Normal Prostatic Development and Function

The prostate gland is the major accessory sex gland in the male dog. It is located just caudal to the bladder in the area of the bladder neck and proximal urethra. Its purpose is to produce prostatic fluid as a transport and support media for sperm during ejaculation. Basal prostatic secretion is constantly entering the prostatic excretory duct and prostatic urethra. In the absence of micturition or ejaculation, urethral pressure moves prostatic fluid cranially into the bladder (a mechanism called prostatic fluid reflux). As the dog grows old, the prostatic parenchyma is characterized by an increase in epithelial cell numbers (hyperplasia) as well as an increase in epithelial cell size (hypertrophy), but the increase in cell number is more marked.¹ This growth process begins as glandular hyperplasia in dogs as young as 2.5 years of age.² Intraparenchymal fluid cysts may develop in association with hyperplasia. Such cysts are variable in size and contour, contain a thin, clear-to-amber fluid and, if intraparenchymal, may communicate with the urethra, thus leading to intermittent haemorrhagic or clear, light yellow urethral discharge.

Benign Prostatic Hyperplasia (BPH)

Due to normal growth and glandular hyperplasia, the prostate of intact normal male dogs increases in weight for the first 5 years, with a peak at 4 years of age.¹ As many as 16% of dogs have been reported to have histologic evidence of benign prostatic hyperplasia (BPH) by 2 years of age.² The incidence of BPH increases to over 80% with advanced age. Senile involution of the prostate occurs in animals aged 11 years or more.¹ Like in humans, the prostate of a mature dog is chronically dependent upon a continuous supply of androgen to maintain its appropriate cell content and functional activity. In particular, prostatic growth and secretion are modulated by 5-alpha-dihydrotestosterone (DHT) that is the active androgen at intracellular level.

The regulation of prostatic content of DHT is determined by the relationship between the rate of production and removal of this steroid in the prostate gland itself rather than by DHT blood levels. Normally, it is adequate to maintain a balance between prostatic cell loss and renewal such that neither involution nor proliferative overgrowth of the gland occurs. In both canine and human BPH, this balance is increasingly being shifted in favour of a large net increase in the total number of prostatic cells with advancing age. In addition, it has been well documented that, even in young dogs, the experimental development of BPH can be induced simply by treatment of animals for 3–4 months with androgen and, in this regard, several androgens have been tested for their potential abilities to induce this disorder. One of the most serious consequence is due to the presence of fluid-filled cysts making the prostate susceptible to infection from bacteria ascending the urethra, as accumulated prostatic fluid is an excellent media for bacterial growth.³ Hematogenous spread of bacteria and spread from the kidneys and bladder via urine or from the testicles and epididymis via semen can also occur. Bacterial prostatic infection can be acute and fulminant or chronic and insidious leading to abscessation.⁴

The hyperplastic prostate is highly vascularized and therefore the gland bleeds easily, which explains the common clinical sign of blood from the tip of the penis or blood in the urine. Blood loss in the prostatic urethra can be so intense that the ejaculate may appear completely red. Although presence of blood in the semen is typically considered to be a cause for infertility, dogs with blood in their ejaculates may be fertile. The reason for BPH being a common cause of infertility in the dog is probably due to the alteration of the biochemistry of the prostatic fluid, whose important action of nutrition of spermatozoa is decreased. Prostatitis or abscessation are likely consequences of presence of blood in the prostate.⁴

Diagnosis of Canine BPH

Benign prostatic hyperplasia is diagnosed based on history (bloody penile discharge, difficulties in defecation/urination, poor semen quality and infertility, absence of haematological/biochemical alterations), physical exam and abdominal ultrasound (increase in prostatic size, presence of prostatic cysts), and, if necessary, a fine needle aspirate.^3-5 Urinalysis helps to rule out urinary tract diseases as a cause of penile discharge (cystitis should be treated prior to onset of BPH therapy to avoid confounding factors in the interpretation of results).

An enlarged, hypertrophic prostate may cause blood dripping from the tip of penis (the most common clinical sign), or it may grow and expand in the rectal canal, causing tenesmus and sometimes difficult defecation (less common).⁶ Other than the above signs, affected dogs are usually normal and the prostate on palpation is non-painful, symmetrically enlarged and with variable consistency. Urine may contain blood (gross or microscopic). If hyperplasia is accompanied by urethral discharge, this is typically haemorrhagic or clear but not purulent.

