DOI 10.1515/jpem-2013-0384 J Pediatr Endocr Met 2014; 27(3-4): 389–390
Letter to the Editor Raffaella Mormile* and Giorgio Vittori
Endometriosis and migraine: what is there behind the scenes? Keywords: endometriosis; pain; migraine. *Corresponding author: Raffaella Mormile, Division of Pediatrics and Neonatology, Moscati Hospital, Via A. Gramsci, 3, 81031 Aversa, Italy, Phone: +390815001503, Mobile: +393392045468, E-mail: [email protected] Giorgio Vittori: Division of Gynecology, San Carlo di Nancy Hospital, Rome, Italy
Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterus (1, 2). It represents a major personal and public health problem (1). It has been estimated that endometriosis affects 6%–10% of women of reproductive age, up to 50% of women suffering from infertility and 50%–60% of patients and teenage girls with a range of pelvic pain symptoms such as chronic dysmenorrhea, dyspareunia, dyschezia, and dyspareunia (2). Until today, the connection between pain and endometriosis is not well defined (2, 3). It is widely recognized that endometriosis is an inflammatory condition, correlated with altered immune cell function, immune cell numbers, and increased levels of inflammatory cytokines (2). Among the cytokines, interferon (IFN)-γ has been shown to be strongly associated with the onset and progression of endometriosis (2). It has been found that polymorphism of IFN-γ gene is related to different stages of the disease (2). Genetic variants in IFN-γ gene have been associated with interethnic differences in endometriosis susceptibility (4). IFN-γ has been reported to activate mitogen-activated protein kinase (MAPK) pathways (5). MAPK has been connected with many cellular reactions such as apoptosis, proliferation, and inflammation (4). MAPK pathways have been implicated directly in regulating the pathophysiology of endometriosis (5, 6). It has been advised that MAPK signaling pathways may play as pivotal intracellular and extracellular signal transducers in endometriotic cells (6, 7). Abnormal activation of MAPK pathways has been linked to enhanced proliferation and survival of eutopic endometrial cells from patients with endometriosis (6, 7). Increasing evidence has emerged regarding the significant role of MAPK signaling
pathways in the regulation of pain hypersensitivity in different injury conditions, implying their involvement in endometriosis-related pain (8). It has been supported the existence of a comorbid relationship between migraine and endometriosis (2). Migraine is a neurovascular disorder correlated with dysfunction of the cerebral nerves and blood vessels (9). The neuropeptide calcitonin generelated peptide (CGRP) has long been proposed to be a critical player in the pathogenesis of migraine (9). It has been demonstrated that MAPK signaling pathways are involved in up-regulation of CGRP synthesis and release (9, 10). It has been suggested that activation of MAPK pathways may increase CGRP gene expression during migraine (10, 11). Women with endometriosis have been shown to have multiple small unmyelinated sensory C nerve fibers in the functional layer of eutopic endometrium, although patients without endometriosis have not any nerve fibers in the functional layer (2). The unmyelinated nerve fibers in the functional layer of eutopic endometrium have been found to express CGRP, suggesting a role in pelvic pain (2). With respect to the above, we advance the hypothesis that women affected by endometriosis may be at risk of developing migraine. We postulate that IFN-γ gene polymorphism may contribute to susceptibility to migraine and pelvic pain in women with endometriosis by increasing the amount of CGRP through MAPK signaling pathways. We suppose that variants of IFN-γ gene may directly influence the levels of pain severity in endometriosis. Genome-wide searches are needed to identify possible ethnic differences in allelic distribution of IFN-γ to utilize as biomarkers for predicting the risk and range of pain in endometriosis worldwide. Pharmacologic chaperone therapy may provide a focus for the development of novel treatment and prevention strategies for endometriosis and endometriosis-related pain. Elucidating the crosstalk mechanism between IFN-γ and CGRP via MAPK signaling pathways may help to better outline the intricate details surrounding the causes, diagnosis, and treatment of endometriosis. Received September 29, 2013; accepted October 9, 2013; previously published online October 30, 2013
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390 Mormile and Vittori: Endometriosis and migraine: what is there behind the scenes?
