Neuroendocrine circuitry and endometriosis: progesterone derivative dampens corticotropin-releasing hormone-induced inflammation by peritoneal cells in vitro

Clinical symptoms of endometriosis, such as pain and infertility, can be described as persistent stressors. Such continuous exposure to stress may severely affect the equilibrium and bidirectional communication of the endocrine and immune system, hereby further aggravating the progression of endometriosis. In the present study, we aimed to tease apart mediators that are involved in the stress response as well as in the progression of endometriosis. Women undergoing diagnostic laparoscopy due to infertility were recruited (n = 69). Within this cohort, early stage of endometriosis were diagnosed in n = 30 and advanced stage of endometriosis in n = 8. Levels of progesterone in serum were determined. Frequency of progesterone receptor (PR) expression on CD56+ and CD8+ peritoneal lymphocytes was analysed by flow cytometry. The production of tumour necrosis factor (TNF) and interleukin (IL)-10 by peritoneal leukocytes upon stimulation with the potent stress mediator corticotropin-releasing hormone (CRH) and the progesterone derivative dydrogesterone, or both, were evaluated. Furthermore, the production of progesterone-induced blocking factor (PIBF) by peritoneal leukocytes and the expression of PR in endometriotic tissue were investigated. Levels of progesterone in serum were decreased in women with endometriosis and inversely correlated to pain scores. Furthermore, an increased frequency of CD56+PR+ and CD8+PR+ peritoneal lymphocytes was present in advanced endometriosis. The TNF/IL-10 ratio, reflecting cytokine secretion by peritoneal cells, was higher in cells derived from endometriosis patients and could be further heightened by CRH stimulation, whereas stimulation with dydrogesterone abrogated the CRH-mediated inflammation. Finally, the expression of PIBF by peritoneal leukocytes was increased in endometriosis. Low levels of progesterone in the follicular phase could be responsible for the progression of endometriosis and related pain. Peripheral CRH, increasing upon high psychological stress, might contribute to the peritoneal inflammation present in endometriosis. The therapeutic application of progesterone derivatives, CRH blocking agents as well as improvement of stress coping may disrupt the vicious circle between the chronic peritoneal inflammation and high perception of psychological stress in endometriosis. Similar content being viewed by others

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We are indebted to the support of the physicians and operation room staff at the DRK Klinikum Westend; without their enthusiasm and continuous support, it would have been impossible to perform the present study. The authors are grateful for the technical support provided by Evelin Hagen, Petra Moschansky and Petra Busse. We also wish to thank Thomas Keil for assistance with statistical analyses. This work was made possible by research grants from the Charité to PCA. This study was integrated in ‘EMBIC’, a Network of Excellence co-financed by the European Commission throughout the FP6 framework programme ‘Life Science, Genomics and Biotechnology for Health’. NT is supported by the German Merit Foundation and a recipient of a Charité stipend. SMB is supported by the Habilitation Program of the Charité. Conflict of interest The authors declare that they have no conflicting interests related to this study. Author information Authors and Affiliations Corresponding author Additional information Friederike Siedentopf and Petra C. Arck jointly supervised this work. Rights and permissions About this article Cite this article Tariverdian, N., Rücke, M., Szekeres-Bartho, J. et al. Neuroendocrine circuitry and endometriosis: progesterone derivative dampens corticotropin-releasing hormone-induced inflammation by peritoneal cells in vitro. J Mol Med 88, 267–278 (2010). https://doi.org/10.1007/s00109-009-0559-8 Received: Revised: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s00109-009-0559-8