A narrative review about the intricate crosstalk among endometrium, adipose tissue, and neurons in endometriosis. The multifaceted role of leptin

A narrative review about the intricate crosstalk among endometrium, adipose tissue, and neurons in endometriosis. The multifaceted role of leptin Corresponding Author Delminda Neves Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Correspondence Delminda Neves, Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal. Email: [email protected] Search for more papers by this authorAna Catarina Neto Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorMaria Salazar Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorAna Sofia Fernandes Department of Obstetrics and Gynecology, Faculty of Medicine of the University of Porto, Porto, Portugal/Centro Hospitalar Universitário S. João, Porto, Portugal Search for more papers by this authorMargarida Martinho Department of Obstetrics and Gynecology, Faculty of Medicine of the University of Porto, Porto, Portugal/Centro Hospitalar Universitário S. João, Porto, Portugal Search for more papers by this authorAna Charrua Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal RISE-HEALTH@FMUP, Porto, Portugal Search for more papers by this authorAdriana Raquel Rodrigues Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorAlexandra Maria Gouveia Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorHenrique Almeida Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorCorresponding Author Delminda Neves Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Correspondence Delminda Neves, Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal. Email: [email protected] Search for more papers by this authorAna Catarina Neto Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorMaria Salazar Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorAna Sofia Fernandes Department of Obstetrics and Gynecology, Faculty of Medicine of the University of Porto, Porto, Portugal/Centro Hospitalar Universitário S. João, Porto, Portugal Search for more papers by this authorMargarida Martinho Department of Obstetrics and Gynecology, Faculty of Medicine of the University of Porto, Porto, Portugal/Centro Hospitalar Universitário S. João, Porto, Portugal Search for more papers by this authorAna Charrua Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal RISE-HEALTH@FMUP, Porto, Portugal Search for more papers by this authorAdriana Raquel Rodrigues Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorAlexandra Maria Gouveia Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorHenrique Almeida Department of Biomedicine - Experimental Biology Unit, Faculty of Medicine of the University of Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal Search for more papers by this authorSummary Endometriosis is a highly prevalent gynecological disease characterized by the presence of endometrium-like tissue outside the uterus, whose etiopathology is far from being elucidated. The most frequent complains of patients are pelvic pain and infertility. Increasing evidence supports the systemic impact of endometriosis suggesting that an intricate crosstalk among distinct organs underlies the development of the disease. In this setting, endometriosis patients present an increased risk for developing other diseases, such as cancer, cardiovascular pathologies, and autoimmune diseases, and manifest neurologic disturbances, including neuropathic hyperalgesia. Whilst the ovary-secreted estrogen dependency of ectopic endometrium growth is well established, we conjecture that adipose tissue-secreted molecules also intervene in endometriosis development and pain manifestation. In fact, women with endometriosis present a peculiar pattern of adipokine secretion that ensues the disease onset. Unexpectedly, the