Prostatic Disorders in the Dog Dr

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Prostatic disorders in the dog dr. Linda Müller clinical veterinarian Department and Clinic of Reproduction University of Veterinary Medicine Prostatic disorders in the dog

• Anatomy • Function • Diagnostic • Prostatic disorders o Benign prostatic hyperplasia - BPH o Squamous metaplasia o Prostatitis o Prostatic cysts o Prostatic abcess o Prostatic neoplasia Anatomy

- Exocrine tubuloalveolar gland - ovoid-shaped, bilobed gland composed of glandular and stromal elements - is enveloped by a fibromuscular capsule, smooth muscle fibers from the wall of the urinary bladder - encircles the urethra of the male dog caudal to the neck of the urinary bladder - It is located dorsal to the pubic symphysis, ventral to the rectum, and caudal to the bladder Anatomy colliculus seminalis Anatomy colliculus seminalis - Prominent median septum separates the prostate into the right and left lobes - Each lobe is further divided into lobules by capsular trabeculae > ~ Approx. 15 lobules – 5-6 smaller lobules are located in the DL part, and 3 larger lobules in the V part in each Active IC androgen lobe of the prostate - Tubuloalveolar glands lined by tall columnar to cuboidal secretory epithelial cells - Secretions leave the gland via small ducts into the urethra. All the prostatic ducts branch circumferentially from the urethra to the capsule with no focal area that resembles the transition zone in humans - Glandular tissue is supported only by a very thin septa of stroma in contrast to the thick muscular region surrounding the glandular structures in the human Anatomy

• Gradual growth up to 11 years and then involution • Glandular tissue and stromal proliferation > ↑ number and size of epithelial cells Function

• The only accessory sex gland of the genital tract in dogs • Prostate fluid gives 90% of the ejaculate • - contributes fluid to the first and third fractions of the ejaculate • is secreted continuously, flows retrograde into the urinary bladder or antegrade out the external urethral orifice • antibacterial activity of normal prostatic fluid > physiological barrier against ascending infection >< disorders > the composition changes Diagnostic

• Digital rectal palpation o size, shape, surface – dorsal sulcus, symmetry, pain, mobility o normal prostate: symmetrical, smooth, with a distinct dorsal median groove, not painful o Asymmetry of the prostate and loss of the dorsal median groove may be observed in cases of severe parenchyma alterations o Pain is sometimes reported in cases of acute prostatitis and prostatic carcinoma, but not in the case of a chronic prostatitis. • Abdominal palpation • Radiograpy o normal gland > is not easily seen in native radiographs o prostate is considered enlarged when the prostatic diameter, as visualized on the lateral radiographic view, is greater than 70% of the pubic–sacral promontory distance (DSPP) o can be identified using retrograde contrast urethrocystography with bladder distension o calcification – carcinoma/ chronic inflammation Richard A.S. White Diagnostic

• Ultrasonography o encircles the urethra as it leaves the bladder neck o homogeneous echodense pattern, more echoic than liver, spleen and renal cortex o On the sagittal (longitudinal) scan, it was seen as an oval structure with a smooth margin and a distinct hyperechoic capsule, the prostatic urethra was identified as an anechoic line passing through the gland. o On the transverse scan the prostate has a bilobed, rounded appearance, with a distinct hyperechoic capsule. The urethra was identified as an echolucent area in the dorsal half of the gland

o Size . 10-20 bw kg 3-4 cm . 20-40 bw kg 4-6 cm . > 40 bw kg 5-7 cm

Atalan et al. 1999. Levy X. et al. 2014. Diagnostic

• Ultrasonography o Morphological signes of disorders • inflammation, hyperplasia or neoplasia o the homogeneous nature of the prostate image is lost, and focal to multifocal areas of hyperechoic and/or hypoechoic tissue become apparent > becomes edemous - radial structure o calcification (hyperechoic area underlined by a shadow cone) may be observed in prostatic tumors or chronic prostatitis o anechoic or hypoechoic areas are present in cases of prostatic cysts or prostatic abscessation o Atrophy – hypoechoic, flattened, carious

