Serum and seminal markers in the diagnosis of disorders of the genital tract of the dog: a mini-review

Serum and seminal biologic substances that are produced either by normal or abnormal tissues of the organism and that can be used to diagnose pathological conditions are usually referred as markers. The aim of this article is to briefly review the most relevant clinical features of the main genital markers in the male dog: alkaline phosphatase (AP), carnitine and canine prostate-specific arginine esterase (CPSE). Carnitine and AP are markers for the presence of epididymal fluid in the ejaculate and their measurement in azoospermic dogs has been used as an indicator of tubular patency of the ductal network. Although AP is not present in high concentrations in the testis, this does not preclude the possibility that testicular cells might secrete some AP. If this were true, AP could also reflect, at least in some degree, germ cell function in this species. Prostate-specific arginine esterase, the major secretory product of the canine prostate, is a known marker of gland secretion in the dog. Tumor markers frequently used in human medicine, such as prostatic acid phosphatase and prostate-specific antigen, are is still controversial in the diagnosis of prostatic carcinoma of the dog. Although further research is necessary to define the exact role of CPSE, it seems to be a promising diagnostic tool in nonneoplasic canine prostatic disorders. Future studies should also address the quantitative relationship among serum and prostatic androgen levels, prostatic androgen-dependent problems and how these are affected by anti-androgen treatment. The aim of this article is to briefly review the most relevant clinical features of three main genital markers of the male dog.     

The effect of Tookad-mediated photodynamic ablation of the prostate gland on adjacent tissues--in vivo study in a canine model.

Photodynamic therapy (PDT) mediated with vascular acting photosensitizer Tookad (Pd-bacteriopheophorbide) was investigated as an alternative modality for treating prostate cancer. Photodynamic effects on the prostate gland and its adjacent tissues were evaluated in a canine model. Interstitial prostate PDT was performed by irradiating individual lobes with a cylindrical diffuser fiber at various drug/light doses. The sensitivity of the adjacent tissues to Tookad PDT was determined by directly irradiating the surface of the bladder, colon, abdominal muscle and pelvic plexus with a microlens fiber at various drug/light doses. The prostate and adjacent tissues were harvested one-week after the treatment and subjected to histopathological examination. PDT-induced prostate lesions were characterized by marked hemorrhagic necrosis. The bladder, colon, abdominal muscle and pelvic plexus appeared to be sensitive to PDT although the Tookad PDT-induced responses in these tissues were minimal compared to that of the prostate gland at the same dose levels. Nevertheless, the protection of the adjacent tissues should be taken into consideration during the total prostate ablation process due to their sensitivity to PDT. The sensitivity of the prostatic urethra is worth further investigation. Direct intraurethral irradiation might provide an ideal means to determine the sensitivity of the prostatic urethra and might lead to transurethral PDT protocols for the management of benign prostatic hyperplasia (BHP).     

CYR61, a cellular proliferation marker in dogs with prostatic disease

The life expectancy of dogs is increasing and is associated with a greater frequency of age-related disease, including that of the prostate gland. A marker of cell proliferation, CYR61, may be detected in a number of conditions in humans, including hyperplasia and neoplasia. The objective of the present study was to investigate the degree of CYR61 expression in a number of different prostate diseases in dogs in order to understand the potential of this marker for diagnosis of prostatic disease. Immunohistochemistry with a CYR61 antibody was performed on prostatic tissue from 22 dogs with different diseases. Intense stromal staining was observed in cases of prostatic dysplasia and benign prostate hyperplasia. In contrast, CYR61 staining was very intense in alveolar epithelial cells in cases of epithelial benign prostate hyperplasia and one case of adenocarcinoma. An obvious CYR61 staining pattern was absent in cases of prostatitis. In conclusion, CYR61 may be a useful marker of cell proliferation in a number of prostatic pathologies, although further studies of normal tissue are warranted.     

