MicroRNAs and Progesterone Receptor Signaling in Endometriosis Pathophysiology

Abstract

Endometriosis is a significant disease characterized by infertility and pelvic pain in which endometrial stromal and glandular tissue grow in ectopic locations. Altered responsiveness to progesterone is a contributing factor to endometriosis pathophysiology, but the precise mechanisms are poorly understood. Progesterone resistance influences both the eutopic and ectopic (endometriotic lesion) endometrium. An inability of the eutopic endometrium to properly respond to progesterone is believed to contribute to the infertility associated with the disease, while an altered responsiveness of endometriotic lesion tissue may contribute to the survival of the ectopic tissue and associated symptoms. Women with endometriosis express altered levels of several endometrial progesterone target genes which may be due to the abnormal expression and/or function of progesterone receptors and/or chaperone proteins, as well as inflammation, genetics, and epigenetics. MiRNAs are a class of epigenetic modulators proposed to play a role in endometriosis pathophysiology, including the modulation of progesterone signaling. In this paper, we summarize the role of progesterone receptors and progesterone signaling in endometriosis pathophysiology, review miRNAs, which are over-expressed in endometriosis tissues and fluids, and follow this with a discussion on the potential regulation of key progesterone signaling components by these miRNAs, concluding with suggestions for future research endeavors in this area.

Extracellular Vesicles Secreted by Pre-Hatching Bovine Embryos Produced In Vitro and In Vivo Alter the Expression of IFNtau-Stimulated Genes in Bovine Endometrial Cells

“…However, in an independent experiment conducted by our research group, several miRNAs that are involved in the regulation of the aforementioned genes were detected in EVs released by bovine embryos [ 72 , 81 ]. For instance, miR29 family genes miR-221 and miR143-3p were detected in embryonic EVs and were related to the regulation of PTGS2, AKR1C4, and progesterone receptors including PAQR8 [ 72 , 73 , 88 ]. The modification of expression pattern of genes related to the IFNT pathway suggest its presence or that of other related molecules in the EVs.…”

Downregulation of DROSHA: Could It Affect miRNA Biogenesis in Endometriotic Menstrual Blood Mesenchymal Stem Cells?

“…In light of these reports, we questioned whether deficient DROSHA expression in endometriosis MenSCs could affect the maturation of a set of miRNAs that depend on the canonical and non-canonical (DICER-independent) pathways. DICER-independent processing has already been well described for the miR-451a [ 62 ], which correlates with the endometriotic tissue survival status [ 63 , 64 ]. Thus, to elucidate the impact of our findings, performing a global analysis of miRNAs and functional tests in endometriotic progenitor cells would be interesting.…”

“…This could explain the change in DROSHA , the altered biogenesis of miRNAs, and consequently, genes regulated by them in these cells, which may contribute to the viability, implantation, and proliferation of endometriotic foci in the pelvic cavity. Steroids modulate miRNA expression at the transcriptional level and regulate their biosynthesis [ 64 ]. Exposure of endometrial epithelial cells to estrogen and progesterone combined alters the expression of DROSHA , DGCR8 , XPO5 , and DICER1 [ 65 ].…”

Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms

“…These findings can partly explain the failure of progesterone to rapidly halt endometrial proliferation and induce a differentiated state in endometriosis. Warren et al [ 74 ] reported that the increased expression of miR-29c-3p and miR-126-3p, which appear to promote some of the cellular events conducive to endometriosis lesion survival and progression, may be causative factors in the development, progression, and progesterone resistance of endometriosis. However, the exact mechanisms by which miR expression is altered remain to be explored.…”