. Richard A.S. White Atalan et al. 1999. Richard A.S. White Diagnostic

• Prostate sampling techniques o Semen collection o Prostatic massage/wash technique o Ultrasound-guided fine-needle aspiration FNA -gold standard o Biopsy Diagnostic • Markers o Human • Acid phosphatase (AP) and Prostate-specific antigen (PSA) o Human prostatespecific antigen (PSA) • Increased PSA serum level > BPH, prostatitis, prostata carcinoma (staging) • more sensitive than the AP o Dog • AP, PSA – appears in healthy, PC, BHP prostate epithelial cells o BUT AP is no different o BUT PSA can not be detected from serum and seminal plasma

• Canine prostate-specific arginine esterase (CPSE) o healthy, hyperplastic and neoplastic cells, seminal fluid o androgen-dependent protein o BHP > healthy, neoplastic, inflammatory o Carcinoma - 44% concomitant appearance of BHP Diagnostic

• Canine prostate-specific arginine esterase (CPSE) o Early diagnosis – fertility preservation o Objective – correlates with volume of prostate but does not depend on estimated volume - from body weight o A) (BPH), C) healthy (prostatitis) (p < 0.001). ≥ 61 ng/ml > BHP Disorders

Acut Chronic

Prostatitis

Septic Aseptic

Endocrin Tumor

BPH Cysts

Metaplasia Intra - Para - prostatic prostatic Disorders

o Benign prostatic hyperplasia - BPH o Squamous metaplasia o Prostatitis o Prostatic cysts o Prostatic abscess o Prostatic neoplasia Clinical Symptoms Common to All Prostatic Diseases Lower urinary tract symptoms o Intermittent pre-putial bloody discharge without urination - - most common clinical sign o Haematuria may occur mostly towards the end of urination o Dysuria is uncommon • In men, dysuria is caused by an increase in pressure on the urethra due to concentral hypertrophy >< In dogs, prostatic hyperplasia is diffuse and the enlarged prostate will change position by moving into the abdominal cavity • Urinary retention (anuria) in dogs is reported when large cavities and neoplasia are present in the prostate Changes in the conformation of semen o Haematospermia without changes in semen quality - in the early stages of benign prostatic hyperplasia and prostatitis o Later stages - a decrease in motility and morphology, tail abnormalities are particularly common Gastrointestinal symptoms o The enlarged prostate may compress the colon leading to constipation, tenesmus or intermittent diarrhea o Severe constipation may promote perineal hernia o Gastrointestinal (GI) symptoms may subside when the enlarged prostate moves beyond the pelvic rim into the abdominal cavity Locomotor disorders o stiffness, lameness, paresis or oedema of the hindlimbs have been reported o infections of the prostate may induce bacterial emboli leading to lumbosacral dyscospondylitis - rare Systemic signs o Hyperthermia or general unexplained deterioration of body condition may be the only clinical manifestation of a prostate disease such as abscess, prostatitis and tumor BPH BPH • a spontaneous and age-related condition • >95% 9 years old intact dogs, mostly asymptomatic • Pathogenesis o is not completely understood o age-related declines ↓T (although T level is not directly related to prostate size)→ ↑E2:T ratio → E excess → stimulates the expression of AR o ↑ 5α reductase ativity → T → DHT conversion → DHT overexpression (primer mediator) o androgenic agents induce hyperplasia and sensitize the cells of the prostate to the estrogenic effect o E2 • increases the number of androgen receptors • induces structural transformation > metapasia • Cell damage < estrogen metabolites as free radicals o prolaktin BPH o DHT directs proliferation and growth of glandular cells o ↑ Size of epithelial cells (hypertrophia) and ↑ number (hyperplasia) o glandularis hyperplasia > ↑ intraglandular pressure > disrupted secretion > accumulation of secretions in the tubules > cyst formation in the parechima o E > metaplasia o Hyperplasia > vascularisatio > bleeding in the prostate o Uniform, diffuse hyperplasia – glandular epithelium is involved in the whole organ, in dogs the stroma is not affected o 5α reductase expression of the epithelial cells in a dog higher than the stroma <> in humans, stroma is affected by hyperplasia BPH

