Abstract
In the healthy endometrium, progesterone and estrogen signaling coordinate in a tightly regulated, dynamic interplay to drive a normal menstrual cycle and promote an embryo-receptive state to allow implantation during the window of receptivity. It is well-established that progesterone and estrogen act primarily through their cognate receptors to set off cascades of signaling pathways and enact large-scale gene expression programs. In endometriosis, when endometrial tissue grows outside the uterine cavity, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance. This hormone imbalance leads to heightened inflammation and may also increase the pelvic pain of the disease and decrease endometrial receptivity to embryo implantation. This review focuses on the molecular mechanisms governing progesterone and estrogen signaling supporting endometrial function and how they become dysregulated in endometriosis. Understanding how these mechanisms contribute to the pelvic pain and infertility associated with endometriosis will open new avenues of targeted medical therapies to give relief to the millions of women suffering its effects.
Highlights
The endometrium is a complex and dynamic tissue composed of epithelial cells, both luminal and glandular, surrounded by supporting stromal cells, together comprising the innermost layer of the uterus
In addition to its regulation by progesterone receptor (PGR) in uterine stromal cells for decidualization, murine gene knockout experiments have shown that C/EBPβ is an E2 target in both the endometrial epithelium and stroma that is critical for proliferation based on its activity regulating cyclin-dependent kinases in the Gap 2 (G2) to mitotic (M) phase cell cycle transition [45,46]
Transcriptomic analysis indicated a role for ARID1A in repressing cell cycle related genes, and further experiments revealed that ARID1A complexes with PGR, PR-A, to inhibit proliferation through the upregulation of Kruppel-like factor 15 (KLF15) [69] and to maintain an endometrium receptive to implantation
Summary
The endometrium is a complex and dynamic tissue composed of epithelial cells, both luminal and glandular, surrounded by supporting stromal cells, together comprising the innermost layer of the uterus. The progesterone (P4) and estrogen (E2)-responsive signaling pathways integral for early pregnancy success are primarily induced through their cognate nuclear receptors, the progesterone receptor (PGR) and estrogen receptors (ESR1 and ESR2), respectively. These pathways are regulated in an epithelial and stromal compartment-specific manner in the endometrium [3,4,5]. It is clear that functional dysregulation of the ovarian steroid hormones P4 and E2 and their downstream signaling targets plays an important role in the development and maintenance of the disease as well as its effects on the eutopic endometrium, primarily through E2-driven inflammation and P4 resistance [6,7]. This review will cover the known roles of P4 and E2 signaling in maintaining endometrial homeostasis and supporting pregnancy establishment before turning to focus on the mechanisms of the P4 and E2 signaling dysregulation of endometriosis, how this dysregulation impacts the clinical symptoms of endometriosis, and how hormone treatment strategies attempt to correct it
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