Prostate disease in the dog Introduction Canine prostatic diseases include benign prostatic hyperplasia (BPH), prostatitis (acute and chronic), prostatic cysts, and prostatic neoplasia. These diseases may occur concurrently or separately. A complete history and appropriate diagnostics are necessary to make an accurate diagnosis. This paper will discuss the signalment, history, clinical signs, diagnostic tools, treatments and prognosis for each causes of prostate disease in the canine. Prostate anatomy The prostate is a bi-lobed, oval to round, organ located within the cranial pelvic canal/caudal abdomen. The proximal urethra runs through the center of both lobes. Testosterone is converted to dihydrotestosterone (DHT) via the enzyme 5α-reductase. DHT stimulates prostatic development, growth and production of glandular secretions. 5α-reductase is found in two distinct isoenzymes (types 1 and 2). Isoenzyme 1 is found in the skin, liver and prostate; while isoenzyme 2 is found only in the prostate and other genital tissues. Testosterone and DHT bind to the same androgen receptors and cause the same tissue effects. DHT binds much more tightly and longer to the androgen receptors than testosterone; thus smaller amounts of DHT will cause an amplified response by the prostate compared to testosterone. Benign Prostatic hyperplasia BPH is the most common disease of the prostate in intact male dogs. Approximately 50% of dogs 5 years of age have some signs of BPH and by 7 years of age, 90% of intact dogs will have signs of BPH. This disease develops directly due to the effect of testosterone on the prostate. Testosterone causes both hyperplasia and hypertrophy. The prostate is highly vascularized with BPH, particularly in the periurethral zone, predisposing to vascular fragility and bleeding from these vessels into the secretory ducts or into retention cysts. The prostate will be symmetrical, non-painful and enlarged. Most dogs with BPH have no clinical signs at all, but when signs develop, they may include sanguinous (fresh or digested) drippings from the penis/prepuce, hematuria, hemospermia, stranguria, dysuria, incontinence, and/or tenesmus. The degree of urinary or fecal signs is directly proportional to the increased size of the gland. Some dogs may present with infertility due to alterations in prostatic fluid pH and osmolarity. Rectal palpation may be accomplished in some dogs depending on their size and the location of the gland within the pelvic canal. Upward pressure on the caudal abdomen may push the gland back into the pelvic canal to facilitate palpation. Care should be taken making any assessment of prostate size unless the entire gland can be palpated. Diagnosis may be accomplished with ultrasonography, prostatic fluid cytology, and/or prostatic cytology or biopsy. Ultrasound usually reveals an enlarged, symmetrical gland with a homogenous but hyperechoic (to normal) echotexture, with or without small-large retention cysts. In dogs with concurrent prostatitis, the echotexture may be mottled, yet hyperechoic to normal. Prostatic fluid may be obtained via prostatic massage for cytology. Cytologic specimens may also be obtained by fine needle aspirate (FNA) or core biopsy. Semen collection can also be used to obtain 3rd fraction fluid which may contain light blood contamination to frank hemorrhage or digested blood (coffee colored secretions). Treatment of BPH involves removing the androgen exposure to the prostate. The most effective and fastest way to treat is via castration. The prostate will be 80% smaller within 3 months of castration. However, in breeding males, this is not an option. For these individuals, there are a number of medications that can be used. 5α-reductase inhibitors. Finasteride is an azasteroid which blocks conversion of testosterone to DHT by inhibiting the action of 5α-reductase type 2. Since testicular testosterone production is unaffected there are no negative effects on libido, erection or spermatogenesis. Without the effect of DHT on the prostate, apoptosis occurs resulting in reduction in prostate size. There is a very wide safety margin for this drug. The dose range is 0.1 – 0.5 mg/kg po qd. The tablets come in 1 or 5 mg sizes so most medium – giant breed dogs would start at 5 mg/day and small/toy breeds would start at 1 mg/day. Some giant breed dogs may require 7.5 mg daily, but most will respond well to the 5 mg/day dose. Care should be taken to avoid inadvertent ingestion of tablets by pregnant bitches as teratogenic effects have been reported in women and rodents taking finasteride. There is no concern over embryotoxicity or bitch fertility when breeding to a male on an active finasteride program. Finasteride should be used continuously until the dog is neutered regardless of active breeding status. Use of 5α-reductase