Prostatic enlargement may be also visualized on abdominal radiography as causing dorsal displacement of the colon and cranial displacement of the bladder.⁵ On retrograde urethrocystography, the prostatic urethra may be normal or narrowed and undulant with mucosal irregularity, and the urethroprostatic reflux may be normal or greater than normal. On ultrasound, the prostate may appear diffusely hyperechoic with parenchymal cavities (which means that intraparenchymal cysts have developed). The canine prostate is best evaluated in the sagittal and transverse planes using 5.0 or preferably 7.5 MHz scanners. An enema should be administered prior to scanning to eliminate colonic contents, which may mimic peripheral prostatic disease. Conditions, such as cysts or abscesses, are visualized easily. Other less distinct but echogenically complex areas may indicate neoplasia or areas of infection within the gland. Although, technically, a definitive diagnosis of BPH is only possible by biopsy, such an invasive approach is not necessary to institute a therapy if clinical signs are present, and from a practical standpoint ultrasound assessment of prostatic size and presence of cysts is often the only thing that is necessary to identify the problem and start dealing with it. No alteration of haematological or biochemical parameters is commonly observed in dogs with BPH.⁷

Canine BPH can be difficult to differentiate from other most common prostatic disorders (prostatitis, prostatic cysts, carcinoma and adenocarcinoma) because of the similarity of clinical findings. In men with prostatic carcinoma the use of serum markers such as acid phosphatase (AcP) and prostate specific antigen (PSA) has facilitated determination of the extent of disease, evaluation of therapeutic response and detection of relapse after therapy. Information about these markers is still controversial in the dog. Serum and seminal prostatic AcP activities do not differ significantly between normal dogs and those with prostatic diseases, or among dogs with different prostatic disorders;⁸ PSA is not detected in canine serum or seminal plasma. The major secretory product of the canine prostate is canine prostate-specific arginine esterase (CPSE) which constitutes more than 90% of seminal proteins in this species. CPSE is a known marker of dog prostatic secretion.^9,10 Screening for CPSE is of potential value in the aging intact male dogs. Its measurement is a useful and accurate method and should be considered as an alternative or complementary tool to conventional methods for the diagnosis of BPH in middle-aged dogs. CPSE is under testosterone control and, therefore, may serve as functional marker of the androgenic state and response to antiandrogenic therapy, either by receptor antagonists or 5-alpha-reductase inhibitors. Although further research is necessary to define the exact role of CPSE, it seems to be a promising diagnostic tool in nonneoplastic canine prostatic disorders.

Treatment for Canine BPH

Surgical or pharmacological castration (using GnRH agonists) or the administration of estrogens, steroidal or nonsteroidal antiandrogens can be used.¹¹ Although occasionally reported as an effective treatment for BPH, estrogens carry the potential risk of serious bone marrow side effects (anemia, leukopenia, thrombocytopenia, pancytopenia) as well as the risk of growth of the fibromuscular stroma of the prostate, which may cause metaplasia of the prostatic glandular epithelium and secretory stasis resulting in prostatic enlargement and predisposition to cyst formation, bacterial infection and abscessation.¹² Therefore, we do not currently advice using estrogens to treat canine prostatic hyperplasia. Estrogen receptor blockers may be used to treat BPH as they compete with androgen receptors, thereby decreasing prostatic size and weight (although the altered ratio estrogen:testosterone is not modified, which means that number and size of prostatic cysts do not change). Recently, tamoxifen (an estrogen receptor blocker with a mixed antagonist-agonist action) has been reported to be efficacious and devoid of side effects in male dogs with BPH (except for a decrease in libido and semen quality);¹³ following 28 days of treatment at the daily dose of 2.5 mg/day, tamoxifen caused a decrease in testicular and prostatic size as well as testosterone and libido¹³. Tamoxifen does not seem to have serious side effects and may be an interesting adjunct treatment for canine BPH, although there is no information on its long-term effect and safety and more studies are probably necessary before it can be prescribed routinely.¹³

Castration

The most effective treatment to induce regression of prostatic hyperplasia is castration, after which prostatic size may decrease as much as 50% in 3 weeks and 70% over 9 weeks.¹⁴ Orchiectomy has long been considered the treatment of choice for those dogs whose reproductive function is not important to the owner. As post-castration involution begins within days of surgery, prostatic size should be assessed 3 weeks postoperatively to make sure the involution rate is normal, thus ruling out a more serious prostatic disease such as neoplasia or abscessation. Surgical castrations should not be performed in the presence of prostatic infections due to the risk of scirrhous cord development, in which case it would be better to administer a specific antibiotic treatment based on semen culture and sensitivity. With regard to orchiectomy, one important thing to consider is that incidence of prostatic carcinoma in adult/elderly dogs could be higher in castrated rather than in intact dogs; reasons for this are not entirely known yet, but it is speculated that once prostatic atrophy starts, neoplastic cells already present will increase their growth rate perhaps due to lack of suppressing action of testosterone.^15-17 For this reason we do not currently advice our clients to castrate their adult-to-elderly dogs unless it is strictly necessary (i.e., if there is a testicular tumor).