levels of adipose tissue-secreted molecules in those women present similarities with those found in patients with obesity, despite the recognized association of low body mass index with endometriosis. Taking this evidence into consideration, we hypothesize that endometriosis patients present a dysfunctional adipose tissue, which is associated with enhanced metabolism and unregulated browning that not only intervene in the control of body weight but also in peculiar pain processing pathways. CONFLICT OF INTEREST STATEMENT The authors declared no conflict of interest. REFERENCES - 1Nnoaham KE, Hummelshoj L, Webster P, et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011; 96(2): 366-373.e8. doi:10.1016/j.fertnstert.2011.05.090 - 2Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020; 382(13): 1244-1256. doi:10.1056/NEJMra1810764 - 3 Classification of endometriosis. The American fertility society. Fertil Steril. 1979; 32(6): 633-634. - 4Revised american society for reproductive medicine classification of endometriosis: 1996. Fertil Steril. 1997; 67(5): 817-821. doi:10.1016/s0015-0282(97)81391-x - 5Adamson GD, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril. 2010; 94(5): 1609-1615. doi:10.1016/j.fertnstert.2009.09.035 - 6Lee SY, Koo YJ, Lee DH. Classification of endometriosis. Yeungnam Univ J Med. 2021; 38(1): 10-18. doi:10.12701/yujm.2020.00444 - 7Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984; 64(2): 151-154. - 8Hapangama DK, Drury J, Da Silva L, et al. Abnormally located SSEA1+/SOX9+ endometrial epithelial cells with a basalis-like phenotype in the eutopic functionalis layer may play a role in the pathogenesis of endometriosis. Hum Reprod. 2019; 34(1): 56-68. doi:10.1093/humrep/dey336 - 9Jerman LF, Hey-Cunningham AJ. The role of the lymphatic system in endometriosis: a comprehensive review of the literature. Biol Reprod. 2015; 92(3): 64. doi:10.1095/biolreprod.114.124313 - 10Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012; 98(3): 511-519. doi:10.1016/j.fertnstert.2012.06.029 - 11Rei C, Williams T, Feloney M. Endometriosis in a man as a rare source of abdominal pain: a case report and review of the literature. Case Rep Obstet Gynecol. 2018; 2018:2083121. doi:10.1155/2018/2083121 - 12Alderman MH 3rd, Yoder N, Taylor HS. The systemic effects of endometriosis. Semin Reprod Med. 2017; 35(3): 263-270. doi:10.1055/s-0037-1603582 - 13Brosens I, Puttemans P, Benagiano G. Endometriosis: a life cycle approach? Am J Obstet Gynecol. 2013; 209(4): 307-316. doi:10.1016/j.ajog.2013.03.009 - 14Kalaitzopoulos DR, Mitsopoulou A, Iliopoulou SM, Daniilidis A, Samartzis EP, Economopoulos KP. Association between endometriosis and gynecological cancers: a critical review of the literature. Arch Gynecol Obstet. 2020; 301(2): 355-367. doi:10.1007/s00404-020-05445-1 - 15Taskin O, Rikhraj K, Tan J, Sedlak T, Rowe TC, Bedaiwy MA. Link between endometriosis, atherosclerotic cardiovascular disease, and the health of women midlife. J Minim Invasive Gynecol. 2019; 26(5): 781-784. doi:10.1016/j.jmig.2019.02.022 - 16Asante A, Taylor RN. Endometriosis: the role of neuroangiogenesis. Annu Rev Physiol. 2011; 73(1): 163-182. doi:10.1146/annurev-physiol-012110-142158 - 17Zeng C, Xu JN, Zhou Y, Yang HX, Zhou YF, Xue Q. C-Jun NH2-terminal kinase and p38 inhibition suppresses prostaglandin E2-stimulated aromatase and estrogen receptor levels in human endometriosis. J Clin Endocrinol Metab. 2015; 100(11): E1404-E1414. doi:10.1210/jc.2015-2031 - 18De Leon FD, Vijayakumar R, Brown M, Rao CV, Yussman MA, Schultz G. Peritoneal fluid volume, estrogen, progesterone, prostaglandin, and epidermal growth factor concentrations in patients with and without endometriosis. Obstet Gynecol. 1986; 68(2): 189-194. - 19Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. The Lancet. 