inhibitors results in decrease secretion from the prostate, particularly the 3rd fraction. In natural mating situations, the third fraction is an important factor in sperm transport, in that it provides a fluid medium for sperm to swim up the cervix and into the uterus. Dogs on daily finasteride may have markedly reduced amounts of fraction 3. It is possible that this may impact their fertility in a natural mating. Thus, once a normal prostatic size is reached, some type of alternate dosing schedule is usually used (every other to every third day treatment, or month on/month off regimen). This dosing schedule must be tailored to the individual dog as some are more sensitive to the effects than others – this may actually have more to do with the size of the dog and the dose he is on rather than individual response to medication. Anti-androgen therapy. Osaterone acetate (Ypozane®, Virbac) is a testosterone analogue that competitively binds to androgen receptors, reduces 5α-reductase concentrations, and inhibits testosterone transport into prostatic cells. The dose is 0.25 - 0.5 mg/kg po qd once daily for 7 days. Treatment lasts for about 5 months. This results in about 40% reduction in prostate volume within 14 days. Fifty percent of dogs have resolution of clinical signs within 2 weeks and eighty-five percent have resolution within 6 months. There are no obvious negative effects on semen quality or fertility. This medication is not labeled for use in the US. Delmadinone acetate (Tardak®, Pfizer Animal Health) is a potent progestin that binds competitively to androgen receptors and suppresses luteinizing hormone (LH) via negative feedback, which in turn decreases circulating testosterone concentrations. There may be effects on fertility and libido so this is not a good choice for actively breeding males. There is also a decrease in cortisol, which may lead to hypoadrenocorticism in some patients. Diabetes mellitus may be exacerbated with this medication. One or two injections (1 - 2 mg/kg IM or SQ) at 14 days intervals is usually used, and results in remission of clinical signs in 50% of dogs within 14 days and 85% by 6 months, with an almost 30% reduction in prostate volume within 14 days. This medication is not labeled for use in the US. Historically, medroxyprogesterone acetate has been used to reduce clinical signs, but it does not significantly reduce prostate volume. It may also cause development of diabetes mellitus or mammary neoplasia, so its use is not currently recommended. Megestrol acetate at 0.55 mg/kg orally once daily for 6-8 weeks has also been used. Decreased libido and semen parameters may occur while the medication is being administered but should return to pre-treatment values within a few months of discontinuing. Antiestrogen therapy. Estrogens are believed to potentially cause BPH or to at least have a permissive role in its development. Therefore, antiestrogens can be used to successfully treat this disorder. Tamoxifen citrate at 2.5 mg/kg po qd, results in a 25-50% reduction in prostate volume within 30 days. Tamoxifen also decreases libido, serum testosterone concentrations, semen quality and testicular size and tone. While on treatment, sperm production will cease and all semen parameters with decline gradually and libido will also decline. Following cessation of therapy, all parameters are expected to return to normal within limits within several months, assuming initial treatment didn’t last more than 30 days. Anastrazole (Arimidex®, AstraZeneca) is a potent, highly selective aromatase inhibitor. A dose of 0.025 mg/kg po qd for 28 days results in rapid reduction of prostate volume by over 20% with no effects on libido, testicular size or tone, or semen parameters. Gonadotropin releasing hormone (GnRH) agonist therapy. Deslorelin acetate® (Suprelorin, Virbac) and azaglynafarelin (Gonazon®, Intervet) are potent GnRH agonists that decrease LH production by desensitizing pituitary gonadotrophs to GnRH and Leydig cells to LH. Following a brief stimulatory period after implant placement, there is long term downregulation of testicular function resulting in poor to no libido and a cessation of spermatogenesis, along with a decrease in prostate volume by as much as 55%. Semen parameters and libido return to normal within 3 months of implant withdrawal. These implants are not labeled for use in the US. Prostatitis Prostatitis is a common disease entity in intact male dogs. Dogs with BPH are predisposed. Clinical signs depend on whether the condition is acute or chronic; with acute cases presenting as sick patients with obvious inflammatory disease and chronic prostatitis cases typically being subclinical in nature. Infection occurs due to ascension of bacteria from the urethra, scrotal contents, bladder or hematogenously. Aerobic bacteria