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

Article


Nesheim, Nils, Ellem, Stuart, Dansranjavin, Temuujin, Kagenkotter, Christina, Berg, Elena, Schambeck, Rupert, Schuppe, Hans-Christian, Pilatz, Adrian, Risbridger, Gail, Weidner, Wolfgang, Wagenlehner, Florian and Schagdarsurengin, Undraga. 2018. "Elevated seminal plasma estradiol and epigenetic inactivation of ESR1 and ESR2 is associated with CP/CPPS." Oncotarget. 9 (28), pp. 19623-19639. https://doi.org/10.18632/oncotarget.24714
Article Title

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

ERA Journal ID201328
Article CategoryArticle
AuthorsNesheim, Nils (Author), Ellem, Stuart (Author), Dansranjavin, Temuujin (Author), Kagenkotter, Christina (Author), Berg, Elena (Author), Schambeck, Rupert (Author), Schuppe, Hans-Christian (Author), Pilatz, Adrian (Author), Risbridger, Gail (Author), Weidner, Wolfgang (Author), Wagenlehner, Florian (Author) and Schagdarsurengin, Undraga (Author)
Journal TitleOncotarget
Journal Citation9 (28), pp. 19623-19639
Number of Pages17
Year2018
Place of PublicationUnited States
ISSN1949-2553
Digital Object Identifier (DOI)https://doi.org/10.18632/oncotarget.24714
Web Address (URL)https://www.oncotarget.com/article/24714/text/
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.

Keywordschronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); epigenetic inactivation; estradiol; estrogene receptor; liquid biopsies
ANZSRC Field of Research 2020320214. Nephrology and urology
321599. Reproductive medicine not elsewhere classified
Byline AffiliationsJustus Liebig-University Giessen, Germany
Monash University
Institution of OriginUniversity of Southern Queensland
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