Comparison of the alpha-adrenoceptor characteristics in human and canine prostate

Alpha adrenoceptors, mediating contraction, have been shown to be present in strips of hypertrophic prostate surgically removed from patients with benign prostatic hypertrophy (BPH), providing a rational explanation for the demonstrated effectiveness of alpha antagonists in the symptomatic treatment of this disease. Inasmuch as the dog develops spontaneous and hormonally induced prostatic enlargement, studies were performed to compare the adrenoceptor characteristics of canine and human prostate to determine whether the dog represents a useful model to search for more effective alpha-adrenolytic therapy for human BPH. Norepinephrine produces contraction in isolated strips of canine prostate although it is only one-tenth as potent as previously reported in human tissue. In contrast, several selective alpha 1-adrenoceptor agonists are potent contractile agents in canine prostate, but are nearly inactive in the human tissue. This difference may be a consequence of their partial agonist character. The potency of selective alpha-adrenoceptor antagonists in blocking the norepinephrine-induced contractile response in both canine and human tissue is consistent with an action of norepinephrine on the alpha 1 adrenoceptor. The receptor dissociation constants for these antagonists are similar in prostatic tissue from dogs and humans, and the values in canine tissue correlate well with those obtained in the rabbit ear artery, a standard model for vascular alpha 1 adrenoceptors. Hence the dog may represent a useful model for studies of the potential responsiveness of human prostate to adrenergic agents.     

Epithelial Na,K-ATPase expression is down-regulated in canine prostate cancer; a possible consequence of metabolic transformation in the process of prostate malignancy

Background  

An important physiological function of the normal prostate gland is the synthesis and secretion of a citrate rich prostatic fluid. In prostate cancer, citrate production levels are reduced as a result of altered cellular metabolism and bioenergetics. Na, K-ATPase is essential for citrate production since the inward Na⁺ gradients it generates are utilized for the Na⁺ dependent uptake of aspartate, a major substrate for citrate synthesis. The objective of this study was to compare the expression of previously identified Na, K-ATPase isoforms in normal canine prostate, benign prostatic hyperplasia (BPH) and prostatic adenocarcinoma (PCa) using immunohistochemistry in order to determine whether reduced citrate levels in PCa are also accompanied by changes in Na, K-ATPase expression.     

5-alpha-Reductase Inhibitors Prevent the Progression of Benign Prostatic Hyperplasia

Lower urinary tract symptoms (LUTS) associated with clinical benign prostatic hyperplasia (BPH) are a common occurrence in aging men, causing bother and interference with daily activities and affecting disease-specific quality of life. There is increasing evidence to suggest that, in many patients, the signs and symptoms of BPH are progressive. Progression can be measured as continued growth of the prostate gland; worsening of symptoms, bother, or quality of life; deterioration of urinary flow rate; episodes of acute urinary retention (AUR); and need for prostate-related surgery. Furthermore, it has become clear that the risk of disease progression increases with age as well as with increasing prostate volume and serum prostate-specific antigen (PSA) level. The 5-alpha-reductase inhibitor finasteride has been shown not only to improve symptoms, bother, and quality of life but also to prevent progression to AUR and surgery, with a relative risk reduction of over 50%. As the risk for such progression is higher in patients with larger glands or higher serum PSA values at baseline, it is in those patients that finasteride induces an even greater risk reduction, making it a cost-effective treatment choice for patients with LUTS associated with prostatic enlargement.     

经直肠B 超诊断前列腺增生的图像特征及其临床意义

目的:探讨前列腺增生(BPH)经直肠B超检查的图像特征及其对治疗的指导作用。方法:回顾性分析103例经术后病理组织学诊断确诊的BPH患者临床资料,总结其经直肠B超图像特征,并根据B超诊断结果选择适宜治疗方法。结果:经直肠B超检出BHP 98例,2例误诊,3例漏诊,诊断符合率、误诊率、漏诊率分别为95.14%、1.94%、2.91%;B超图像显示BPH病灶呈细小均匀光点,前列腺变圆、增大,内腺以低回声为主,外腺以低回声及中、低混合回声为主;包膜清晰占62.92%;98例确诊为BPH的患者当中,66例行经尿道电切术、16例在B超引导下行无水乙醇注射,16例行开放性手术。结论:直肠B超通过观察回声、内外腺前后径比例、有无包膜、分界情况等准确诊断前列腺增生,同时可通过测量前列腺重量指导临床治疗。     

Tissue interactions and prostatic growth. I. Induction of adult mouse prostatic hyperplasia by fetal urogenital sinus implants