such as Escherichia coli, Staph spp, Strep spp, Pseudomonas, Pasteurella, Proteus, Mycoplasma and Ureaplasma are all common pathogens, along with any other opportunistic bacteria that may be present. Anaerobic infection is less common but possible. Fungal organisms (particularly Blastomyces) have an affinity for the prostate and testicles and should be considered if signs of systemic fungal infection are present. Dogs with acute prostatitis may present with fever, malaise, dehydration, vomiting, diarrhea, stiff/stilted hind limb gait, back pain, +/- abdominal pain. There may be hemospermia, hematuria, pyospermia, or pyuria. Semen quality and libido may be decreased. It can be difficult to determine if bladder or prostate infection was the initiating cause as the two tracts are so interconnected. Rectal examination will typically reveal an enlarged, asymmetrical and painful prostate, if it can be palpated in the pelvic canal. If the prostate is markedly enlarged it may reside entirely in the abdominal cavity. Diagnostics include ultrasonography (heterogenous architecture with hypoechoic parenchyma with or without cavitation), radiography, prostatic fluid evaluation (collection is often impossible due to pain associated with ejaculation, so prostatic massage, under sedation, may be necessary), complete blood count (CBC) and serum chemistry. Cytology usually reveals increased numbers of neutrophils often with intracellular bacteria. Culture of prostatic fluid is recommended for aerobic, anaerobic and/or fungal (if suspected) organisms. Fine needle aspiration or core biopsy is contraindicated in cases of suspected acute prostatitis because the needle tract may be seeded with bacteria. Dogs with chronic prostatitis are typically asymptomatic unless they have concurrent signs of BPH. They may present with infertility due to descending testicular/epididymal infection or alterations in prostatic secretions (ph and osmolarity). Rectal palpation may reveal an asymmetrical, non-painful, but enlarged, prostate. Diagnosis is via ultrasonography (enlarged, asymmetrical, heterogenous architecture with normal to slightly hyperechoic echotexture), cytology and culture of the third fraction (collected either by ejaculation, prostatic massage or FNA), culture of the third fraction or by prostatic aspirate or core biopsy, and histopathology via core biopsy. Cytology may or may not reveal increased numbers of neutrophils depending on whether the infected areas of the prostate are walled off to the secretory ducts; therefore a lack of neutrophils, does not rule out chronic prostatitis. In long-standing cases of chronic prostatitis, the gland may actually be smaller than normal, due to fibrosis and contracture, but it is still asymmetrical and non-painful. Prostatic abscessation may occur with acute prostatitis. It is difficult to differentiate retention cysts from abscessation on ultrasound, so this is typically determined based on risk and clinical picture (dogs with acute or chronic prostatitis are at high risk for abscessation, while dogs with BPH are not). Complete blood count usually reveals a marked leukocytosis with neutrophilia and a degenerative left shift with prostatic abscessation. For dogs no longer being used for breeding, castration with appropriate antibiotic therapy and supportive care is indicated as soon as the patient is stable. For breeding males, treatment involves supportive care (IV fluids, NSAIDs, pain management), appropriate antibiotic therapy based on culture results and treatment of concurrent BPH. With acute prostatitis, the blood-prostate barrier is broken, allowing most antibiotics access to the prostatic tissue. In a normal prostate, antibiotic penetration occurs via concentration gradients and diffusion. The bloodprostate barrier normally only allows lipophilic drugs that are not highly protein bound to diffuse across. The pH of the prostate is more acidic than blood (normal pH of prostatic fluid is 6.1-6.5). Ion trapping also affects the ability of antibiotics to penetrate the intact prostate. All drugs have a charged fraction (ionized) and an uncharged fraction. The uncharged fraction of lipophilic drugs equilibrate on both sides of a membrane, while the charged portion concentrates on one side or the other depending on pH of the fluid on either side of the membrane. Drugs are more concentrated on the side with greatest ionization. Thus in a normal prostate, weak bases will concentrate within the prostatic tissue (since the secretions are acidic). If prostatic secretions are altered, and pH is more basic, weak acids may be a better choice. With chronic prostatitis, antibiotics should be continued for at least 4-6 weeks and sometimes longer. The prostatic fluid should be recultured and ultrasound repeated at the end of treatment to ensure