• Continuous enlargement of the prostate gland during a dog’s lifetime which leads to a BPH is not often associated with overt clinical signs • Signes ~after 8 years of age o Discharge (yellowish-bloody) dripping from the urethra regardless of urination o Hematuria o Tenesmus, constipation (dysuria) o Abdominal pain o Haemospermia, infertility • ROS ↑, ↓antioxidant protection+ Spermatozoa is very sensitive to the oxidative stress → biochemical processes and DNA integrity- , mitochondrial activity damage • motility and morphological damage • Size determination – rectal palpation/ US • X-ray is not a reliable examination technique for the diagnosis of BPH as it tends to overestimate the size of the gland • Prostatic fluid collected from a prostatic massage, or semen collection > Bacteriological analysis is negative • Markers o (CPSE) canine prostate-specific arginine eaterase ELISA BPH

Lévy X. et al. 2014 BPH - Therapy

Prevention / suppression of androgenic effect / synthesis

Surgical castration Conservative treatment

- 70% reduction in size is already from 7-14. - !!! Prostate neoplasia, - cysts, severe symptoms, day extreme enlargement - 6-12 weeks (4 months) complete involutio - !!! Testicular tumor > E > metaplasia Chemical castration o Deslorelin o Progestagens o Oestrogens o TypeII 5α reductase inhibitors – Finasteride o Steroid receptor inhibitors – Osaterone acetate o (Tamoxifen – antioestogens) BPH - Therapy Deslorelin (GnRH analogues – buserelin, nafarelin) o 6 weeks after implantation> 50% reduction in size o ~ 40. day > aspermia o Without reimplantation the prostate is recovered during 48 weeks (12 months) o 0,5-1 mg/ttkg deslorelin > decreased size for 7-11 months o „flare-up effect” ? - Progestagenes o Slower effect > Ozateron acetát

Polisca et al. (2013) Clinical Efficacy of the GnRH Agonist (Deslorelin) in Dogs Affected by Benign Prostatic Hyperplasia and Evaluation of Prostatic Blood Flow by Doppler Ultrasound. Reproduction in domestic animals BPH - Therapy

Prevention / suppression of androgenic effect / synthesis

Surgical castration Conservative treatment

1. Progestagens – antiandrogen effect • Level of HT, negative feedback mech. > decrease the T level, the LH level is not change • In combination with GnRH analogues • Newer agents >< side effects • Inhibited spermatogenesis, asthenozoospermia, teratozoospermia o Medroxyprogesterone acetate (3 mg/kg, sc inj. 1x (every 5 months)) asymptomatic during 4-6 weeks, for 10 months o Megestrol acetate (0,5mg/kg/day) for 2 month > It reduces prostate size during 1-2 months BPH - Terápia 1. Progestagens – antiandrogen effect • Level of HT, negative feedback mech. > decrease the T level, the LH level is not change • In combination with GnRH analogues • Newer agents >< side effects • Inhibited spermatogenesis, asthenozoospermia, teratozoospermia o Medroxyprogesterone acetate (3 mg/kg, sc inj. 1x (every 5 months)) asymptomatic during 4-6 weeks, for 10 months o Megestrol acetate (0,5mg/kg/day) for 2 month > It reduces prostate size during 1-2 months

2. Oestrogens – HPG axis suppression > Decreased T level • DES • Side effects o Squamous cell metaplasia o Inhibited spermatogenezis o Bone marrow suppression • Thrombocytopenia, leukopenia, aplastic anaemia BPH - Terápia

3. 5α reduktáz inhibitor - T DHT • Competitive – Finastreride o Decreased DHT conc., increased T level in the serum and prostate o 0,1-0,5 mg/kg po 24h, for 16 weeks o 1 mg/dog/day, for 3-21 weeks o Diameter ↓20% , volume ↓43% - 16 weeks treatment o Spermiogenesis, motility, morphology of sperm, libidó, T level > fertility does not change o Continuous dosing is needed o without treatment, the prostate is recovered within 2 months BPH - Terápia o 4. Steroid receptor inhibitors –T receptor inhibitor • Osaterone acetate o Decreased DHT effect in the prostate o Direct reducing effect on DHT/androgen nuclear receptor expression in the prostate o does not affect the testes and LH producing cells o T decreases slightly > marginal antigonadotrophic effect

