Research Papers:

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

Nils Nesheim, Stuart Ellem, Temuujin Dansranjavin, Christina Hagenkötter, Elena Berg, Rupert Schambeck, Hans-Christian Schuppe, Adrian Pilatz, Gail Risbridger, Wolfgang Weidner, Florian Wagenlehner and Undraga Schagdarsurengin _

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Oncotarget. 2018; 9:19623-19639. https://doi.org/10.18632/oncotarget.24714

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Nils Nesheim1,2, Stuart Ellem3,4, Temuujin Dansranjavin1, Christina Hagenkötter1,2, Elena Berg1,2, Rupert Schambeck1,2, Hans-Christian Schuppe1, Adrian Pilatz1, Gail Risbridger3, Wolfgang Weidner1, Florian Wagenlehner1,* and Undraga Schagdarsurengin1,2,*

1Clinic of Urology, Pediatric Urology and Andrology, Justus Liebig University, Giessen, Germany

2Working Group Epigenetics of the Urogenital System, Clinic of Urology, Pediatric Urology and Andrology, Justus Liebig University, Giessen, Germany

3Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia

4Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

*These authors contributed equally

Correspondence to:

Undraga Schagdarsurengin, email: [email protected]

Florian Wagenlehner, email: [email protected]

Keywords: chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); liquid biopsies; estradiol; estrogene receptor; epigenetic inactivation

Received: October 05, 2017     Accepted: February 24, 2018     Published: April 13, 2018


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.

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