MEDICAL TREATMENT OF CANINE PROSTATIC DISEASE

Root Kustritz, M.V.

DVM, PhD, DACT - University of Minnesota College of Veterinary Medicine

St. Paul, MN 55108

The prostate is the only accessory sex gland of the male dog.1 It is a retroperitoneal organ with only the craniodorsal surface covered by peritoneum.1 It is bounded by the rectum dorsally and the symphysis pubis ventrally.1 The prostate completely encircles the urethra at the bladder neck. It is surrounded by a fibromuscular capsule and divided into two lobes by a median raphe which is palpable on the dorsal surface per rectum.1-3 Its position is pelvic until it becomes enlarged with advancing age or disease, at which time it may pull the bladder cranially and be palpable abdominally.1,4

Histologically, the glandular epithelial cell population differs with distance from the urethra, from low cuboidal to tall columnar.5 These glandular cells are divided into indistinct lobules by bands of smooth muscle.3,4 Blood is supplied by branches of the prostatic artery and drained by the prostatic and urethral veins.1 Lymph drainage is to the iliac lymph nodes.1 The hypogastric and pelvic nerves provide sympathetic and parasympathetic innervation, respectively.6

Prostate growth and secretion is androgen-dependent.2 Castration leads to decreased prostate volume and atrophy of glandular and stromal elements, with decreased ability to take up and metabolize androgens.2,7,8 The principle androgen regulating prostatic growth is 5a-dihydrotestosterone (5a-DHT), which is formed from testosterone by the enzyme 5a reductase.7 Locally manifested growth factors may also act as modulators of epithelial cell growth and function.5,9

The prostate gland secretes seminal plasma under the control of hormonal factors and stimulation by the parasympathetic nervous system.6 Expulsion of prostatic fluid into the urethra is stimulated by the sympathetic nervous system.6 Prostatic fluid makes up the first and third fractions of the canine ejaculate and acts to thin and increase volume of the ejaculate, and possibly aid sperm transport.2,10 Prostatic fluid is secreted constitutively, and is normally expelled into the prostatic urethra, from where it drains into the urinary bladder and along the penile urethra.

Prostatic disease is fairly common in the dog, with a reported incidence of 2.5%.11 The normal prostate gland grows until the dog reaches 4 years of age, at which time growth plateaus and prostatic function, as assessed by ejaculate volume, peaks before abruptly declining.12 Incidence of all types of prostatic disease increases with advancing age, with a mean reported age of 8.9 years before onset of clinical signs.11 Prostatic diseases reported in the dog include benign prostatic hypertrophy/hyperplasia (BPH), acute and chronic bacterial prostatitis, prostatic abscesses, prostatic retention (true) cysts and paraprostatic cysts, and prostatic neoplasia.

Diagnosis of all prostatic diseases requires (1) assessment of prostate size by rectal palpation, contrast radiography and/or ultrasonography, (2) evaluation of prostatic fluid, collected by ejaculation or prostatic massage, for inflammatory changes and presence of bacteria, and (3) possible prostatic biopsy. In man, measurement of a secretory protein, prostate specific antigen (PSA), can be used in diagnosis and assessment of efficacy of treatment of prostatic diseases. A related but distinct protein, canine specific arginine esterase (CSAE) has been identified in the dog.13,14 While this protein makes up 90% of secretory proteins found in canine seminal plasma and is almost exclusively expressed in the prostate, concentrations in serum and seminal fluid have not been demonstrated to differ significantly between normal dogs and dogs with different prostate diseases,13-16 limiting our ability to use serologic tests to verify or assess progression of canine prostatic disease.

BENIGN PROSTATIC HYPERTROPHY/HYPERPLASIA (BPH)

Benign prostatic hypertrophy/hyperplasia (BPH) is a condition commonly seen in aged men. The dog is the only domestic species known to exhibit this disorder.3 In men, it is characterized by hyperplasia of stromal cells within periurethral tissues.4 In the dog, both hypertrophy (increased cell size) and hyperplasia (increased cell number) occur, with diffuse glandular proliferation and overall increase in volume and weight of the prostate.4

BPH is a natural consequence of aging; in one study, 50% of dogs examined had histologic evidence of BPH by 4-5 years of age.17 Both estrogens and androgens must be present for significant hypertrophy/hyperplasia to occur.2,4,12,18-24 Estrogens may act by increasing the number of androgen receptors in prostatic tissue,4,18,19 or by forming metabolites with free radical activity which damage the prostate, altering its response to 5a-DHT.19 Prostates affected with BPH apparently also have increased ability to metabolize androgens; a high correlation exists between size of the prostate and ability to form 5a-DHT from testosterone.25 Local growth factors and catecholamines may also have a role in mediating growth and contractility of the gland.5,26,27 Small cysts containing bloody or serosanguinous fluid may form, and as the gland develops increased vascularity, there is an increased tendency for prostatic bleeding.4,18

In man, pollakiuria (increased frequency of passage of small amounts of urine) is the most common presenting sign of disease, presumably due to the periurethral location of hyperplasia and increased contractility of the gland.4,26,27 In the dog, signs are referable to increased size of the gland and subsequent pressure on the rectum and surrounding structures. Bloody to serosanguinous urethral discharge unrelated to urination, hematuria, tenesmus, hemospermia, and infertility may be seen.2,28,29 Systemic signs of disease are uncommon. BPH is only seen in intact animals.

