Wilson JD: Regulation of cytoplasmic dihydrotestosterone binding in dog prostate by estradiol. J 
 Clin Invest 1979;63:351-357. 
39. Cunha GR, Cooke PS, Kurita T: Role of stromal-epithelial interactions in hormonal responses. Arch Histol Cytol 
 2004;67:417-434. 
40. Diniz SA, Melo MS, Borges AM, et al: Genital lesions associated with visceral leishmaniasis and shedding of 
 Leishmania sp. in the semen of naturally infected dogs. Vet Pathol 2005;42:650-658. 
41. Brennan SJ, Ngeleka M, Philibert HM, et al: Canine brucellosis in a Saskatchewan kennel. Can Vet J 2008;49:703-708. 
42. Weaver AD: Discrete prostatic (paraprostatic) cysts in the dog. Vet Rec 1978;102:435-440. 
43. Girard C, Despots J: Mineralized paraprostatic cyst in a dog. Can Vet J 1995;36:573-574. 
44. Head LL, Francis DA: Mineralized paraprostatic cyst as a potential contributing factor in the development of perineal 
 hernias in a dog. J Am Vet Med Assoc 2002;221:533-535. 
45. Leav I, Ling GV: Adenocarcinoma of the canine prostate. Cancer 1968;22:1329-1345. 
46. Bell RW, Klausner JS, Hayden DW, et al: Clinical and pathologic features of prostatic adenocarcinoma in sexually 
 intact and castrated dogs: 31 cases (1970-1987). J Am Vet Med Assoc 1991;199:1623-1630. 
47. Teske E, Naan EC, van Dijk EM, et al: Canine prostate carcinoma: epidemiological evidence of an increased risk in 
 castrated dogs. Mol Cell Endocrinol 2002;197:251-255. 
48. Cornell KK, Bostwick DG, Cooley DM, et al: Clinical and pathologic aspects of spontaneous canine prostatic 
 carcinoma: a retrospective analysis of 76 cases. Prostate 2000;45:173-183. 
49. Weaver AD: Fifteen cases of prostatic carcinoma in the dog. Vet Rec 1981;109:71-75. 
50. LeRoy BE, Nadella MVP, Toribio RE, et al: Canine prostate carcinomas express markers of urothelial and prostatic 
 differentiation. Vet Pathol 2004;41:131-140. 
51. LeRoy BE, Painter A, Sheppard H, et al: Protein expression profiling of normal and neoplastic canine prostate and 
 bladder tissue. Vet Comp Oncol 2007;5:119-130. 
52. Durham SK, Dietze AE: Prostatic adenocarcinoma with and without metastasis to bones in dogs. J Am Vet Med Assoc 
 1986;188:1432-1436. 
53. Lai C-L, van den Ham R, Mol J, et al: Immunostaining of the androgen receptor and sequence analysis of its DNA-
 binding domain in canine prostate cancer. Vet J 2009;181:256-260. 
54. Grieco V, Patton V, Romussi S, et al: Cytokeratin and vimentin expression in normal and neoplastic canine prostate. J 
 Comp Pathol 2003;129:78-84. 
55. Grieco V, Riccardi E, Rondena M, et al: The distribution of oestrogen receptors in normal, hyperplastic and neoplastic 
 canine prostate, as demonstrated immunohistochemically. J Comp Pathol 2006;135:11-16. 
56. Gallardo F, Mogas T, Baró T, et al: Expression of androgen, oestrogen alpha and beta, and progesterone receptors in 
 the canine prostate: differences between normal, inflamed, hyperplastic and neoplastic glands. J Comp Pathol 
 2007;136:1-8. 
57. Matsuzaki P, Cogliati B, Sanches DS, et al: Immunohistochemical characterization of canine prostatic intraepithelial 
 neoplasia. J Comp Pathol 2010;142:84-88. 
58. Madewell BR, Gandour-Edwards R, DeVere White RW: Canine prostatic intraepithelial neoplasia: is the comparative 
 model relevant? Prostate 2004;58:314-317. 
59. Waters DJ, Bostwick DG: Prostatic intraepithelial neoplasia occurs spontaneously in the canine prostate. J Urol 
 1997;157:713-716. 
60. Waters DJ, Hayden DW, Bell FW, et al: Prostatic intraepithelial neoplasia in dogs with spontaneouos prostate cancer. 
 Prostate 1997;30:92-97. 
61. Winkler S, Murua Escobar H, Eberle N, et al: Establishment of a cell line derived from a canine prostate carcinoma 
 with a highly rearranged karyotype. J Hered 2005;96:782-785. 
62. Winkler S, Reimann-Berg N, Escobar HM, et al: Polysomy 13 in a canine prostate carcinoma underlining its 
 significance in the development of prostate cancer. Cancer Genet Cytogenet 2006;169:154-158. 
63. Martınez MF, Arteaga AA, Barth AD: Intraglandular injection of antibiotics for the treatment of vesicular adenitis in 
 bulls Anim Reprod Sci 2008;104:201-211. 
64. Bagshaw PA, Ladds PW: Pathology of the accessory sex glands of the bull. Vet Bull 1974;44:343-348. 
65. Dargatz DA, Mortimer RG, Ball L: Vesicular adenitis of bulls: a review. Theriogenology 1987;28:513-521. 
66. Grotelueschen DM, Mortimer RG, Ellis RP: Vesicular adenitis syndrome in beef bulls. J Am Vet Med Assoc 
 1994;205:874-877. 
67. Memon MA, Dawson LJ, Usenik EA, et al: Preputial injuries in beef bulls: 172 cases (1980-1985). J Am Vet Med 
 Assoc 1988;193:481-485. 