Steroidal Antiandrogens

Steroidal antiandrogens compete with androgen receptors and perhaps also with DHT receptors at the cellular level in target organs. Compounds such as megestrol acetate, medroxyprogesterone acetate, delmadinone acetate, chlormadinone acetate and ciproterone acetate have been successfully used in the dog, although for the majority of them there is only a limited amount of experimental data on their effectiveness in the canine. Their action causes a sort of pharmacologic castration and is rather precociously observed during treatment, as improvement can be observed already after 7–15 days. Medroxyprogesterone acetate has been used as a single SC dose of 4 mg/kg; although prostatic effects were not assessed, the treatment significantly reduced sperm testosterone concentrations, which implies that it might be used also for the treatment of BPH.¹⁸ Chlormadinone acetate has been used at the dose of 1–2 mg/kg orally for 1 month, or as a subcutaneous 12-month implant of 5.0 mg/kg,¹⁹ but oral doses as low as 0.03 to 0.3 mg/ kg/day are effective in dogs with BPH²⁰. Delmadinone acetate has also been used at doses of 1.5 to 5.0 mg/kg SC to be repeated every 1–2 weeks^21-23 with the lower dosage being the one prescribed in commercial veterinary formulations. Ciproterone acetate is another progesterone derivative with a very strong antagonistic effect on DHT receptors when used at the daily dose of 0.5–1.0 mg/kg per os for at least 2–4 weeks; the drug is well tolerated in dogs and causes decreased libido and spermatogenesis and reduces prostatic size.^24,25 We currently use it as an adjunct treatment in dogs with acute clinical signs of BPH such as rectal compression, urethral compression or signs of prostatitis. Cyproterone acetate has a very quick action with signs disappearing already at the end of the first week of treatment; therefore it is helpful whenever the dog is suffering from signs related to BPH or when a worsening of the condition is anticipated such as during the first 1–2 weeks following administration of a GnRH agonist implant (see over). Its effects are rather long-lasting, with a 3–4-week course of oral administration being enough to maintain the dog for a few months without clinical signs.

Osaterone acetate (OA) is a more recent progesterone derivative commercially available in several European countries as a veterinary product for use in dogs with BPH.^26,27 As an antiandrogen, OA is an analog of chlormadinone acetate (but it is 5 times more potent in vitro than chlormadinone itself) with a specific inhibitory action on prostatic volume in laboratory animals and dogs.²³ It is marketed as an oral medication with each package containing 7 pills of different dosages depending on body weight: 1.875 mg, 3.75 mg, 7.5 mg and 15 mg for dogs of 3–7.5 kg, 7.5–15 kg, 15–30 kg and 30–60 kg, respectively. Dosage is 0.25–0.50 mg/kg. Treatment consists of 1 pill/day for 7 consecutive days. OA is slowly metabolized by the liver with a very long half-life of 198±110 h. For this reason, a 7-day course of treatment allows for a pharmacological concentration of the drug to last for 6 months. OA is very effective in treating canine BPH, and works well also in case of prostatitis.²⁸ Being a progestogen derivative, OA may cause suppression of the pituitary-hypophysial-adrenal axis with reduced cortisol production and/or low or no response to ACTH stimulation tests lasting for days or weeks after treatment withdrawal. Although this is normally not a problem in healthy dogs, it should be considered when dealing with postoperative cases or in case of trauma, while treatment with OA should be avoided in dogs with hypoadrenocorticism. Semen quality appears not to be affected initially, and may actually improve when poor at treatment onset due to the prostatic condition. However, progestogens are known to cause a progressive deterioration of semen quality with time; in the case of OA, there are few, if any, data on fertility during the last half of the 6-month treatment.