The hypertrophied/hyperplastic prostate will be symmetrically enlarged and non-painful when palpated per rectum.28 Radiographically, the gland will be enlarged and may displace the bladder cranially and the rectum dorsally.30 Mean normal area will not be as large nor the gland as asymmetrical as in neoplasia or cystic prostatic disease.2 The prostate is enlarged if it encompasses $70% of the distance from the cranial aspect of the pubic bone to the sacral promontory on a lateral projection radiograph.30 Ultrasonographically, the homogeneous parenchyma will be normal to slightly hyperechoic.31 Prostatic fluid cytology will be non-inflammatory and cultures will be non-significant (< 100,000 bacteria/ml). Prostatic biopsy is rarely necessary to confirm the diagnosis.

* Treatment *

(1) Castration

Bilateral orchiectomy is the treatment of choice. No medical therapy has yet been shown to be as effective as castration in decreasing prostatic size and causing resolution of clinical signs long-term.7 However, castration causes permanent infertility, and so may be inappropriate as a first-choice treatment in valuable breeding animals.

(2) Estrogens

Oral and injectable estrogen preparations have been shown to decrease prostatic size and signs of BPH.4,18 Estrogen will prohibit pituitary LH release by negative feedback, with subsequent decline in serum testosterone concentrations.2,4,32 However, estrogens also induce squamous metaplasia of the gland and secretory stasis, which predispose the gland to ascending infection.2,4,18,23,33 In one study, complete degeneration of testicular germ cells was noted 40 days after administration of estrogen.32 Estrogens may also cause fatal bone marrow suppression in susceptible animals.4 An anti-estrogen compound, tamoxifen, has been shown to have some effect on decreasing prostatic size in BPH, but does not inhibit androgen-induced stromal proliferation.33 Estrogens cannot be recommended as a routinely successful treatment for BPH at this time.

(3) Progestins

Megestrol acetate (OvabanJ, Schering; 0.5 mg/kg/day po x 4-8 weeks) and medroxyprogesterone acetate (3-4 mg/kg SQ) have been shown to decrease serum testosterone concentrations, and possibly competitively inhibit binding of 5a-DHT to intracellular receptors, inhibit 5a reductase activity, and decrease prostatic androgen receptor number.4,18,28,32,34-36 Prostate size was decreased and clinical signs resolved within 4-7 weeks of therapy.34-36 No changes were noted in total sperm number, libido, or testicular size and consistency after treatment.34,35 Signs recurred 10-24 months after treatment with a single dose of medroxyprogesterone acetate.35 Progestins are not approved for use in male dogs in the United States.

(4) 5a reductase inhibitors

Several types of 5a reductase inhibitors, which act by suppressing conversion of testosterone to 5a-DHT, are described in the literature. Chlormadinone acetate and others described will cause a decrease in prostatic size and resolution of clinical signs, but may cause reduced fertility.37-41 Finasteride (ProscarJ, Merck) is, to date, the drug of this class best evaluated, and apparently most effective in treatment of canine BPH.7,42-44

At doses of 1-5 mg/kg/day, finasteride will cause atrophy of both the glandular and stromal compartments of the prostate with a subsequent decrease in prostatic weight and volume.7,42,43,45 Prostatic size will decrease significantly by 4 weeks of treatment, and reach maximal atrophy, a 33-50% reduction in pre-treatment volume, by 6 weeks of treatment.7,46 Intraprostatic 5a-DHT concentrations will decrease with treatment; serum concentrations may not.7,43,47 At present, treatment with a lower dose of finasteride (0.1-0.5 mg/kg/day) is being investigated and appears to be effective.48 Treatment with finasteride has not been demonstrated to cause changes in testicular weight or histomorphology, or daily sperm production.45,49 Finasteride has not been evaluated for teratogenicity, and it is not recommended that men attempt to father children while on the drug. Finasteride is not approved for use in male dogs in the United States.