543



68. Musser JMB, St Jean G, Vestweber JG, et al: Penile hematoma in bulls: 60 cases (1979-1990). J Am Vet Med Assoc 
 1992;201:1416-1418. 
69. Simmons HA, Cox JE, Edwards GB, et al: Paraphimosis in seven debilitated horses. Vet Rec 1985;116:126-127. 
70. Dent CHR: Ulcerative vulvitis and posthitis in Australian sheep and cattle. Vet Bull 1971;41:719-723. 
71. Loste A, Ramos JJ, Garcia L, et al: High prevalence of ulcerative posthitis in Rasa Aragonesa rams associated with a 
 legume rich diet. J Vet Med A Physiol Pathol Clin Med 2005; 52:176-179. 
72. Cohen D: The transmissible venereal tumor of the dog–a naturally occurring allograft? A review. Isr J Med Sci 
 1978;14:14-19. 
73. Mukaratirwa S, Gruys E; Canine transmissible venereal tumour: cytogenetic origin, immunophenotype, and 
 immunobiology. A review. Vet Q 2003;25:101-111. 
74. Mello-Martins MI, Ferreira de Souza F, Gobello C: Canine transmissible venereal tumor: etiology, pathology, 
 diagnosis and treatment. In: Concannon PW, England G, Verstgegen J, et al, editors. Recent advances in small animal 
 reproduction. Ithaca: International Veterinary Information Service; 2005 [cited 2010 April 5]. Available from: 
 http://www.ivis.org/advances/Concannon/toc.asp. 
75. Murgia C, Pritchard JK, Kim SY, et al: Clonal origin and evolution of a transmissible cancer. Cell 2006;126:477-487. 
76. Liao KW, Hung SW, Hsiao YW, et al: Canine transmissible venereal tumor cell depletion of B lymphocytes: 
 molecule(s) specifically toxic for B cells. Vet Immunol Immunopathol 2003;92:149-162. 
77. Hsiao YW, Liao KW, Hung SW, et al: Effect of tumor infiltrating lymphocytes on the expression of MHC molecules in 
 canine transmissible venereal tumor cells. Vet Immunol Immunopathol 2002;87:19-27. 
78. Howarth S, Lucke VM, Pearson H: Squamous cell carcinoma of the equine external genitalia: a review and assessment 
 of penile amputation and urethrostomy as a surgical treatment. Equine Vet J 1991;23:53-58 
79. van den Top JG, de Heer N, Klein WR, et al: Penile and preputial tumours in the horse: a retrospective study of 114 
 affected horses. Equine Vet J 2008;40:528-532. 
80. Campo MS: Animal models of papillomavirus pathogenesis. Virus Res 2002;89:249-261. 

544