complete resolution. These dogs will be predisposed to recurrent infection. Good antibiotic choices include the fluoroquinolones, trimethoprim-sulfa, the macrolides and chloramphenicol. The fluoroquinolones are zwitterions (have both a positive and a negative charge), they are not basic or acidic, and therefore penetrate the prostate regardless of pH. They are effective against most aerobic bacteria including Mycoplasma and Ureaplasma. They are not effective against fungal organisms or anaerobes. They are typically the antibiotic of choice while waiting for culture results. Trimethoprim is a weak base and has broad spectrum activity, but may be associated with side effects with long term use (i.e. keratoconjunctivitis sicca, blood dyscrasias). The macrolide antibiotics (erythromycin, tylosin) penetrate the prostate well but are only effective against gram positive organisms so should not be used until a sensitivity has been obtained. Chloramphenicol crosses the blood-prostate barrier well and is effective against anaerobes. Humans should wear gloves when administering this medication to their pets. Prostatic abscesses usually require surgical drainage unless they are very small, as it is difficult to get high enough antibiotic concentrations into the center of the abscess. Large prostatic abscesses or those close to the surface of the gland are at high risk for rupture into the abdominal cavity resulting in septic peritonitis and a very high mortality rate. Surgical techniques include omentalization, marsupialization and penrose drain placement. Omentalization is currently the surgical treatment of choice. There are more complications with penrose drain placement and marsupialization so these are typically only used if omentalization is not successful. Prostatic Cysts These may occur within the parenchyma (retention cysts) and are associated with BPH or they may be paraprostatic (remnants of the tubular paramesonephric ducts). Cysts may cause no signs at all, or if they become large enough may cause stranguria, dysuria, tenesmus or constipation. Intraprostatic cysts predispose to abscessation. Paraprostatic cysts can be surgically resected. Treatment for BPH will often reduce the size of smaller retention cysts, but large retention cysts require surgical removal, using the same techniques described above for abscessation. Prostatic Neoplasia Adenocarcinoma and transitional cell carcinoma are the 2 most common neoplastic conditions of the canine prostate. These neoplasms tend to be aggressive and metastasize quickly. Liver and lung are the most common metastatic targets. Prostatic neoplasia is not androgen dependent and as such occurs more commonly in neutered males than intact males. Androgens may in fact be protective against neoplastic transformation. Castration may also cause a shift in the prostatic stroma from actin-positive smooth muscle cells to vimentin-positive mesenchymal cells, which may favor tumor formation. Furthermore, castrated animals may live longer than their intact counterparts predisposing them to age-related neoplastic processes. Clinical signs may include dysuria, stranguria, tenesmus, constipation, back pain, stiff/stilted hind limb gait, or abdominal pain. Rectal palpation may reveal a painful prostate if it can be palpated. Diagnosis is via ultrasonography (heterogenous architecture, asymmetrical), FNA, or core biopsy. Diagnosis does not tend to occur until late in the disease process and metastasis are common. Treatment is usually palliative and does not result in significantly extending the lifespan of the patient. Surgery may be considered if there are no signs of metastasis and involves total prostatectomy. Urinary incontinence is common following this procedure. Another surgical procedure is subtotal intra-capsular prostatectomy (open procedure or with Nd:YAG laser). There may be increased survival time with this procedure and less chance of urinary incontinence. Transurethral resection of the prostate is a third surgical possibility and results in decreased clinical signs but no improvement in survival time. Dogs with dysuria may benefit from tube cystotomy or urethral stent placement. Radiation therapy does not improve quality of life or extend survival times and is fraught with complications including colitis, GI stricture or perforation, skin ulceration, bladder wall thickening, chronic cystitis, urethral stricture, ileosacral osteosarcoma, osteopenia, pelvic limb edema, and perianal pain. At this time, radiation therapy is not a viable treatment alternative. Non-traditional chemotherapy with NSAIDS like piroxicam and carprofen may be of benefit because neoplastic prostate cells express COX-2. Increased survival times (up to 7 months) may be seen with these NSAIDs. The bisphosphates are osteoclast inhibitors and may help