Jordan Dimitrakov

Adrenocortical Hormone Abnormalities in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome

OBJECTIVES To identify adrenocortical hormone abnormalities as indicators of endocrine dysfunction in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS We simultaneously measured the serum concentrations of 12 steroids in patients with CP/CPPS and controls, using isotope dilution liquid chromatography, followed by atmospheric pressure photospray ionization and tandem mass spectrometry. RESULTS We evaluated 27 patients with CP/CPPS and 29 age-matched asymptomatic healthy controls. In the mineralocorticoid pathway, progesterone was significantly greater, and the corticosterone and aldosterone concentrations were significantly lower, in the patients with CP/CPPS than in the controls. In the glucocorticoid pathway, 11-deoxycortisol was significantly lower and the cortisol concentrations were not different between the patients and controls. In the sex steroid pathway, the androstenedione and testosterone concentrations were significantly greater in those with CP/CPPS than in the controls. The estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate concentrations were not different between the patients and controls. The National Institutes of Health-Chronic Prostatitis Symptom Index total and pain domain scores correlated positively with the 17-hydroxyprogesterone and aldosterone (P <0.001) and negatively with the cortisol (P <0.001) concentrations. CONCLUSIONS Our results suggest reduced activity of CYP21A2 (P450c21), the enzyme that converts progesterone to corticosterone and 17-hydroxyprogesterone to 11-deoxycortisol. Furthermore, these results provide insights into the biologic basis of CP/CPPS. Follow-up studies should explore the possibility that patients with CP/CPPS meet the diagnostic criteria for nonclassic congenital adrenal hyperplasia and whether the hormonal findings improve or worsen in parallel with symptom severity.

p53 mediates interstitial cystitis antiproliferative factor (APF)-induced growth inhibition of human urothelial cells

Antiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis, a urinary bladder disorder of unknown etiology that is characterized by chronic pelvic pain. The present study was directed toward uncovering a pathway through which APF signals. Treatment of human urothelial cells with native APF resulted in growth inhibition accompanied by blockade of cell cycle transit and increased p53. Reduced expression of p53 by RNA interference diminished, while ectopic expression of p53 mimicked, the effects of APF. These are the first findings implicating the network of p53 target genes in urothelial defects associated with interstitial cystitis.

New treatments for chronic prostatitis/chronic pelvic pain syndrome

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition among men of a wide age range, with detrimental effects on quality of life. The etiology, pathogenesis, and optimal treatment of CP/CPPS remain unknown, although progress has been made in these domains in recent years. A wide variety of pharmacologic and nonpharmacologic therapies have been studied in clinical trials, but most have shown limited efficacy in symptom alleviation. CP/CPPS is increasingly viewed as a condition that involves variable degrees of neuropathic pain. Medications such as gabapentin, pregabalin, memantine, and tricyclic antidepressants are often used in other neuropathic pain conditions and, therefore, are considered potential treatments for CP/CPPS. Few studies of these agents in patients with CP/CPPS have been reported, but future clinical trials should help to determine their utility and to characterize the pathogenetic mechanisms of pain in CP/CPPS. Combining treatment trials with biomarker, genomic, and imaging studies, in addition to epidemiologic and symptom-based assessments, will maximize the ability to probe disease etiology and pathogenesis, as well as identify effective treatment.