A homologous chimeric prostate was produced by implantation of intact fetal urogenital sinus(es) (UGS) into the ventral prostate gland (VP) of an adult athymic mouse. A 10- to 20-fold overgrowth of the chimeric lobe of ventral prostate gland, as measured by glandular wet weight and by DNA content, was observed 4 to 9 wk following UGS implantation. The overgrowth was prostate-like as indicated by histologic composition and by responses to endogenous androgen, and was composed of both host and donor cells in about equal proportions as shown by glucose phosphate isomerase isozymic profiles. Unlike the canine model for prostatic hyperplasia, the mouse prostatic overgrowth occurred in the complete absence of exogenous sex steroids. The histoarchitecture of the chimeric VP and the isozymic detection of the contribution to the overgrowth by host cells have provided strong evidence that adult prostatic cells have been recruited to respond proliferatively by cellular interactions with fetal UGS. The demonstration of cellular interactions followed by reactivation of the fetal growth potential provides direct experimental evidence in support of McNeal's hypothesis that the reactivation of fetal growth potential may account for the development of human benign prostatic hyperplasia (BPH).     

Immunocytochemical technique for detection of prolactin (PRL) and growth hormone (GH) in hyperplastic and neoplastic lesions of dog prostate and mammary gland.

An immunocytochemical technique was described to test for immunoreactive prolactin (PRL) and growth hormone (GH) in spontaneous and experimentally induced hyperplastic and neoplastic lesions of the prostate and mammary gland. The dog was used as an animal model. The specificity and validity of the immunocytochemical staining procedure and of the antisera to canine PRL and canine GH can be regarded as established for the demonstration of PRL- and GH-dependent staining respectively. In mammary and prostatic tissues, both endogenous PRL and GH as well as intracellular free binding sites (for exogenous PRL and GH) were detected immunocytochemically. The technique presented seems to be an important tool to localize putative target sites for pituitary hormones in hormone-dependent hyperplasia and neoplasia.     

A new dihydrotestosterone-forming index (DHTi)

A new index (DHTi) for the net formation of dihydrotestosterone (DHT) in a specific tissue is presented. This index is based on the main metabolic pathways forming DHT as well as on the main enzymatic activities removing DHT from the tissue. In the rat prostate, the DHTi is different in the various prostatic lobes. The index is highest in the ventral prostatic lobe, intermediate in the dorsal prostate and coagulating gland, and very low or undetectable in the seminal vesicles and the lateral prostatic lobe. With increasing age of the rats, the DHTi decreased. Testosterone treatment to old rats leads to an increased index.     

The female prostate and prostate-specific antigen. Immunohistochemical localization, implications of this prostate marker in women and reasons for using the term "prostate" in the human female

Prostate-specific antigen (PSA) is currently the most frequently used marker for the identification of normal and pathologically altered prostatic tissue in the male and female. Immunohistochemically PSA is expressed in the highly specialized apically-superficial layer of female and male secretory cells of the prostate gland, and as well as in uroepithelial cells at other sites of the urogenital tract of both sexes. Unique active moieties of cells of the female and the male prostate gland and in other parts of the urogenital tract are indicative of secretory and protective function of specialized prostatic and uroepithelial cells with strong immunological properties given by the presence of PSA. In clinical practice, PSA is a valuable marker for the diagnosis and monitoring of diseases of the male and the female prostate, especially carcinoma. In the female, similarly as in the male, the prostate (Skene's gland) is the principal source of PSA. The value of PSA in women increases in the pathological female prostate, e.g., carcinoma. Nevertheless, the total amount of PSA in the female is the sum of normal or pathological female prostate and non-prostatic female tissues production, e.g., of diseased female breast tissue. The expression of an antigen specific for the male prostate, i.e., PSA in female Skene's glands and ducts, and structural and functional parameters and diseases similar to that of the male prostate, have provided convincing evidence of the existence of a prostate in women and definitive preference of the term "prostate" over that of Skene's glands and ducts. The use of the term Skene's glands incorrectly implies that some other structure rather than prostate is involved, promoting the vestigial position of this female organ.     

Prostate epithelial stem cell culture

The prostate gland is the site of the second most common cancer in men in the UK, with 9,280 deaths recorded in 2000. Another common disease of the prostate is benign prostatic hyperplasia and both conditions are believed to arise as a result of changes in the balance between cell proliferation and differentiation. There are three types of prostatic epithelial cell, proliferative basal, secretory luminal, and neuroendocrine. All three are believed to be derived from a common stem cell through differentiation along different pathways but the mechanisms behind these processes is poorly understood. In particular, there has until recently been very little information about prostate stem cell growth and differentiation. This review will discuss ways of distinguishing these prostate cell types using markers, such as keratins. Methods available for the culture of prostate epithelial cells and for the characterisation of stem cells both in monolayer and three-dimensional models are examined. This revised version was published online in July 2006 with corrections to the Cover Date.     

