Early Detection of Bilateral Testicular Metastases From Prostatic Adenocarcinoma Using 68Ga-PSMA Ligand PET/CT.

We present the case of a 76-year-old man with biochemical relapse after primary therapy for prostate cancer. Ga prostate-specific membrane antigen (PSMA) ligand PET/CT performed for localization of recurrent disease revealed bilateral metastases to the testes. Histopathologic evaluation after bilateral orchiectomy revealed testicular metastases. Metastases to the testes are rare and usually seen in advanced stages. Ga-PSMA ligand PET/CT is a highly sensitive and specific imaging method for the detection of primary and metastatic prostate cancer and has refined diagnostic approaches. This case highlights the potential of PSMA-targeted PET/CT for detection of prostate cancer metastases, even in very unusual localizations.

Exposure of human seminal vesicle tissue to phosphodiesterase (PDE) inhibitors antagonizes the contraction induced by norepinephrine and increases production of cyclic nucleotides.

OBJECTIVES: To investigate further the role of phosphodiesterase (PDE) isoenzymes in the control of human seminal vesicle (SV) smooth muscle contractility, we examined the functional responses of isolated SV tissue to various PDE inhibitors. It has been suggested that the application of inhibitors of the PDE type 5 may facilitate SV smooth muscle relaxation and, subsequently, retard ejaculatory response. METHODS: Using the organ bath technique, strip preparations of human SV were exposed for 5 minutes to 1 µM of the PDE inhibitors milrinone (PDE3 inhibitor), rolipram, Ro 20-1724 (PDE4 inhibitors), and sildenafil (PDE5 inhibitor). Norepinephrine (NE, alpha agonist) was then added (0,1 µM, 1 µM, and 10 µM) and isometric responses were recorded. A contraction-response curve to NE in the absence of PDE inhibitors was also generated. Drug effects on the production of cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) were measured by means of radioimmunometric assays. RESULTS: The contraction induced by NE was effectively antagonized by 1 µM of rolipram (83.3% inhibition), Ro 20-1724 (72.3% inhibition), sildenafil (41.6% inhibition), and milrinone (37.5% inhibition). The inhibition of force generation was paralleled by a 1.6-fold to 2.8-fold increase in tissue cyclic AMP (induced by milrinone, rolipram, Ro 20-1724), and a 12-fold rise in cyclic GMP (induced by sildenafil). CONCLUSION: The findings demonstrate that PDE inhibitors can counteract the contraction of human SV mediated by alpha-adrenergic receptors and enhance levels of cyclic nucleotides. This might be of importance with regard to the identification of new options for the pharmacological treatment of premature ejaculation.

Characterization of the effects of various drugs likely to affect smooth muscle tension on isolated human seminal vesicle tissue.

OBJECTIVES: To investigate the effects of different classes of drugs on the isometric tension of isolated human seminal vesicle (SV) tissue. The contractility of human SV contributes to the process of seminal emission during ejaculation. Different endogenous compounds, such as serotonin (5-HT), adenosine triphosphate (ATP), and nitric oxide, have been suggested to be involved in the control of contraction and relaxation of human SV smooth muscle. However, only limited data are available regarding the effects of compounds known to affect smooth musculature on SV contractile activity. METHODS: Using the organ bath technique, the effects of increasing concentrations (10 nm-1 microm/10 microm) of norepinephrine (NE), phenylephrine, endothelin 1, ATP, and 5-HT on human SV tissue at basal tension were studied. In another set-up, SV strip preparations were preincubated with prazosin (alpha-adrenergic blocker), nifedipine and verapamil (Ca(2+)-channel blockers), 2-aminoethoxydiphenyl borate [inositol 1,4,5-trisphosphate (IP(3)) antagonist], cromakalim (K(+)-channel opener), or Y-27632 (ROK inhibitor) (1 microm each, for 10 minutes), followed by the application of NE (0.1 microM, 1 microM, and 10 microm). RESULTS: SV smooth muscle was most effectively contracted by NE (mean = 75% of calibrated scale), phenylephrine (mean = 82% of calibrated scale), and endothelin 1 (mean = 70% calibrated scale), whereas only minor responses to ATP (mean = 10.65% calibrated scale) and 5-HT (mean = 6.3% calibrated scale) were observed. The contraction induced by NE was significantly inhibited after pre-exposure of the tissue to prazosin (-92.4%), cromakalim (-83.7%), 2-aminoethoxydiphenyl borate (-43.1%), Y-27632 (-42.8%), and nifedipine (-32.7%). CONCLUSIONS: alpha-adrenoceptor antagonism, activation of potassium channels, and inhibition of Rho-kinase decrease the sympathetic contraction of SV smooth muscle. This might be of significance with regard to the identification of new pharmacologic avenues to affect the male ejaculatory system.

Prostanoid transport by multidrug resistance protein 4 (MRP4/ABCC4) localized in tissues of the human urogenital tract.