(5) Miscellaneous treatments

These include DHT receptor blockers,14,18,50 ketoconazole,18,28 nutritional supplements (ProstsafeJ, Whitewing Laboratories; UrozincJ, Prostahelp Inc.), smooth muscle relaxants (doxasin mesylate, CarduraJ, Pfizer), catecholamine receptor blockers,51 gossypol,52 electrovaporization,53,54 transurethral collagenase injection,55 transurethral light treatment after photosensitization,56 transurethral high-intensity focused ultrasound,57,58 and rotoresect, mechanical ablation plus high-frequency tissue coagulation.59

PROSTATITIS / PROSTATIC ABSCESS

Prostatitis is bacterial infection of the prostate, usually due to ascending infection by a member of the normal urethral flora.60 Prostatitis often develops as a secondary disorder. A primary disorder such as BPH, squamous metaplasia, or neoplasia predisposes the gland to infection by altering defense mechanisms which normally prevent retrograde movement of bacteria, such as urine flow during micturition, a urethral high-pressure zone, bactericidal effects of prostatic fluid and local IgA production, and offering media for bacterial growth, such as serosanguinous fluid retained within a cystic prostate.4,61 Organisms most commonly isolated are E. coli, Mycoplasma sp., Staphylococcus sp., Streptococcus sp., Klebsiella and Proteus.2,4,11,62 Brucella canis has also been isolated from canine prostatitis.4 In 70% of cases of bacterial prostatitis, a single causative organism will be isolated.63

Presenting clinical signs will vary with course of the disease. Acutely infected animals will be painful, febrile and lethargic, and may exhibit hematuria or locomotor difficulties, or present for infertility or unwillingness to breed.11,28 In chronically infected dogs, fewer systemic signs will be seen.28 Dogs with prostatic abscessation may be nearly asymptomatic or present with signs of sepsis due to fulminating infection and peritonitis.4 All dogs with prostatitis are likely to show evidence of urinary tract infection (UTI); all intact male dogs with recurrent UTI should be assumed to have prostatic involvement.11,63,64 Prostatitis is more likely to be seen in intact than in neutered dogs.65

The infected prostate gland may or may not be enlarged. Asymmetrical prostatomegaly may be severe if a prostatic abscess is present. Radiographically, prostatomegaly and mineralization may be evident.30 Chronic prostatitis will appear as diffusely increased echogenicity of the prostatic parenchyma by ultrasound.31 Abscesses will be visible ultrasonographically as hypo- to anechoic lesions with distant enhancement, and cannot be differentiated from cysts or hematomas.31

Positive culture and inflammatory cytology of prostatic fluid, collected by ejaculation or prostatic massage, are more definitive diagnostic tests.28,61 Inflammatory cytology of prostatic fluid and pure growth of greater than 100,000 bacteria/ml of a single organism have been shown to have 87% and 68-80% correlation with histopathology of the infected prostate, respectively.64,66 As UTI is a common concomitant disease process which may hinder ability to diagnose prostate disease, some authors recommend evaluation of urine, collected by antepubic cystocentesis, and urethral cytology and culture specimens concurrently with prostatic fluid.62,66 Blood leukocyte count has not been demonstrated to reflect infection within the prostate.64 Changes in pH of prostatic fluid are also non-diagnostic for canine prostatitis.67

Prostatic biopsy is another definitive test for canine prostatitis. However, biopsy or fine-needle aspirate of the prostate in the presence of infection may lead to seeding of bacteria along the needle tract with subsequent peritonitis.2,68

* Treatment*

(1) Castration

Infection will be more readily cleared from the prostate of castrated dogs than intact dogs.65 Castration may also promote resolution of disorders underlying prostatitis, for example BPH.

(2) Antibiotic therapy

Antibiotic choice should be based on culture and sensitivity results whenever possible. In acute prostatitis, the blood/prostate barrier is disrupted, allowing most antibiotics to readily diffuse into prostatic tissue.4 In chronic prostatitis or abscessation, antibiotics that can penetrate the intact blood/prostate barrier must be used. Characteristics of a suitable antibiotic include high lipid solubility, low protein binding and pKa complementary to the pH of the prostatic fluid, allowing ionization and subsequent trapping of the antibiotic within the prostate.4,28,61 Acidic prostatic fluid (pH < 7.2) will ionize antibiotics with a high pKa, and basic prostatic fluid (pH > 7.4) will ionize antibiotics with a low pKa.4,61 Examples of antibiotics with poor movement into prostatic tissue due to low lipid solubility include tetracyclines, aminoglycosides, cephalosporins and ampicillin.4,61 Examples of antibiotics that readily penetrate the prostatic capsule include chloramphenicol, trimethroprim-sulfa and enrofloxacin.28 Chloramphenicol has high protein binding and so must be used at the high end of the dose range.4 Owners should be cautioned of the human health hazards of this drug. Trimethoprim-sulfa may cause secondary signs of anemia and keratoconjunctivitis sicca if given long-term. Concurrent administration of 5 mg/day folic acid may ameliorate these problems.69 Enrofloxacin (BaytrilJ, Bayer) has a low molecular weight favoring tissue penetration, is a zwitterion with 2 pKa's and is highly lipid soluble.70 It achieves serum and intraprostatic concentrations well above the minimum inhibitory concentration of most pathogens when administered at a dose of 5 mg/kg BID.70 Ciprofloxacin does not penetrate the prostate as well as enrofloxacin.70