Troubles sexuels après curiethérapie par implants permanents d’I-125 dans le cancer localisé de prostate

Brachytherapy by permanent implants is an alternative to radical prostatectomy or external beam radiotherapy for good prognosis localized prostate cancer. The advantages of this treatment are effective and precise irradiation, limited to the prostate gland with moderate and transient morbidity. Erectile dysfunction, frequent erection after surgery and external beam radiotherapy, is observed in 6% to 61% of cases in the literature after brachytherapy. This wide range is related to differences in terms of follow-up, definition of sexual disorders, and the measuring instruments used. These erectile disorders occur between 9 and 17 months after treatment and appear to be related to vascular radiation lesions of the erectile bodies close to the prostatic apex (urethral bulb and base of the corpora cavernosa). However, the majority of erectile disorders respond favourably to oral treatments such as yohimbine or sildenafil. Among the various curative treatment options for localized prostate cancer, permanent implant brachytherapy is the treatment ensuring the best preservation of erectile function.     

Testosterone effect on immature prostate gland development associated with suppression of transforming growth factor-beta

The aim of this study was to evaluate the effect of testosterone treatment on the pattern of prostate cell proliferation and differentiation and their correlation with the expression of transforming growth factor-beta (TGF-beta). Prostate gland development was compared in intact immature dogs with one-month testosterone-treated immature dogs. Testosterone treatment resulted in a tenfold increase in prostate gland weight compared to untreated dogs, with a typical organization of the gland into a structure similar to that observed in mature dogs. The narrow acini which contain flat basal cells in immature glands were transformed into tubuloacinar structures containing columnar secretory cells and basal cells. The stromal compartments showed an increase in the muscular component as evidenced by the high reactivity to alpha-actin with no remarkable changes in the vimentin expression. In addition, testosterone treatment induced a significant reduction in the proliferation capacity of stromal cells but with no noticeable changes in the proliferation pattern of epithelial cells. These changes in the prostate are associated with a twofold decrease in TGF-beta mRNA expression as assessed by Real-Time PCR. However, the immunolocalization of TGF-beta was shifted slightly from the epithelial cells in untreated animals to the stromal cells of treated animals. Based on these results it appears that testosterone acts to coordinate prostatic cell proliferation and differentiation and direct their organization into a structure resembling that of the mature gland. The testosterone regulation of the prostate gland appears to involve the regulation of TGF-beta gene expression.     

Évolution de la cellule normale à la cellule cancéreuse prostatique hormonodépendante–hormono-indépendante

The prostatic gland is androgen-dependent. The role of androgens in the development, function and pathology of the prostatic gland (benign hypertrophy or cancer) derives from: direct evidence, resulting from experimental models (in vitro–in vivo) or from the biological analysis of normal and pathological human prostatic tissues. These data make it possible to describe the current point of our knowledge concerning the molecular, cellular, and tissular mechanisms involved; indirect data resulting from epidemiologic and clinical studies describing the impact of androgen suppression or supplementation on the prostatic gland. At the experimental level, it is generally allowed that the growth of prostate is controlled by androgens (testosterone and its metabolites). A suitable circulating testosterone level is necessary to maintain the growth, development, differentiation and function of the prostatic gland. Bilateral orchidectomy induces programmed cellular death (apoptosis) and the gland involution; exogenic testosterone administration is then able to induce the prostatic growth up to the normal level. The same applies when an impubescent animal is treated. The response of prostate to exogenic testosterone thus does not produce a growth beyond the normal volume, which is maintained by balance between proliferation and cellular death in the presence of physiological levels of androgens. The study of the mechanisms of regulation of the prostatic growth provides a fundamental justification to the chemical and hormonal treatments used by the urologists in the treatment of prostate benign hypertophy and cancer. Within the framework of the androgenic deficit related to age, a doubt persists about a potentially harmful action of the substitute androgenic treatment on prostate.     