Genetics and Phenotyping of Urological Chronic Pelvic Pain Syndrome

PURPOSE Interstitial cystitis/painful bladder syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively renamed urological chronic pelvic pain syndromes, are a group of medically unexplained physical symptoms. Diagnosis depends on excluding all possible causes of pain and treatment targets symptoms alone. An emerging body of research implicates systemic factors in the pathogenesis of urological chronic pelvic pain syndromes including abnormal sympathetic nervous system and hypothalamic-pituitary-adrenal axis activity. Several new lines of evidence also suggest a genetic component to disease pathogenesis. Despite ongoing efforts, neither effective treatments nor mechanistic understanding of the pathogenesis of urological chronic pelvic pain syndromes exists. MATERIALS AND METHODS We performed a survey of the available literature on urological chronic pelvic pain syndromes. We reviewed recent research implicating genetic mechanisms in the development of urological chronic pelvic pain syndromes to find a systematic approach of rigorous phenotyping on which to base further investigation of these chronic pain conditions. RESULTS Three studies revealed identifying genetic risk factors for disease. In addition, increasing lines of evidence of familial clustering and twin studies suggested a genetic basis for disease. CONCLUSIONS Given the success of genome-wide association studies in quantifying genetic risk in several polygenic diseases, we suggest a similar genome-wide approach to the study of urological chronic pelvic pain syndromes. As genome-wide association studies depend on carefully defined patient populations, we provide an outline for a thorough and multidisciplinary characterization of patient phenotypes. Although urological chronic pelvic pain syndromes continue to mystify clinicians and researchers alike, we believe the powerful new methods of unbiased interrogation of the whole genome based on systematically grouped patients possess enormous potential for progress in treating and understanding this disease.

A case of familial clustering of interstitial cystitis and chronic pelvic pain syndrome

A case of familial clustering of interstitial cystitis (IC) and chronic pelvic pain syndrome (CPPS), a symptom complex similar to IC that occurs in men, is reported. The proband was a 28-year-old woman with a 6-month history of severe frequency, urgency, and genital pain. After cystoscopy with hydrodistention and biopsy, a diagnosis of IC was made. IC was also diagnosed in the patients mother and in two of her brothers, previously considered to have CPPS (category IIIB CPPS). A third brother was asymptomatic. This case highlights the importance of genetic factors in the onset of symptoms and natural history of IC and CPPS.

A candidate serum biomarker for bladder pain syndrome/interstitial cystitis.

Reliable diagnostic markers for Bladder Pain Syndrome/Interstitial Cystitis (IC) currently are not available. This study evaluated the feasibility of diagnosing IC in humans and domestic cats from the spectra of dried serum films (DSFs) using infrared microspectroscopy. Spectra were obtained from films from 29 humans and 34 domestic cats to create classification models using Soft Independent Modeling by Class Analogy (SIMCA). Ultrafiltration of serum improved discrimination capability. The classification models for both species successfully classified spectra based on condition (healthy/sick), and a different set of masked spectra correctly predicted the condition of 100% of the subjects. Classification required information from the 1500-1800 cm(-1) spectral region to discriminate between subjects with IC, other disorders, and healthy subjects. Analysis of cat samples using liquid chromatography-mass spectroscopy revealed differences in the concentration of tryptophan and its metabolites between healthy and affected cats. These results demonstrate the potential utility of infrared microspectroscopy to diagnose IC in both humans and cats.

Recent developments in diagnosis and therapy of the prostatitis syndromes.

Chronic pelvic pain syndromes, including prostatitis, remain a difficult clinical entity in terms of diagnosis and treatment to both urologists and patients. This review attempts to highlight the most recent developments and advances in the field of chronic pelvic pain syndromes in terms of prevalence, aetiology, pathogenesis, diagnosis, and current approaches to treatment.<

Pathologic Features of Necrotizing Adenoviral Prostatitis in an AIDS Patient

Adenovirus has been implicated as a cause of opportunistic infections in immunocompromised patients, frequently with multiorgan involvement and a fatal outcome. We describe a case of necrotizing adenoviral prostatitis in a 35-year-old man with terminal AIDS and generalized adenoviral infection. The histopathologic findings of intraacinar necrotizing inflammation, prominent viral nuclear inclusions in residual epithelium, and mild T-lymphocyte and macrophageal inflammatory reaction were observed in the prostate. The presence of adenovirus was confirmed by electron microscopy and immunohistochemistry. Squamous metaplasia was present in the surrounding acini. This case of adenoviral prostatitis appears to be the first report of its kind in medical literature and demonstrates another aspect of the diversity of organ manifestations seen in this infection. This lesion should be included in the differential diagnosis of necrotizing prostatic diseases.

