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Review
. 2013 Jul-Aug;19(4):406-18.
doi: 10.1093/humupd/dmt010. Epub 2013 Mar 28.

Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis

Fernando M Reis  1 , Felice Petraglia, Robert N Taylor
Affiliations
Review

Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis

Fernando M Reis et al. Hum Reprod Update. 2013 Jul-Aug.

Abstract

Background: The recruitment of immune cells by chemokines and the regulation of endometrial cell apoptosis are critical aspects of endometriosis biology. Here, we review the local (paracrine) and systemic hormone (endocrine) modulation of these two specific, but highly related phenomena.

Methods: We searched Pubmed for items published in English between September 1991 and September 2011 and selected the studies evaluating the effects of hormones on chemokines or apoptosis in normal human endometrium and endometriosis.

Results: Estradiol has proinflammatory and antiapoptotic effects in endometrial cells, and these effects appear to be exacerbated in women with endometriosis. In these women, physiological estradiol concentrations are able to induce an enhanced inflammatory response mediated by local chemokine production and to reinforce mechanisms of cell survival mediated by extracellular signal-regulated kinases and Bcl-2. The main effect of progestogens is to inhibit interleukin-8 and other chemokines in stromal cells from both eutopic and ectopic endometrium. Progesterone is also effective in inducing apoptosis in endometrial and endometriotic cells through the inhibition of Bcl-2 and nuclear factor-κB.

Conclusions: Estrogens and progestogens modulate chemotaxis and apoptosis in human endometrium and endometriotic cells and tissues. These endocrine and paracrine pathways are perturbed in women with endometriosis, contributing to inflammatory responses, abnormal tissue remodeling, therapeutic refractoriness and disease persistence. Ultimately, they promote adhesion formation and the clinical symptoms of pelvic pain and infertility. A more detailed understanding of the molecular mechanisms involved will offer new opportunities for novel pharmacological strategies to diagnose and treat endometriosis.

Keywords: apoptosis; chemokines; endometriosis; endometrium; hormones.

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Figures

Figure 1
Figure 1
Chemokines identified in endometriosis. The upper box shows members of the CC family and the lower box shows members of the CXC family and one member of the CX3C family. Each receptor is represented by a different color, which is reproduced in its corresponding, high-affinity ligands and target cells. The chemokines are identified by their old names or abbreviations (first column) and by the current nomenclature (second column). MCP, monocyte chemoattractant protein; MIP, monocyte inflammatory protein; RANTES, regulated on activation, normal T cell expressed and secreted; SLC, secondary lymphoid tissue chemokine; GRO, growth-related oncogene; ENA, epithelial neutrophil-activating peptide; IL, interleukin; MIG, monokine induced by gamma interferon; IP, interferon-inducible protein; ITAC, Interferon-inducible T-cell alpha chemoattractant; SDF, stromal cell-derived factor; BCA, B-cell-attracting chemokine.
Figure 2
Figure 2
CC chemokines: endocrine and paracrine regulation in human endometrium and endometriosis. ↑ stimulation; ⊥ inhibition. The bold, pink signs indicate abnormal responses observed in endometriosis. Note that leukocytes are attracted by chemokines released by the endometrial or endometriotic cell in response to estradiol and/or proinflammatory cytokines, such as TNF-α. In endometriotic cells, sex steroids may abnormally stimulate, rather than inhibit MCP-1. NF, nuclear factor; CCR, CC chemokine receptor; MIP, monocyte inflammatory protein.
Figure 3
Figure 3
CXC chemokines: endocrine and paracrine regulation in endometrial cells (stromal, epithelial and endothelial) and mesothelial cells. ↑ stimulation; ⊥ inhibition. The bold, pink signs indicate abnormal responses observed in endometriosis. Observe that both stromal cells and peritoneal (mesothelial) cells release IL-8 after estradiol stimulation, which recruits leukocytes and enhances the local inflammatory response in endometriosis. TNF, tumor necrosis factor; CXCR, CXC chemokine receptor.
Figure 4
Figure 4
Apoptosis regulation by estradiol in human endometrium and endometriosis. ↑ stimulation; ⊥ inhibition. The bold, pink signs indicate abnormal responses observed in endometriosis. These include an enhanced activation (phosphorylation) of protein kinases (ERK1/2, Akt), increased levels of NF-κB and the cleavage of SRC-1, all converging to inhibit apoptosis. Bcl, B-cell leukemia/lymphoma; p-ERK, phosphorylated extracellular signal-regulated kinase; p-Akt, phosphorylated serine/threonine protein kinase B; MMP, matrix metalloproteinase.
Figure 5
Figure 5
Apoptosis regulation by progestogens in human endometrium and endometriosis. ↑ stimulation; ⊥ inhibition. The bold, pink signs indicate abnormal responses observed in endometriosis. FABP, fatty acid-binding protein; CRABP, cellular retinoic acid-binding protein; PR, progesterone receptor.
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References

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