References 1. Bhanothu V, Rozati R, Theophilus J. Prevalence and polymorphism in interferon-γ gene (CA) repeats with different stage of endometriosis. Am J Med Biol Res 2013;1:1–5. 2. Yang M-H, Wang P-H, Wang S-J, Sun W-Z, Oyang YJ, et al. Women with endometriosis are more likely to suffer from migraines: a population based study. PLoS One 2012;7:e33941. 3. Al-Jefout M, Dezarnaulds G, Cooper M, Tokushige N, Luscombe GM, et al. Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study. Hum Reprod 2009;24:3019–24. 4. Kim J, Choi Y, Hwang S, Yoon S, Lee GH, et al. Association of the interferon-γ gene (CA)n repeat polymorphism with endometriosis. BJOG 2011;118:1061–6. 5. Matsuzawa T, Kim B-H, Shenoy AR, Kamitani S, Miyake M, et al. IFN-γ elicits macrophage autophagy via the p38 MAPK signaling pathway. J Immunol 2012;15:813–8.
6. Zhou WD, Chen QH, Chen QX. The action of p38MAP kinase and its inhibitors on endometriosis. Yao Xue Xue Bao 2010;45:548–54. 7. Yoshino O, Osuga Y, Hirota Y, Koga K, Hirata T, et al. Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis. Am J Reprod Immunol 2004;52:306–11. 8. Ru-Rong Ji, Gereau RW, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev 2009;60:135–48. 9. Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache 2006;46:S3–8. 10. Durham PI, Russo AF. Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinase and repression by an antimigraine drug in trigeminal ganglia neurons. J Neurosci 2003;23:807–15. 11. Lei L, Yuan X, Wang S, Zhang F, Han Y, et al. Mitogen-activated protein kinase pathways are involved in the upregulation of calcitonin gene-related peptide of rat trigeminal ganglion after organ culture. J Mol Neurosci 2012;48:53–65.
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 7:51 PM
Letter to the Editor Raffaella Mormile* and Giorgio Vittori
Endometriosis and migraine: what is there behind the scenes? Keywords: endometriosis; pain; migraine. *Corresponding author: Raffaella Mormile, Division of Pediatrics and Neonatology, Moscati Hospital, Via A. Gramsci, 3, 81031 Aversa, Italy, Phone: +390815001503, Mobile: +393392045468, E-mail: [email protected] Giorgio Vittori: Division of Gynecology, San Carlo di Nancy Hospital, Rome, Italy
Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterus (1, 2). It represents a major personal and public health problem (1). It has been estimated that endometriosis affects 6%–10% of women of reproductive age, up to 50% of women suffering from infertility and 50%–60% of patients and teenage girls with a range of pelvic pain symptoms such as chronic dysmenorrhea, dyspareunia, dyschezia, and dyspareunia (2). Until today, the connection between pain and endometriosis is not well defined (2, 3). It is widely recognized that endometriosis is an inflammatory condition, correlated with altered immune cell function, immune cell numbers, and increased levels of inflammatory cytokines (2). Among the cytokines, interferon (IFN)-γ has been shown to be strongly associated with the onset and progression of endometriosis (2). It has been found that polymorphism of IFN-γ gene is related to different stages of the disease (2). Genetic variants in IFN-γ gene have been associated with interethnic differences in endometriosis susceptibility (4). IFN-γ has been reported to activate mitogen-activated protein kinase (MAPK) pathways (5). MAPK has been connected with many cellular reactions such as apoptosis, proliferation, and inflammation (4). MAPK pathways have been implicated directly in regulating the pathophysiology of endometriosis (5, 6). It has been advised that MAPK signaling pathways may play as pivotal intracellular and extracellular signal transducers in endometriotic cells (6, 7). Abnormal activation of MAPK pathways has been linked to enhanced proliferation and survival of eutopic endometrial cells from patients with endometriosis (6, 7). Increasing evidence has emerged regarding the significant role of MAPK signaling