A Road Map to Biomarker Discovery and Validation in Urological Chronic Pelvic Pain Syndrome

Biomarkers and surrogate end points are important tools in the diagnostic and therapeutic armamentarium. By definition a biomarker is a biological characteristic that is measured and evaluated objectively as an indicator of normal biological or pathogenic processes (a diagnostic biomarker), or a pharmacological response to therapeutic intervention (a therapeutic biomarker).1 Thus, any patient parameter that can be measured, for example, mRNA expression profiles, proteomic signatures, protein or lipid levels, imaging methods or electrical signals, may serve as a biomarker. The best biomarkers are accurate, relatively noninvasive and easy to perform tests that can be done at the bedside or in the outpatient setting. In contrast, a surrogate end point marker is the rare biomarker that can substitute (or be a surrogate) for a clinical end point such as survival, stroke, fracture or cancer recurrence.1 CD4 counts are typically used as surrogate end point markers in the treatment of patients with HIV. Hewitt et al recently described 11 steps in the development and validation of urinary, serum and tissue biomarkers.2 Two articles in this issue of The Journal provide a road map to biomarker discovery and validation in chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS) and interstitial cystitis/painful bladder syndrome (IC/PBS). Expanding on their previous findings in a well characterized patient cohort, Desireddi et al (page 000) reported on 2 candidate diagnostic biomarkers for CP/CPPS, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). ROC analysis incorporating expressed prostatic secretion (EPS) MCP-1 levels greater than 704 pg/ml and MIP-1α levels greater than 146 pg/ml correctly distinguished patients with CP/CPPS from controls with an accuracy of 90%. In addition, MIP-1α levels strongly correlated with the pain domain subscore of the National Institutes of Health-Chronic Prostatitis Symptom Index (p=0.0007). On the other hand Erickson et al (page 000) found a positive association between urinary interleukin (IL)-8 levels and bladder mast cell counts, but did not observe a robust association among urinary IL-6, cyclic guanosine monophosphate, heparin-binding epidermal growth factor-like growth factor, epidermal growth factor, antiproliferative factor and bladder biopsy findings in patients with or without ulcer. As noted by Hewitt et al the road to biomarker discovery starts with understanding and defining the disease.2 However, the symptoms of IC/PBS and CP/CPPS significantly overlap with other common conditions, and are not associated with any pathognomonic changes. In this respect the main issue in diagnosing CP/CPPS and IC/PBS appears to be the fact that researchers have traditionally attempted to define those conditions as “categorical” entitites, that is, as states that can be qualitatively separated from the state of being “well”. However, it is well-known by practicing clinicians that CP/CPPS and IC/PBS might be better conceptualized as “dimensional” conditions. Similar to the situation in neuroscience, dimensional or quantitative traits are considered to be continuous with the “normal” state and at the gene level are consistent with the polygenic mode of inheritance. In this respect the articles by Desireddi and Erickson et al provide the guiding signs on the road map for CP/CPPS and IC/PBS biomarker discovery. MCP-1 and MIP-1α levels in EPS and urinary IL-8 can be used as potential therapeutic biomarkers to select a potential, well characterized patient population for targeted therapeutic intervention. In addition, they can provide good therapeutic biomarker based end points in future clinical trials on CP/CPPS and IC/PBS. The implications of these 2 studies actually go well beyond the clinical application of the biomarkers. Mechanistically Desireddi et al implicated the prostate in the pathogenesis of CP/CPPS symptoms, and Erickson et al describe an association of IL-8 and mast cells in bladder biopsies. It is a well-known fact in clinical practice that while patients often present with end organ (bladder or prostate) disease, a significant number of them also have systemic symptoms, eg fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, etc. In this respect the biomarkers described in the 2 articles can also be used to define a population that can perhaps benefit from end organ interventions, eg intraprostatic injections or bladder instillation. Several recent lines of evidence suggest that CP/CPPS and IC/PBS result from different environmental triggers in a genetically susceptible individual (see figure).3–5 Emerging evidence from twin and family based studies of CP/CPPS and IC/PBS suggests that what we now consider a single disorder might actually result from the interaction of a large number of common genetic variants, with no variant proving necessary or sufficient for the condition to develop. Alternatively, similar to the situation in depression and anxiety, CP/CPPS and IC/PBS might actually result from diverse individual mutations and, thus, represent a large family of rare Mendelian diseases with a similar pathophysiology, as has been shown to be the case with retinitis pigmentosa.6 A third and more recent hypothesis for the pathogenesis of IC/PBS and CP/CPPS is that they might result from new germline mutations that act against certain genetic backgrounds as suggested for some cases of autism and schizophrenia.7 The value of examining those possibilities is that defining a genetic biomarker for IC/PBS and CP/CPPS can provide important insights into the validation of other protein based biomarker assays, as well as provide the mechanistic basis for therapeutic clinical trials. Figure Significance of urinary and EPS biomarkers in context of CPPS mechanisms. CCL, cysteine-cysteine ligand. GAG, glycosaminoglycan. Asterisk indicates Erickson et al. Dagger indicates Desireddi et al. In this respect IC/PBS and CP/CPPS are best conceptualized as a spectrum of clinical phenomena in a genetically susceptible individual. An environmental trigger provides the “second hit,” and sets the stage for an abnormal and inadequately controlled inflammatory response with subsequent inflammatory mediator release as shown in the 2 studies (see figure). Subsequent changes in bladder and prostatic tissue chemical milieu result in downstream molecular and cellular events which eventually culminate in the symptoms of CP/CPPS and IC/PBS. Future clinical studies, ideally using high-throughput genomic and proteomic approaches, should define the exact molecular and cellular events that are involved in those clinical phenomena. Such studies should provide information on hundreds and thousands of genes and proteins that mediate the link between the observed cytokine and chemokine levels, and the clinical phenomena of pain and voiding symptoms that are characteristic of CP/CPPS and IC/PBS.