Changes in dihydrotestosterone metabolism and the development of benign prostatic hyperplasia in the aging beagle

Previous studies have demonstrated that the 2-3--fold abnormal elevation in prostatic dihydrotestosterone (DHT) content characteristically associated with canine benign prostatic hyperplasia (BPH) is due to a shift in the overall balance in the complex metabolism of DHT in the gland itself [1, 2]. Since the incidence of canine BPH increases with host age [3], the question arises as to whether the characteristic shift in DHT metabolism is associated with the general process of aging or with the specific development of BPH. To resolve this issue, the activities of prostatic androgen metabolism were quantitatively assayed in prostatic tissue from a large series of age-matched normal and BPH dogs ranging in age from 0.7-9.0 years. These analyses revealed that, regardless of the age of the host, there is a consistent statistical increase in several of the activities which produce DHT (i.e. 5 alpha-reductase, 3 alpha-HSOR oxidase, and 17 beta-HSOR reductase) without a concomitant increase in any of the activities which remove this steroid in BPH as compared to age-matched normal prostatic tissue. These results suggest that in canine BPH tissue the characteristic changes in DHT metabolism which increase the tissue's ability for net formation of DHT are specifically associated with the development of BPH itself and not due simply to the general process of aging per se.     

Inhibition of experimentally induced mouse prostatic hyperplasia by castration or steroid antagonist administration.

Mouse prostatic hyperplasia has been induced experimentally by implanting fetal urogenital sinus tissue into the prostate gland of syngeneic mice. We compared the effects of castration and steroid antagonist administration on the growth of the prostate gland during both the early (15 days) and late (30 days) phases of prostatic enlargement. Castration at the time of induction of prostatic hyperplasia is by far the most effective method of inhibiting prostatic overgrowth. A comparison of castration for 7 days with the short-term (7 days) administration of steroid antagonists showed that during the early phase of prostatic enlargement castration is more effective than antiandrogen, which is more effective than 5 alpha-reductase inhibitors. In the late phase of mouse prostatic enlargement, castration for 7 days is less effective than treatment with either antiandrogen or a 5 alpha-reductase inhibitor. Our data indicate that treatment with a combination of an antiestrogen (keoxifene) with a 5 alpha-reductase inhibitor (in particular, 6-methylene progesterone) is the most effective combination for reducing prostatic overgrowth. The antiestrogen (keoxifene) treatment alone was ineffective in both the early and late phases of prostatic overgrowth.     

Effects of 1,25(OH)2D3, 25OHD3, and EB1089 on cell growth and Vitamin D receptor mRNA and 1alpha-hydroxylase mRNA expression in primary cultures of the canine prostate

The aim of this study was to investigate effects of 1,25(OH)(2)D(3) (calcitriol), 25OHD(3), and EB1089 on cell growth and on Vitamin D receptor (VDR) mRNA and 1alpha-hydroxylase (1alpha-OHase) mRNA expression in normal canine prostatic primary cultures. Canine prostatic epithelial cells were isolated, cultured, and treated with vehicle (ethanol), calcitriol, 25OHD(3), and EB1089 at 10(-9) and 10(-7)M. The VDR was present in epithelial and stromal cells of the canine prostate gland. 1,25(OH)(2)D(3), 25OHD(3), and EB1089 inhibited epithelial cell growth at 10(-7)M compared to vehicle-treated controls [calcitriol (P < 0.01), EB1089 (P < 0.01), and 25OHD(3) (P < 0.05)]. Epithelial cells treated with calcitriol and EB1089 at 10(-7)M had slightly increased VDR mRNA expression (0.2-0.3-fold) at 6 and 12h compared to controls. There was no difference in 1alpha-OHase mRNA expression in epithelial cells treated with these three compounds. 1,25(OH)(2)D(3) and its analogs may be effective antiproliferative agents of epithelial cells in certain types of prostate cancer.     

Age-related changes in the innervation of the prostate gland

The adult prostate gland grows and develops under hormonal control while its physiological functions are controlled by the autonomic nervous system. The prostate gland receives sympathetic input via the hypogastric nerve and parasympathetic input via the pelvic nerve. In addition, the hypogastric and pelvic nerves also provide sensory inputs to the gland. This review provides a summary of the innervation of the adult prostate gland and describes the changes which occur with age and disease. Growth and development of the prostate gland is age dependent as is the occurrence of both benign prostate disease and prostate cancer. In parallel, the activity and influence of both the sympathetic and parasympathetic nervous system changes with age. The influence of the sympathetic nervous system on benign prostatic hyperplasia is well documented and this review considers the possibility of a link between changes in autonomic innervation and prostate cancer progression.