3 - 7,5 kg YPOZANE® 1,875 mg; 1x1, 7 napig 7,5 - 15 kg YPOZANE® 3,75 mg; 1x1, 7 napig 15 - 30 kg YPOZANE® 7,5 mg; 1x1, 7 napig 30 - 60 kg YPOZANE® 15 mg; 1x1, 7 napig BPH - Terápia o 4. 4. Steroid receptor inhibitors –T receptor inhibitor • Osaterone acetate o Decreased DHT effect in the prostate o Direct reducing effect on DHT/androgen nuclear receptor expression in the prostate o does not affect the testes and LH producing cells o T decreases slightly > marginal antigonadotrophic effect

• 60-80% reduction in size during the first week • 7 days treatment > 5-month effect • Spermatogenesis is not significantly affected • the ratio of morphological abnormalities is temporarily increasing • The amount of prostate fluid decreases 2-4 weeks after the start of treatment • Overall, the fertility is maintained • There is no significant side effect - mild hair loss, lethargy, appetite increase in 1-3. week BPH – Therapy- with preserving fertility

Prevention / suppression of androgenic effect / synthesis

Surgical castration Conservative treatment

- 70% reduction in size is already from 7-14. - !!! Prostate neoplasia, - cysts, severe day symptoms, extreme enlargement - 6-12 weeks (4 months) complete involutio - !!! Testicular tumor > E > metaplasia Chemical castration o Deslorelin o Progestagens o Oestrogens o TypeII 5α reductase inhibitors – Finasteride o Steroid receptor inhibitors – Osaterone acetate o (Tamoxifen – antioestogens) Prostate metaplasia • Normal: single-layered cuboidal cell layer > folded concentrically into several cell layers toward the middle of the acinus • Squamous cell metaplasia > epithelial cell degeneration induced by increased estrogenic activity • Sertolis cell tumor > E • It is predisposed to o ascending infections > prostatitis o Cyst formation Prostata metaplázia • Normal: single-layered cuboidal cell layer > folded concentrically into several cell layers toward the middle of the acinus • Squamous cell metaplasia > epithelial cell degeneration induced by increased estrogenic activity • Sertolis cell tumor > E • It is predisposed to o ascending infections > prostatitis o Cyst formation Prostatitis • Defensive mechanisms of prostate and prostatic urethra: o flushing action from unobstructed flow of urine, urethral peristalsis, the urethral high-pressure zone, composition of prostatic fluid (pH, zinc content), surface characteristics of the urethral mucosa, local IgA production • Causes o Disorders that increase bacterial numbers in the prostatic urethra (e.g., bacterial cystitis, urethral calculi, neoplasia) o compromise local immunity, or alter the architecture of the prostate (e.g., squamous metaplasia, hyperplasia) • Age independent, mostly active, intact dogs • The role of androgenic effect is likely to be present in pathogenesis, especially with estrogen • Septic form is a prevalent condition in dogs <> aseptic form mostly seen in humans • Colonized by bacteria that asced up the urethra or hematogenous spread • Mostly a concurrent urinary tract infection

Acut - Preputial discharge – bloody, purulent - Systemic symptoms (48%) - anorexia, fever, depression - GI (37%) abdominal pain, tenesmus,obstipatio, diarrhea - LUT (26%) – dysuria, hematura, pyuria - painful, edematous testicle, epididymis - predisposition factors: BHP, cysts, metaplasia, neoplasia, cystitis - bacterial isolate is E.coli (Streptococcus, Staphylococcus, Klebsiella, Proteus, Mycoplasma, Pseudomonas) Prostatitis • Defensive mechanisms of prostate and prostatic urethra: o flushing action from unobstructed flow of urine, urethral peristalsis, the urethral high-pressure zone, composition of prostatic fluid (pH, zinc content), surface characteristics of the urethral mucosa, local IgA production • Causes o Disorders that increase bacterial numbers in the prostatic urethra (e.g., bacterial cystitis, urethral calculi, neoplasia) o compromise local immunity, or alter the architecture of the prostate (e.g., squamous metaplasia, hyperplasia) • Age independent, mostly active, intact dogs • The role of androgenic effect is likely to be present in pathogenesis, especially with estrogen • Septic form is a prevalent condition in dogs <> aseptic form mostly seen in humans • Colonized by bacteria that asced up the urethra or hematogenous spread • Mostly a concurrent urinary tract infection