2021; 397(10276): 839-852. doi:10.1016/S0140-6736(21)00389-5 - 20Hogg C, Panir K, Dhami P, et al. Macrophages inhibit and enhance endometriosis depending on their origin. Proc Natl Acad Sci U S A. 2021; 118(6):e2013776118. doi:10.1073/pnas.2013776118 - 21Forster R, Sarginson A, Velichkova A, et al. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis. FASEB J. 2019; 33(10): 11210-11222. doi:10.1096/fj.201900797R - 22Ferrero S, Anserini P, Remorgida V, Ragni N. Body mass index in endometriosis. Eur J Obstet Gynecol Reprod Biol. 2005; 121(1): 94-98. doi:10.1016/j.ejogrb.2004.11.019 - 23Gavin KM, Sullivan TM, Kohrt WM, Majka SM, Klemm DJ. Ovarian hormones regulate the production of adipocytes from bone marrow-derived cells. Front Endocrinol (Lausanne). 2018; 9: 276. doi:10.3389/fendo.2018.00276 - 24Luo F, Huang WY, Guo Y, Ruan GY, Peng R, Li XP. 17β-estradiol lowers triglycerides in adipocytes via estrogen receptor α and it may be attenuated by inflammation. Lipids Health Dis. 2017; 16(1): 182. doi:10.1186/s12944-017-0575-6 - 25Hong J, Yi KW. What is the link between endometriosis and adiposity? Obstet Gynecol Sci. 2022; 65(3): 227-233. doi:10.5468/ogs.21343 - 26Pantelis A, Machairiotis N, Lapatsanis DP. The formidable yet unresolved interplay between endometriosis and obesity. ScientificWorldJournal. 2021; 2021:6653677. doi:10.1155/2021/6653677 - 27Rahmioglu N, Macgregor S, Drong AW, et al. Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci. Hum Mol Genet. 2015; 24(4): 1185-1199. doi:10.1093/hmg/ddu516 - 28Zolbin MM, Mamillapalli R, Nematian SE, Goetz TG, Taylor HS. Adipocyte alterations in endometriosis: reduced numbers of stem cells and microRNA induced alterations in adipocyte metabolic gene expression. Reprod Biol Endocrinol. 2019; 17(1):36. doi:10.1186/s12958-019-0480-0 - 29Rodrigues AR, Salazar MJ, Gouveia AM. Obesity and adipose tissue remodeling. In: Recent Advances in Obesity Research Understanding Obesity: From Its Causes to Impact on Life. Bentham Science Publisher; 2020: 55-80. doi:10.2174/9789811442636120010006 10.2174/9789811442636120010006Google Scholar - 30Salazar MJ, Rodrigues AR, Sousa M, et al. Characterization of α-MSH browning effect in diverse mice white adipose tissue depots. J Mol Endocrinol. 2021; 66(1): 23-34. doi:10.1530/jme-20-0002 - 31Abobeleira JP, Neto AC, Mauersberger J, et al. Evidence of browning and inflammation features in visceral adipose tissue of women with endometriosis. Arch Med Res. 2024; 55(7):103064. doi:10.1016/j.arcmed.2024.103064 - 32Abdullahi A, Jeschke MG. White adipose tissue browning: a double-edged sword. Trends Endocrinol Metab. 2016; 27(8): 542-552. doi:10.1016/j.tem.2016.06.006 - 33Heard ME, Melnyk SB, Simmen FA, Yang Y, Pabona JM, Simmen RC. High-fat diet promotion of endometriosis in an immunocompetent mouse model is associated with altered peripheral and ectopic lesion redox and inflammatory status. Endocrinology. 2016; 157(7): 2870-2882. doi:10.1210/en.2016-1092 - 34Yin B, Liu X, Guo S-W. Caloric restriction dramatically stalls lesion growth in mice with induced endometriosis. Reprod Sci. 2018; 25(7): 1024-1036. doi:10.1177/1933719118756755 - 35Zhu Y, Liu W, Qi Z. Adipose tissue browning and thermogenesis under physiologically energetic challenges: a remodelled thermogenic system. J Physiol. 2024; 602(1): 23-48. doi:10.1113/jp285269 - 36Barquissau V, Léger B, Beuzelin D, et al. Caloric restriction and diet-induced weight loss do not induce browning of human subcutaneous white adipose tissue in women and men with obesity. Cell Rep. 2018; 22(4): 1079-1089. doi:10.1016/j.celrep.2017.12.102 - 37Hipólito-Reis M, Neto AC, Neves D. Impact of curcumin, quercetin, or resveratrol on the pathophysiology of endometriosis: a systematic review. Phytother Res. 2022; 36(6): 2416-2433. doi:10.1002/ptr.7464 - 38Lind L, Strand R, Kullberg J, Ahlström H. Cardiovascular-related proteins and the abdominal visceral to subcutaneous adipose tissue ratio. Nutr Metab Cardiovasc Dis. 2021; 31(2): 532-539. doi:10.1016/j.numecd.2020.09.010 - 39Backonja U, Hediger ML, Chen Z, et al. Beyond body mass index: using anthropometric measures and body composition indicators to assess odds of an endometriosis diagnosis. J Womens Health (Larchmt). 