increase bone density and thereby decrease pain and chances of fracture associated with metastasis. They may also control hypocalcaemia of malignancy. Conclusion Most dogs with prostate disease are intact. Accurate diagnosis of prostatic disorders present will allow for appropriate therapy to treat all aspects of disease present. It is important to remember that more than one prostatic disease may exist at one time and so all components must be addressed with appropriate therapy to affect a successful outcome for the dog. Neutered males dogs with prostate disease will most likely be neoplastic unless the dog was recently neutered. Resources: 1) Albouy M, Sanquer A, Maynard L, et al: Efficacies of osaterone and delmadinone in the treatment of benign prostatic hyperplasia in dogs. Vet Rec 2008;163:179-183. 2) Christensen B. Treatment of Prostatic Disease. Clinical Theriogenology 2011; 3: 233-243. 3) Cornell KK, Bostwick DG, Cooley DM, et al: Clinical and pathologic aspects of spontaneous canine prostate carcinoma: a retrospective analysis of 76 cases. Prostate 2000;45:173-183. 4) Corrada Y, Arias D, RodrÌguez R, et al: Effect of tamoxifen citrate on reproductive parameters of male dogs. Theriogenology 2004;61:1327-1341. 5) Fontaine E, Mir F, VAnnier F, et al. Fertility after osaterone acetate treatment in breeding dogs suffering from prostatic diseases [abstract]. Reprod Domest Anim Suppl 3 2010;45:60. 6) Freitag T, Jerram RM, Walker AM, et al: Surgical management of common canine prostatic conditions. Compend Contin Educ Vet 2007;29:656-663 7) Gobello C, Corrada Y: Noninfectious prostatic disease in dogs. Compend Contin Educ Pract Vet 2002;24:99-107. 8) Gonzalez G, Guendulain C, Maffrand C, et al: Comparison of the effect of the aromatase inhibitor, anastrazole, to the antioestrogen, tamoxifen citrate, on canine prostate and semen. Reprod Domest Anim 2009;44:316-319. 9) Hosgood G: The omentum–the forgotten organ: physiology and potential surgical applications in the dog and cat. Compend Contin Educ Pract Vet 1990;12:45-51. 10) Iguer-Ouada M, Verstegen JP: Effect of finasteride (Proscar MSD) on seminal composition, prostate function and fertility in male dogs. J Reprod Fertil Suppl 1997;51:139-149. 11) Johnston SD, Kamolpatana K, Root-Kustritz MV, et al: Prostatic disorders in the dog. Anim Reprod Sci 2000;60-61:405-415. 12) Kutzler M, Yeager A: Prostatic diseases. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. St. Louis: WB Saunders; 2005. p. 1809-1819. 13) Lange K, Cordes EK, Hoppen HO, et al: Determination of concentrations of sex steroids in blood plasma and semen of male dogs treated with delmadinone acetate or finasteride. J Reprod Fertil Suppl 2001;57:83-91. 14) Laroque PA, Prahalada S, Gordon LR, et al: Effects of chronic oral administration of a selective 5αreductase inhibitor, finasteride, on the dog prostate. Prostate 1994;24:93-100. 15) L'Eplattenier HF, Van Nimwegen SA, Van Sluijs FJ, et al: Partial prostatectomy using Nd:YAG laser for management of canine prostate carcinoma. Vet Surg 2006;35:406-411. 16) LeRoy BE, Northrup N: Prostate cancer in dogs: comparative and clinical aspects. Vet J 2009;180:149162. 17) Liptak JM, Brutscher SP, Monnet E, et al: Transurethral resection in the management of urethral and prostatic neoplasia in 6 dogs. Vet Surg 2004;33:505-516. 18) Madsen PO, Whalen PR: Interaction between antimicrobial agents and prostatic tissue extract and fluid. Infection Suppl 1978;6:75-77. 19) Milner RJ, Farese J, Henry CJ, et al: Bisphosphonates and cancer. J Vet Intern Med 2004;18:597-604. 20) Mullen HS, Matthiesen DT, Scavelli TD: Results of surgery and postoperative complications in 92 dogs treated for prostatic abscessation by a multiple Penrose drain technique. J Am Anim Hosp Assoc 1990;26:369-379. 21) Sirinarumitr K, Sirinarumitr T, Johnston SD, et al: Finasteride-induced prostatic involution by apoptosis in dogs with benign prostatic hypertrophy. Am J Vet Res 2002;63:495-498. 22) Smith J: Canine prostatic disease: a review of anatomy, pathology, diagnosis, and treatment. Theriogenology. 2008;70:375-383. 23) Sorenmo KU, Goldschmidt MH, Shofer FS, et al: Evaluation of cyclooxygenase-1 and cyclooxygenase2 expression and the effect of cyclooxygenase inhibitors in canine prostatic carcinoma. Vet Comp Oncol 2004;2:13-23. 24) Stamey TA, Meares EM, Winningham G: Chronic bacterial prostatitis and the diffusion of drugs into the prostatic fluid. J Urol 1970;103:187-194. 25) Trigg TE, Wright PJ, Armour AF, et al: Use of a GnRH analogue implant to produce reversible longterm suppression of reproductive function inmale and female domestic dogs. J Reprod Fertil Suppl 2001;57:255-261. 26) White RA, Williams JM: Intracapsular prostatic omentalization: a new technique for management of prostatic abscesses in dogs. Vet Surg 1995;24:390-395.