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

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 (<i>n</i><b><i>=</i></b> 50; median age 39.8, range 23-65) and age-matched controls (<i>n</i><b><i>=</i></b> 61; median age 36.8, range 20-69), considering biochemical parameters of blood and ejaculates, and epigenetic regulation of the estrogen receptor genes (<i>ESR1</i> and <i>ESR2</i>) 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 <i>ESR1</i> and <i>ESR2</i> 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 <i>ESR1</i> and <i>ESR2,</i> 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.