2017; 26(9): 941-950. doi:10.1089/jwh.2016.6128 - 40Byun J, Peterson CM, Backonja U, et al. Adiposity and endometriosis severity and typology. J Minim Invasive Gynecol. 2020; 27(7): 1516-1523. doi:10.1016/j.jmig.2020.01.002 - 41Matarese G, Alviggi C, Sanna V, et al. Increased leptin levels in serum and peritoneal fluid of patients with pelvic endometriosis. J Clin Endocrinol Metab. 2000; 85(7): 2483-2487. doi:10.1210/jcem.85.7.6703 - 42Shah DK, Correia KF, Harris HR, Missmer SA. Plasma adipokines and endometriosis risk: a prospective nested case-control investigation from the nurses' health study II. Hum Reprod. 2013; 28(2): 315-321. doi:10.1093/humrep/des411 - 43Viganò P, Somigliana E, Matrone R, et al. Serum leptin concentrations in endometriosis. J Clin Endocrinol Metab. 2002; 87(3): 1085-1087. doi:10.1210/jcem.87.3.8286 - 44Gungor T, Kanat-Pektas M, Karayalcin R, Mollamahmutoglu L. Peritoneal fluid and serum leptin concentrations in women with primary infertility. Arch Gynecol Obstet. 2009; 279(3): 361-364. doi:10.1007/s00404-008-0744-y - 45Mahutte NG, Matalliotakis IM, Goumenou AG, Vassiliadis S, Koumantakis GE, Arici A. Inverse correlation between peritoneal fluid leptin concentrations and the extent of endometriosis. Hum Reprod. 2003; 18(6): 1205-1209. doi:10.1093/humrep/deg233 - 46Wertel I, Gogacz M, Polak G, Jakowicki J, Kotarski J. Leptin is not involved in the pathophysiology of endometriosis-related infertility. Eur J Obstet Gynecol Reprod Biol. 2005; 119(2): 206-209. doi:10.1016/j.ejogrb.2004.08.004 - 47Kitawaki J, Koshiba H, Ishihara H, Kusuki I, Tsukamoto K, Honjo H. Expression of leptin receptor in human endometrium and fluctuation during the menstrual cycle. J Clin Endocrinol Metab. 2000; 85(5): 1946-1950. doi:10.1210/jcem.85.5.6567 - 48Zendron C, Gonçalves HF, Cavalcante FS, et al. Increased expression of the leptin receptor in human ovaries affected by endometrioma and detection of high levels of leptin in the ovarian endometriomal fluid. J Ovarian Res. 2014; 7(1): 2. doi:10.1186/1757-2215-7-2 - 49Wu MH, Chuang PC, Chen HM, Lin CC, Tsai SJ. Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation. Mol Hum Reprod. 2002; 8(5): 456-464. doi:10.1093/molehr/8.5.456 - 50Wu MH, Chen KF, Lin SC, Lgu CW, Tsai SJ. Aberrant expression of leptin in human endometriotic stromal cells is induced by elevated levels of hypoxia inducible factor-1alpha. Am J Pathol. 2007; 170(2): 590-598. doi:10.2353/ajpath.2007.060477 - 51Ahn JH, Choi YS, Choi JH. Leptin promotes human endometriotic cell migration and invasion by up-regulating MMP-2 through the JAK2/STAT3 signaling pathway. Mol Hum Reprod. 2015; 21(10): 792-802. doi:10.1093/molehr/gav039 - 52Oh HK, Choi YS, Yang YI, Kim JH, Leung PC, Choi JH. Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. Mol Hum Reprod. 2013; 19(3): 160-168. doi:10.1093/molehr/gas055 - 53Milewski Ł, Barcz E, Dziunycz P, et al. Association of leptin with inflammatory cytokines and lymphocyte subpopulations in peritoneal fluid of patients with endometriosis. J Reprod Immunol. 2008; 79(1): 111-117. doi:10.1016/j.jri.2008.08.007 - 54Wu MH, Huang MF, Chang FM, Tsai SJ. Leptin on peritoneal macrophages of patients with endometriosis. Am J Reprod Immunol. 