pathways in the regulation of pain hypersensitivity in different injury conditions, implying their involvement in endometriosis-related pain (8). It has been supported the existence of a comorbid relationship between migraine and endometriosis (2). Migraine is a neurovascular disorder correlated with dysfunction of the cerebral nerves and blood vessels (9). The neuropeptide calcitonin generelated peptide (CGRP) has long been proposed to be a critical player in the pathogenesis of migraine (9). It has been demonstrated that MAPK signaling pathways are involved in up-regulation of CGRP synthesis and release (9, 10). It has been suggested that activation of MAPK pathways may increase CGRP gene expression during migraine (10, 11). Women with endometriosis have been shown to have multiple small unmyelinated sensory C nerve fibers in the functional layer of eutopic endometrium, although patients without endometriosis have not any nerve fibers in the functional layer (2). The unmyelinated nerve fibers in the functional layer of eutopic endometrium have been found to express CGRP, suggesting a role in pelvic pain (2). With respect to the above, we advance the hypothesis that women affected by endometriosis may be at risk of developing migraine. We postulate that IFN-γ gene polymorphism may contribute to susceptibility to migraine and pelvic pain in women with endometriosis by increasing the amount of CGRP through MAPK signaling pathways. We suppose that variants of IFN-γ gene may directly influence the levels of pain severity in endometriosis. Genome-wide searches are needed to identify possible ethnic differences in allelic distribution of IFN-γ to utilize as biomarkers for predicting the risk and range of pain in endometriosis worldwide. Pharmacologic chaperone therapy may provide a focus for the development of novel treatment and prevention strategies for endometriosis and endometriosis-related pain. Elucidating the crosstalk mechanism between IFN-γ and CGRP via MAPK signaling pathways may help to better outline the intricate details surrounding the causes, diagnosis, and treatment of endometriosis. Received September 29, 2013; accepted October 9, 2013; previously published online October 30, 2013
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 7:51 PM
390 Mormile and Vittori: Endometriosis and migraine: what is there behind the scenes?
References 1. Bhanothu V, Rozati R, Theophilus J. Prevalence and polymorphism in interferon-γ gene (CA) repeats with different stage of endometriosis. Am J Med Biol Res 2013;1:1–5. 2. Yang M-H, Wang P-H, Wang S-J, Sun W-Z, Oyang YJ, et al. Women with endometriosis are more likely to suffer from migraines: a population based study. PLoS One 2012;7:e33941. 3. Al-Jefout M, Dezarnaulds G, Cooper M, Tokushige N, Luscombe GM, et al. Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study. Hum Reprod 2009;24:3019–24. 4. Kim J, Choi Y, Hwang S, Yoon S, Lee GH, et al. Association of the interferon-γ gene (CA)n repeat polymorphism with endometriosis. BJOG 2011;118:1061–6. 5. Matsuzawa T, Kim B-H, Shenoy AR, Kamitani S, Miyake M, et al. IFN-γ elicits macrophage autophagy via the p38 MAPK signaling pathway. J Immunol 2012;15:813–8.
6. Zhou WD, Chen QH, Chen QX. The action of p38MAP kinase and its inhibitors on endometriosis. Yao Xue Xue Bao 2010;45:548–54. 7. Yoshino O, Osuga Y, Hirota Y, Koga K, Hirata T, et al. Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis. Am J Reprod Immunol 2004;52:306–11. 8. Ru-Rong Ji, Gereau RW, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev 2009;60:135–48. 9. Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache 2006;46:S3–8. 10. Durham PI, Russo AF. Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinase and repression by an antimigraine drug in trigeminal ganglia neurons. J Neurosci 2003;23:807–15. 11. Lei L, Yuan X, Wang S, Zhang F, Han Y, et al. Mitogen-activated protein kinase pathways are involved in the upregulation of calcitonin gene-related peptide of rat trigeminal ganglion after organ culture. J Mol Neurosci 2012;48:53–65.
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