Chronic - more common - It is only revealed by sperm testing - incidental findings - infertility, recurrent UTI, preputial discharge - Palpatio - , not painful, not bigger Prostatitis

Bacteriological analysis

• In the case of (c)overt cystitis urine bacteria analysis (by cystocentesis) appears to be correlated with bacteria isolated in the prostatic gland • By contrast, in the absence of suggestive signs of cystitis, bacteriological examination of urine provides no information on the infectious status of the gland • (Semen collection) • Prostatic fluid collected from a prostatic massage is often contaminated by bacteria from the urethra, the isolated bacteria are often not specific from the prostatic parenchyma, and results are not reliable • Prostatitis without signs of cystitis, prostatic tissue culture from an ultrasound guided biopsy is the most reliable diagnostic tool and can therefore be considered as the ‘gold standard’ Prostatitis - Therapy

Combination bph+prostatitis Castratio/finasterid + AB

• Based on resistance and pharmacokinetics • Double lipid membrane > lipid-soluble • Prostatic fluid pH 6,4 > basic antibiotics

Fluoroquinolones Potential sulfonamides Phenicols Prostatitis - Therapy

Fluoroquinolones • 2. generation – Enrofloxacin, Marbofloxacin • wide spectrum, especially G- • Enterobacteriaceae • Mycoplasma spp. • Chlamidia spp. • Proteus spp. • Pseudomonas spp. – rather the Marbofloxacin • 2. generation + (G+) Staphylococcus spp. + anaerob – 4. generation – Pradofloxacin

• Enrofloxacin 10-20 mg/ttkg, 1(-2)x • Marbofloxacin 2-4 (6) mg/ttkg, 1x • Pradofloxacin 3-5 mg/ttkg, 1x

Fluoroquinolones Potential sulfonamides Phenicols Prostatitis - Therapy

Potential sulfonamides • Szulfadiazin + trimetoprim (Norodine inj.) • Szulfametoxazol + trimetoprim (Sumetrolim)

Fluoroquinolones Potential 15-30 mg/ttkg, 2x sulfonamides Phenicols Crystalluria!!! Local irritation Allergia – Dobermann AIHA Prostatitis - Therapy

Phenicols • Chloramphenicol, Florphenicol

• wide spectrum, bacteriostatic effect • E.coli?, Pseudomonas aeruginosa? • only - fluorocinolone resistance

• 30mg/ttkg 2x (im, sc, po)

Fluoroquinolones Potential sulfonamides Phenicols Prostatitis - Therapy

Acut > injured blood-prostate

Acut -Chronic> prolonged treatment - 4-6 weeks

Fluoroquinolones Potential sulfonamides Fenikolok Prostatic cysts

Retention cysts Paraprostatic cysts • Concomitant with BPH or metaplasia • Craniolateral, caudal • Microscopic > macroscopic • The remains of the Müllerian tube • Cysts are found in approximately 15% of dogs over 7 years • can be large and single, or more commonly multiple and small • 42% has evidence of bacterial infection • Size determination by US > 1 cm > regression by antiandrogenic treatment

Drainage, omentalisatio Excision

Richard A.S. White

Prostatic abcessation

• Complication of an infected cyst, or severe prostatitis - merging area • Septic state, severe systemic signs