2010; 63(3): 214-221. doi:10.1111/j.1600-0897.2009.00779.x - 55Styer AK, Sullivan BT, Puder M, et al. Ablation of leptin signaling disrupts the establishment, development, and maintenance of endometriosis-like lesions in a murine model. Endocrinology. 2008; 149(2): 506-514. doi:10.1210/en.2007-1225 - 56Choi YS, Oh HK, Choi JH. Expression of adiponectin, leptin, and their receptors in ovarian endometrioma. Fertil Steril. 2013; 100(1): 135-41.e1–2. doi:10.1016/j.fertnstert.2013.03.019 - 57Krasnyi AM, Sadekova AA, Smolnova TY, et al. The levels of ghrelin, glucagon, visfatin and Glp-1 are decreased in the peritoneal fluid of women with endometriosis along with the increased expression of the CD10 protease by the macrophages. Int J Mol Sci. 2022; 23(18):10361. doi:10.3390/ijms231810361 - 58Alvarez P, Bogen O, Chen X, Giudice LC, Levine JD. Ectopic endometrium-derived leptin produces estrogen-dependent chronic pain in a rat model of endometriosis. Neuroscience. 2014; 258: 111-120. doi:10.1016/j.neuroscience.2013.11.008 - 59Bedaiwy MA, Falcone T, Goldberg JM, Sharma RK, Nelson DR, Agarwal A. Peritoneal fluid leptin is associated with chronic pelvic pain but not infertility in endometriosis patients. Hum Reprod. 2006; 21(3): 788-791. doi:10.1093/humrep/dei376 - 60Oh YK, Ha YR, Yi KW, et al. Increased expression of resistin in ectopic endometrial tissue of women with endometriosis. Am J Reprod Immunol. 2017; 78(5). doi:10.1111/aji.12726 - 61Yi KW, Shin JH, Park HT, Kim T, Kim SH, Hur JY. Resistin concentration is increased in the peritoneal fluid of women with endometriosis. Am J Reprod Immunol. 2010; 64(5): 318-323. doi:10.1111/j.1600-0897.2010.00840.x - 62Zhang QF, Chen GY, Liu Y, Huang HJ, Song YF. Relationship between resistin and IL-23 levels in follicular fluid in infertile patients with endometriosis undergoing IVF-ET. Adv Clin Exp Med. 2017; 26(9): 1431-1435. doi:10.17219/acem/41149 - 63Abolghasemi M, Esmaeilzadeh S, Mahjoub S, HashemiKarouei S, Mirabi P. Resistin and chemerin levels in follicular fluid of infertile women with endometriosis undergoing ICSI. J Obstet Gynaecol. 2022; 42(2): 322-326. doi:10.1080/01443615.2021.1904231 - 64Kaya Sezginer E, Kırlangıç ÖF, Eşkin Tanrıverdi MD, Topçu HO, Gür S. Analysis of changes in serum levels and gene expression profiles of novel adipocytokines (omentin, vaspin, irisin and visfatin) and their correlation with serum c-reactive protein levels in women diagnosed with endometriosis. Turk J Pharm Sci. 2022; 19(1): 48-53. doi:10.4274/tjps.galenos.2021.52284 - 65Jin CH, Yi KW, Ha YR, et al. Chemerin expression in the peritoneal fluid, serum, and ovarian endometrioma of women with endometriosis. Am J Reprod Immunol. 2015; 74(4): 379-386. doi:10.1111/aji.12405 - 66Lee JC, Kim SH, Oh YS, Kim JH, Lee SR, Chae HD. Increased expression of retinol-binding protein 4 in ovarian endometrioma and its possible role in the pathogenesis of endometriosis. Int J Mol Sci. 2021; 22(11):5827. doi:10.3390/ijms22115827 - 67Takemura Y, Osuga Y, Harada M, et al. Concentration of adiponectin in peritoneal fluid is decreased in women with endometriosis. Am J Reprod Immunol. 2005; 54(4): 217-221. doi:10.1111/j.1600-0897.2005.00300.x - 68Bohlouli S, Khazaei M, Teshfam M, Hassanpour H. Adiponectin effect on the viability of human endometrial stromal cells and mRNA expression of adiponectin receptors. Int J Fertil Steril. 2013; 7(1): 43-48. - 69Takemura Y, Osuga Y, Yamauchi T, et al. Expression of adiponectin receptors and its possible implication in the human endometrium. Endocrinology. 2006; 147(7): 3203-3210. doi:10.1210/en.2005-1510 - 70Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci USA. 2001; 98(11): 6390-6395. doi:10.1073/pnas.101564798 - 71Tripathi D, Kant S, Pandey S, Ehtesham NZ. Resistin in metabolism, inflammation, and disease. FEBS J. 2020; 287(15): 3141-3149. doi:10.1111/febs.15322 - 72Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001; 7(8): 941-946. doi:10.1038/90984 - 73Zhang HH, Kumar S, Barnett AH, Eggo MC. Tumour necrosis factor-alpha exerts dual effects on human adipose leptin synthesis and release. Mol Cell Endocrinol. 