Das Prostatitissyndrom Ejakulatveränderungen und Auswirkungen auf die Fertilität

ZusammenfassungEntzündungen und Infektionen des männlichen Genitaltrakts stellen einen wichtigen und potentiell therapierbaren Faktor männlicher Subfertilität dar. Voraussetzung einer exakten Bewertung von Ejakulatveränderungen ist eine standardisierte Diagnostik. Dies gilt in besonderem Maße für die verschiedenen Formen des Prostatitissyndroms. Verschiedene entzündungs- und infektionsbedingte Veränderungen des Ejakulats wurden beim Prostatitissyndrom gefunden und sollen die Ejakulatqualität mindern.Neben den Auswirkungen von Leukozyto- und Bakteriospermie werden heute insbesondere Entzündungsmediatoren wie Zytokine oder reaktive Sauerstoffspezies als relevante Pathomechanismen diskutiert. Zunehmend wird versucht, diese Parameter in die Diagnostik zu integrieren. Klinische Studien zur Ejakulatqualität bei den verschiedenen Formen des Prostatitissyndroms sind uneinheitlich. Als therapeutische Option ist bisher nur die antimikrobielle Therapie ausreichend beschrieben. Entscheidend für die Zukunft wird die Integration funktioneller und molekularer Parameter für die Definition einer Interaktion zwischen urogenitaler Entzündung und männlicher Fertilität sein.AbstractInflammation and infections of the male reproductive tract represent an important factor in male infertility that is potentially responsive to successful therapy. A standardized diagnostic procedure is a prerequisite for the exact evaluation of alterations of ejaculate specimens, especially in cases of the different forms of the prostatitis syndrome. Several alterations in ejaculate due to inflammation and infection have been identified that have a negative impact on the quality of sperm. Besides the influence of leuko- and bacteriospermia, the effect of inflammatory mediators, such as cytokines and reactive oxygen species (ROS), are being discussed as relevant pathomechanisms.These parameters just recently were incorporated into the conventional range of diagnostic criteria. Clinical studies that investigate the quality of ejaculate in the different forms of the prostatitis syndrome yielded contradictory results. Only antimicrobial therapy has been sufficiently described as a therapeutic option. In the future, it will be decisive to include novel functional and molecular parameters to define an interaction of urogenital infection and male infertility.