Abstract
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 17β-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.
Highlights
The prostate is susceptible to disease, with ~90% of men developing histological benign prostatic hyperplasia (BPH) by the age of 80 [1], ~11.6% of all men developing prostate cancer (PCa) during their lifetime [2], and up to 16% developing chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) [3]
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 estrogen receptor beta (ESR2)) in leukocytes isolated from blood and in somatic cells isolated from ejaculates
The seminal plasma E2 concentrations were analyzed in patients and controls with regard to the chronic prostatitis symptom index (CPSI), an evaluation system for the severity of CP/CPPS which comprises the subscores for urinary tract symptoms, pain and quality of life
Summary
The prostate is susceptible to disease, with ~90% of men developing histological benign prostatic hyperplasia (BPH) by the age of 80 [1], ~11.6% of all men developing prostate cancer (PCa) during their lifetime [2], and up to 16% developing chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) [3]. Classification as inflammatory (IIIa: leukocytes) or non-inflammatory (IIIb: no leukocytes) is based on upon the presence or absence of leukocytes in expressed prostatic secretions or post prostatic massage urine [5]. This classification does not have implications for differential treatment [6], nor does the presence of leukocytes in prostatic secretions correlate with severity of symptoms [7]. The high prevalence and morbidity of CP/CPPS, as well as the possible link to PCa and/or BPH upon aging, stresses the need for a deeper understanding of the underlying mechanisms
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