Chronic Prostatitis Affects Male Reproductive Health and Is Associated with Systemic and Local Epigenetic Inactivation of C-X-C Motif Chemokine 12 Receptor C-X-C Chemokine Receptor Type 4.

Background/Aims/Objectives: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has detrimental effects on the quality of life including the aspect of sexual dysfunction. The aim of the study was to identify if there was an adverse effect on the male genital compartment and if there are systemic or compartment-specific local signals for epigenetic dysregulation of inflammatory factors in CP/CPPS patients. METHODS: One hundred five NIH IIIb CP/CPPS patients and 41 healthy men were recruited and underwent investigations of urines, semen and blood. Promoter methylation and expression of the chemokine C-X-C motif chemokine 12 and its receptor C-X-C chemokine receptor type 4 (CXCR4) (involved in the recruitment of mast cells) were analyzed in prostate epithelial cell lines and in healthy volunteers' and patients' blood, ejaculate cell pellets, and separated ejaculate fractions (sperm and seminal somatic cells). RESULTS: Independently from age, CP/CPPS NIH IIIb was associated with significant impairment of sperm motility, morphology and semen pH (p < 0.001). Patients older than 33 years showed significantly increased seminal interleukin-8 and serum prostate specific antigen values. In patients, the CXCR4 mRNA-expression was significantly decreased in whole blood and ejaculate cell pellets due to promoter hypermethylation. Analyses on separated fractions of sperm and seminal somatic cells revealed that sperm DNA was unaffected, whereas somatic cell DNA was differentially methylated. CONCLUSIONS: NIH IIIb CP/CPPS has negative effects on surrogate parameters of male fertility and is associated significantly with systemic and local epigenetic inactivation of CXCR4.

Elevated seminal plasma estradiol and epigenetic inactivation of ESR1 and ESR2 is associated with CP/CPPS.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is associated with urinary tract symptoms and hormonal imbalances amongst others. The heterogeneous clinical presentation, unexplored molecular background and lack of prostate biopsies complicate therapy. Here, using liquid biopsies, we performed a comprehensive translational study on men diagnosed with CP/CPPS type III (n= 50; median age 39.8, range 23-65) and age-matched controls (n= 61; median age 36.8, range 20-69), considering biochemical parameters of blood and ejaculates, and epigenetic regulation of the estrogen receptor genes (ESR1 and ESR2) in leukocytes isolated from blood (systemic regulation) and in somatic cells isolated from ejaculates (local regulation). We found elevated 17ß-estradiol (E2) levels in seminal plasma, but not in blood plasma, that was significantly associated with CP/CPPS and impaired urinary tract symptoms. In ejaculated somatic cells of CP/CPPS patients we found that ESR1 and ESR2 were both significantly higher methylated in CpG-promoters and expressionally down-regulated in comparison to controls. Mast cells are reported to contribute to CP/CPPS and are estrogen responsive. Consistent with this, we found that E2 -treatment of human mast cell lines (HMC-1 and LAD2) resulted in altered cytokine and chemokine expression. Interestingly, in HMC-1 cells, possessing epigenetically inactivated ESR1 and ESR2, E2 -treatment led to a reduced transcription of a number of inflammatory genes. Overall, these data suggest that elevated local E2 levels associate with an epigenetic down-regulation of the estrogen receptors and have a prominent role in CP/CPPS. Investigating E2 levels in semen could therefore serve as a promising biomarker to select patients for estrogen targeted therapy.