Lévy X. et al. 2014

Richard A.S. White Prostatic neoplasia

• Similarities - Differences > Model • Human prostate carcinoma – peripheral zone >< Canine PC periurethral zone > zona ductularis epithelium > involvement the prostate and urethra! • Starting point: – acinar/ductal epithelium, urothelium of prostatic urethra (transitional cell carcinoma) • Fibrosarcoma, leiomyosarcoma, hemangiosarcoma, lymphoma • Often contained in foci - BPH, cysts, inflammation • Invasive, penetrates the capsule • Metastasis - 51.3%- lymphonodes, 50% lungs, 22.4% bone – 80% spine, mainly osteoblastic or mixed

LeRoy, B.E. and Northrup N. (2009) - The Veterinary Journal 180 149–162 Prostatic neoplasia

• Uncommon, 5-7% of prostate disorders • Prevalence range from 0,2 to 0,6%, under-diagnosed o Early stage – no markers o Late stage – spine-, bone metastasis –like primer tumor • Malignant, agressive, very poor prognosis • ~ 10 years of age • In a neoplastic prostate BHP-related lesions also appear but there is no histopathological relationship between the two entities> BPH is not a predisposing factor !!!

LeRoy, B.E. and Northrup N. (2009) - The Veterinary Journal 180 149–162 Prostatic neoplasia Effects of the castration • 2.38x risc in castrated dogs (Bell et al. 1991) • Increased rick after castration (odds ratio 3.86-4,34) (Bryan et al. 2007; Teske et al. 2002; Sorenmo et al. 2003) • PC cells - AR expression not typical!!!!!!!!!!!!!!! • Castration > decrease the size of non-neoplastic prostate but has no effect on the progression of neoplastic processes

Neutered 2,8x (4x) – early castration • Androgens - protective effect - antiproliferative effect on ductal-, transitional epithel • Androgen independent tumor > accommodation – intraprostatic activation of adrenal hormons, other groth factors • Eg. Endothelin – stimulate cell proliferation • Castration > increased expression of endothelin receptors !!! • Castration induces the stromal remodeling > favors the development of tumors Actin+ smooth muscle : vimentin+ mesenchimal cells • Has no effects on metastasis formation Intact - well differentiated PCA, Castrated - anaplastic, urethralis, non-androgen dependent tumors (prepubertal gonadectomy) Initiation – Progression Decreased SOD activity – oxigen radicals Prostatic neoplasia

Symptoms o Stranguria, dysuria, hematuria (66%), pyuria (62%) o Constipatio - , tenesmus / diarrhoea o Ataxia, pain and paresis of the hindlimbs– nerve compression and vertebral metastasis (L7-S1) o Concurrent prostatitis o Anorexia, weight loss, cahexia o Dyspnoe (lungs metastasis) o Pathological fractures - osteoblastic / -clastic process o PU/PD, hyperthermia Prostatic neoplasia

• Rectal palpation: immobile, is strongly bound to the periosteum of the pelvis • X-ray> calcificatio, lungs-, bones metastasis • US > focal or diffuse hyperechogenicity, enitás, kalcifikálódó területek • disintegrating structure of parenchyma and integrity of capsule • transabdom. us guided biopsy , fna – but ttc!!!! <> poor prognosis

• Average survival - weeks-months (76% mortality, within 10 days of diagnosis) Prostatic neoplasia – Therapy

o Human – rutin PSA screening > early diagnosis, more local/systemic treatment options (radical prostatectomy, radiation therapy, anti-androgen treatment, chemotherapy) o Canine – agressive, late diagnosis, metastasis

o Surgical therapy totalprostatectomy (TP) – mean survival time <50 day sub-total intra-capsular prostatectomy (SIP; cytoreduction) - mean survival time < 220 palliative therapy(cystostomy tube/ urethral stenting)

o Chemotherapy o Photodynamic therapy (PDT) NSAIDs – multifactorial effects • (COX)-2 inhibition o Radiation therapy - 94.1% COX-1 expresszió (healthy and tumor cells), - 88.2% COX-2 expresszió (only tumor cells) o Additional therapy • Inhibition of angiogenesis NSAID > maen survival time 6.9 month >< without treatment

Selenium supplementation - reduces DNA fragmentation and increases apoptosis of epithelial cells in the prostate in elderly dogs> protective antiploriferous effect Take home message