PURPOSE: The seminal vesicles are the major source of prostaglandins in seminal fluid. For prostanoid action on cell surfaces they must be released from synthesizing cells. MRP4/ABCC4 (multidrug resistance protein 4 adenosine triphosphate-binding cassette, subfamily C, member 4) is an adenosine triphosphate dependent export pump for organic anions that may mediate prostanoid transport across the plasma membranes. Therefore, we analyzed whether MRP4 is expressed in the seminal vesicles and other tissues of the human urogenital tract, whether MRP4 and prostanoid synthesizing enzymes are co-expressed in the same cell type and whether MRP4 functions as a prostanoid export pump. MATERIALS AND METHODS: The expression and localization of MRP4 and prostanoid synthesizing enzymes were investigated in several tissues of the male human urogenital tract by immunoblot and immunofluorescence analyses. Prostanoid transport was measured into inside-out membrane vesicles from cells expressing recombinant human MRP4. RESULTS: MRP4 and prostanoid synthesizing enzymes were co-expressed in the epithelial cells of human seminal vesicles. Moreover, MRP4 was localized in the plasma membrane of epithelial cells of the ureter, in the basolateral membrane of glandular epithelial cells of the prostate, and in smooth muscle cells of the bladder and corpus cavernosum. Transport studies established MRP4 as an efflux pump for prostaglandin E2 (Michaelis constant [Km] 3.5 muM), thromboxane B2 (Km 9.9 muM) and prostaglandin F2alpha (Km 12.6 muM). CONCLUSIONS: The co-expression of prostanoid synthesizing enzymes and MRP4 in epithelial cells of the human seminal vesicles and the function of MRP4 as a prostanoid efflux pump indicate that MRP4 mediates prostanoid transport from these cells, which are the main prostanoid synthesizing cells in the male urogenital tract.

Immunolocalization of multidrug resistance protein 5 in the human genitourinary system.

PURPOSE: The intracellular messenger cyclic guanosine monophosphate (cGMP) has an important role in regulating smooth muscle tone. An increase in intracellular cGMP levels is a prerequisite for penile erection. Inhibition of cGMP degradation by cGMP specific phosphodiesterase 5 has been used for treating erectile dysfunction. In addition to degradation by phosphodiesterase, cGMP is exported from cells by multidrug resistance protein 5 (MRP5), also called ABCC5, which we recently identified as an adenosine triphosphate dependent export pump for cGMP. MRP5 is potently inhibited by substances known as phosphodiesterase inhibitors, including sildenafil and trequinsin. Therefore, we analyzed whether MRP5 is expressed in tissues of the human genitourinary system and whether MRP5 and phosphodiesterase 5 proteins are localized in the same cell types. MATERIALS AND METHODS: Localization of MRP5 and phosphodiesterase 5 was analyzed by immunofluorescence microscopy in cryosections of various tissues of the human genitourinary system. RESULTS: MRP5 and phosphodiesterase 5 were co-expressed in smooth muscle cells of the corpus cavernosum, ureter, urethra and bladder. In addition, MRP5 and phosphodiesterase 5 were localized in epithelial cells of the mucosa in the ureter and urethra, and in blood vessels of the lamina propria. CONCLUSIONS: The co-expression of MRP5 and phosphodiesterase 5 in smooth muscle cells of the genitourinary system indicates 2 distinct pathways for cGMP removal. Thus, MRP5 inhibition represents a new approach for enhancing cGMP levels in smooth muscle cells and developing drugs for erectile dysfunction.

Sacral electrical neuromodulation as an alternative treatment option for lower urinary tract dysfunction.

Temporary electrical stimulation using anal or vaginal electrodes and an external pulse generator has been a treatment modality for urinary urge incontinence for nearly three decades. In 1981 Tanagho and Schmidt introduced chronic electrical stimulation of the sacral spinal nerves using a permanently implanted sacral foramen electrode and a battery powered pulse generator for treatment of different kinds of lower urinary tract dysfunction, refractory to conservative treatment. At our department chronic unilateral electrical stimulation of the S3 sacral spinal nerve has been used for treatment of vesi-courethral dysfunction in 43 patients with a mean postoperative follow up of 43,6 months. Lasting symptomatic improvement by more than 50 % could be achieved in 13 of 18 patients with motor urge incontinence (72,2 %) and in 18 of the 21 patients with urinary retention (85,7 %). Implants offer a sustained therapeutic effect to treatment responders, which is not achieved by temporary neuromodulation. Chronic neuromodulation should be predominantly considered in patients with urinary retention. Furthermore in patients with motor urge incontinence, refusing temporary techniques or in those requiring too much effort to achieve a sustained clinical effect. Despite high initial costs chronic sacral neuromodulation is an economically reasonable treatment option in the long run, when comparing it to the more invasive remaining therapeutic alternatives.