Antibiotic therapy should be continued for at least 3-4 weeks.28 Prostatic fluid should be cultured 1-2 weeks after completion of treatment, and again 2-4 weeks later to ensure clearance of infection.28,65 Chronically infected dogs may benefit from long-term treatment with a 50%-reduced dose of antibiotic given once daily, or castration.61,65

(3) Abscess resolution

Antibiotic therapy should be instituted as described above. Safe retrieval of a sample for culture and sensitivity may be difficult in a large, solitary abscess. Empirical treatment with a highly diffusible antibiotic, like enrofloxacin, may be required. Abscesses may resolve with medical treatment to decrease prostatic size, such as finasteride.48 Oftentimes, marsupialization or placement of Penrose drains is necessary.71 Morbidity is high in dogs requiring surgical drainage of abscesses, with reported complications including incontinence, chronic draining stomas, peritonitis, septic shock and death.4,61 New surgical techniques have been described which appear to show decreased morbidity.72,73

PROSTATIC RETENTION (TRUE) CYSTS / PARAPROSTATIC CYSTS

Numerous small cysts may be seen as a component of BPH and are treated accordingly.2,28 Retention (true) cysts are thin walled structures within the prostatic parenchyma containing non-purulent fluid. Etiology is unknown; some hypotheses are that cysts are either prostatic ducts that have become obstructed and dilated secondary to squamous metaplasia from exposure to endogenous or exogenous estrogens, or calcified fibrous walls of resolving prostatic hematomas.2,28 Paraprostatic cysts are most commonly seen craniolateral or caudal to the bladder and prostate in older, large breed dogs.28,74 They are thin walled structures outside the prostatic parenchyma that often contain malodorous fluid containing fibronecrotic debris.74-76 Etiology is again unknown; these may be vestiges of the Mhllerian ducts.2

With either retention cysts or paraprostatic cysts, the dogs may present with anorexia, weakness, abdominal distension and other gastrointestinal signs, and urinary tract signs such as hematuria or dysuria.11,74-76 Radiographically, these dogs will have apparent prostatomegaly.30 Contrast radiography may be required to differentiate a paraprostatic cyst from true prostatomegaly. Mineralization may be present in the wall of paraprostatic cysts.74 Ultrasound may also be used to differentiate retention cysts from paraprostatic cysts. Infusion of saline into the urinary bladder through a urethral catheter may be helpful in defining structures.74

Both retention cysts and paraprostatic cysts are best treated by surgical removal.28 Surgical drainage may be attempted but infection is a common complication.28 Castration may aid in resolution of retention cysts. Effect of castration on resolution of paraprostatic cysts is unknown.

PROSTATIC NEOPLASIA

Although metastatic prostatic neoplasia (for example, transitional cell carcinoma) and possible benign prostatic neoplasia have been reported,4,77 primary prostatic adenocarcinoma is the most common prostatic neoplasm.4,28 It is a locally invasive tumor that readily metastasizes to the iliac lymph nodes, lungs and lumbar vertebrae.28 It is most common in aged dogs; one report documented a mean age at diagnosis of 10 years.11 The tumor does not appear to be androgen-dependent.78 Age at castration therefore has no sparing effect on its incidence.78 It may be seen in intact or castrated animals, and is the only prostatic disease reported in castrated animals.11

Dogs with neoplasia are likely to present with systemic signs as the tumor has often metastasized by the time of diagnosis.11 Signs seen include pain, hindlimb weakness, tenesmus, weight loss, stranguria and urethral bleeding.11,28 The prostate will be palpably enlarged and may be asymmetrical and firm. Survey radiographs will demonstrate prostatomegaly and possibly mineralization.30 Contrast radiographs show destruction or distortion of the prostatic urethra.30 Ultrasonographically, capsular disruption, focal or multifocal mineralization and parenchymal asymmetry will be evident.31

Treatment is palliative. Prostatectomy, chemotherapy and radiation therapy may be attempted.28 Hormonal therapy, as used in man, is unlikely to be effective in the dog.78

CONCLUSION

Castration is the treatment of choice for most dogs with prostatic disease. Medical treatment in general is best used for valuable breeding animals. Because the dog is a model for human prostate disease, new treatment modalities are likely to emerge in the future.

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