Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

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.

Keywords: endometriosis; endometrium; estrogen; infertility; progesterone; progesterone resistance.

Figure 1

Schematic diagram illustrating the primary known signaling pathways and transcriptional regulators involved in P4 and E2 governance of endometrial epithelial-stromal crosstalk that are dysregulated in endometriosis. P4 resistance and E2 dominance in endometriosis results in epithelial proliferation and defective decidualization that can compromise endometrial function. Abbreviations: ARID1A, AT-rich interaction domain 1A; BCL6, B cell CLL/lymphoma 6; COUPTFII, chicken ovalbumin upstream promoter-transcription factor II; E2, estrogen; ERK, extracellular signal-regulated kinase; ESR1, estrogen receptor 1; FGF, fibroblast growth factor; FKBP52, FK506 binding protein prolyl isomerase 4; FOXO1, Forhead box O1; GATA2, GATA binding protein 2; HAND2, heart and neural crest derivatives expressed 2; HOXA10, homeobox protein-A10; IHH, Indian hedgehog; MAPK, mitogen-activated protein kinase; P4, progesterone; PGR, progesterone receptor; SIRT1, Sirtuin 1; SOX17, sex determining region Y box 17; WNT4, Wnt family member 4.