Nonsteroidal Antiandrogens

Nonsteroidal antiandrogens include finasteride and flutamide. Finasteride inhibits 5-a-reductase (the enzyme responsible for the final transformation of testosterone into dihydrotestosterone or DHT), thereby lowering the concentration of DHT which is the active metabolite at the level of target tissues, without altering serum testosterone concentrations. This leaves spermatozoa production undisturbed, which makes finasteride a goodchoice for breeders (although a chronic use may be associated with a decrease in ejaculate volume as well as decrease in semen quality). Finasteride is only approved for use in men, but it is well known to produce a dose-dependent decrease in prostatic size also in dogs. It can be used at the daily dose of 1 mg/kg/day, PO, for up to 4 months resulting in a 50–70% reduction in prostatic hypertrophy with no negative effect on semen quality.²⁹ Lower dosages of finasteride (0.1–0.5 mg/kg/ day, PO, for 4 months) cause a slightly lower but still curative effect in terms of reduction of prostatic volume by >40%, resolution of clinical signs, reduction of DHT concentration, maintenance of normal testosterone levels, and have no deleterious effect on semen quality, fertility, or libido.³⁰ The low dosage (0.1–0.5 mg/kg) of finasteride allows for a convenient dosing of one 5-mg capsule/day for dogs weighing 10–50 kg; however, it is advisable to use 1.5 mg (approximately 1/3 of a 5.0 mg pill) for dogs ≤15kg body weight, 2.5 mg (approximately half pill) for dogs of 15–30 kg body weight, and 5.0 mg for dogs of >30 kg body weight. Finasteride is well tolerated and can be administered for long periods of time. We currently use finasteride in breeding dogs both to induce remission of clinical signs of BPH as well as to keep the condition under control with 1–2 treatment cycles/year depending on severity of clinical signs. Unlike cyproterone acetate, finasteride is fairly slow to show its efficacy, as clinical signs may take up to 3–4 weeks to disappear, and tend to appear again within a few weeks of treatment withdrawal. Flutamide is a human antiandrogen which can cause a significant decrease in prostatic size as detected by ultrasonography within 10 days. When administered to research dogs at 5 mg/kg/day PO for 1 year, it did not alter libido or sperm production.³¹ Also flutamide is a human drug not approved for use in veterinary medicine, although it appears safe, effective and well tolerated in dogs.

GnRH Agonists

Following administration of a GnRH agonist, prostatic size decreases in parallel with the decrease of testosterone. When adult dogs are implanted with 4.7 or 9.4 mg deslorelin, their prostatic volume decreases more than 50% from week 6 onwards,^32,33 and serum T concentrations decreases 90% from week 3 onwards³⁴. We have observed disappearance of conspicuous (>17 mm diameter) prostatic cysts following treatment with a single 4.7 mg deslorelin implant³⁵ as well as of larger (20x25 mm) prostatic cysts in adult male dogs with clinical signs of benign prostatic hypertrophy undergoing treatment with a 4.7 mg deslorelin acetate administered every 6 months (unpublished observation). In milder or less complicated cases of BPH, an improvement of the clinical situation of treated dogs is observed often without any additional pharmacological treatment already at the first follow-up visit. In cases in which prostatic size is markedly increased and in the presence of rectal or urethral constriction or other signs of discomfort, deslorelin may cause a temporary worsening of the clinical situation because of the initial (first week) rise in testosterone secretion due to temporary hypersecretion of pituitary gonadotrophins (flare effect); in these cases, we normally add a 2-week course of a progestogen derivative such as cyproterone acetate. The mechanism of action of GnRH agonists in achieving a decreased prostatic size is probably through the decrease in serum testosterone, which also causes a (reversible) sterility. Therefore, GnRH agonists should not be used for the treatment of BPH in male dogs intended to be used for breeding.

Clinical Management of Canine BPH

The best way to prevent the development of clinical BPH in the dog is to identify its early pre-clinical signs by performing a regular monitoring of prostatic conditions by ultrasound. If signs of BPH (such as presence of prostatic cysts or increased prostatic size) are observed during a routine check while the dog is asymptomatic, owners should be advised to watch for the development of clinical signs in order to start treatment as soon as possible. There is little information on the value of a preventive treatment for BPH in the dog. In men, preventive treatment is often discouraged because of the many side effects which may be caused by alpha-1 adrenergic antagonists (the most common treatment for human BPH). However, incidence of side effects of such drugs in the dog is unknown and, most importantly, alpha-1 adrenergic antagonists are not 1st-choice drugs for canine BPH, while steroidal or nonsteroidal antiandrogens or GnRH agonists are more indicated for this purpose. Side effects of long-term treatment with steroidal antiandrogen include temporary adrenocortical suppression and a decrease in libido and semen quality. All steroidal antiandrogens should be avoided in breeding animals because of their potential negative impact on fertility. However, the use of medroxyprogesterone acetate (4 mg/kg SC every 3–5 months), chlormadinone acetate (0.1–0.3 mg/kg/day per os for 6 months) as well as osaterone acetate in its well-known weekly treatment regimen have been associated with a normal or acceptable fertility in male dogs at least for the first few weeks and therefore might be used for limited amounts of time in these patients.

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