2000; 159(1–2): 79-88. doi:10.1016/s0303-7207(99)00194-x - 74Barbe A, Bongrani A, Mellouk N, et al. Mechanisms of adiponectin action in fertility: an overview from gametogenesis to gestation in humans and animal models in normal and pathological conditions. Int J Mol Sci. 2019; 20(7): 1526. doi:10.3390/ijms20071526 - 75Machado DE, Abrao MS, Berardo PT, Takiya CM, Nasciutti LE. Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum. Fertil Steril. 2008; 90(1): 148-155. doi:10.1016/j.fertnstert.2007.05.076 - 76Wei Y, Liang Y, Lin H, Dai Y, Yao S. Autonomic nervous system and inflammation interaction in endometriosis-associated pain. J Neuroinflammation. 2020; 17(1):80. doi:10.1186/s12974-020-01752-1 - 77Wang G, Tokushige N, Markham R, Fraser IS. Rich innervation of deep infiltrating endometriosis. Hum Reprod. 2009; 24(4): 827-834. doi:10.1093/humrep/den464 - 78Dewanto A, Dudas J, Glueckert R, et al. Localization of TrkB and p75 receptors in peritoneal and deep infiltrating endometriosis: an immunohistochemical study. Reprod Biol Endocrinol. 2016; 14(1): 43. doi:10.1186/s12958-016-0178-5 - 79Sawada J, Itakura A, Tanaka A, Furusaka T, Matsuda H. Nerve growth factor functions as a chemoattractant for mast cells through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways. Blood. 2000; 95(6): 2052-2058. - 80Arnold J, Barcena de Arellano ML, Rüster C, et al. Imbalance between sympathetic and sensory innervation in peritoneal endometriosis. Brain Behav Immun. 2012; 26(1): 132-141. doi:10.1016/j.bbi.2011.08.004 - 81Chen Y, Li D, Zhang Z, Takushige N, Kong BH, Wang GY. Effect of siRNA against β-NGF on nerve fibers of a rat model with endometriosis. Reprod Sci. 2014; 21(3): 329-339. doi:10.1177/1933719113497279 - 82Wang S, Duan H, Li B, et al. BDNF and TrKB expression levels in patients with endometriosis and their associations with dysmenorrhoea. J Ovarian Res. 2022; 15(1):35. doi:10.1186/s13048-022-00963-9 - 83Sun W, Li C, Zhang Y, et al. Gene expression changes of thermo-sensitive transient receptor potential channels in obese mice. Cell Biol Int. 2017; 41(8): 908-913. doi:10.1002/cbin.10783 - 84Bohonyi N, Pohóczky K, Szalontai B, et al. Local upregulation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 ion channels in rectosigmoid deep infiltrating endometriosis. Mol Pain. 2017; 13:1744806917705564. doi:10.1177/1744806917705564 - 85Rocha MG, e Silva JC, Ribeiro da Silva A, Candido Dos Reis FJ, Nogueira AA, Poli-Neto OB. TRPV1 expression on peritoneal endometriosis foci is associated with chronic pelvic pain. Reprod Sci. 2011; 18(6): 511-515. doi:10.1177/1933719110391279 - 86Greaves E, Grieve K, Horne AW, Saunders PT. Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis. J Clin Endocrinol Metab. 2014; 99(9): E1738-E1743. doi:10.1210/jc.2014-2282 - 87Zhu H, Wang Y, He Y, Yu W. Inflammation-mediated macrophage polarization induces TRPV1/TRPA1 heteromers in endometriosis. Am J Transl Res. 2022; 14(5): 3066-3078. - 88Wu J, Xie H, Yao S, Liang Y. Macrophage and nerve interaction in endometriosis. J Neuroinflammation. 2017; 14(1):53. doi:10.1186/s12974-017-0828-3 - 89Sanchez AM, Cioffi R, Viganò P, et al. Elevated systemic levels of endocannabinoids and related mediators across the menstrual cycle in women with endometriosis. Reprod Sci. 2016; 23(8): 1071-1079. doi:10.1177/1933719116630414 - 90Luschnig P, Schicho R. Cannabinoids in gynecological diseases. Med Cannabis Cannabinoids. 2019; 2(1): 14-21. doi:10.1159/000499164 - 91Scheerer C, Frangini S, Chiantera V, Mechsner S. Reduced sympathetic innervation in endometriosis is associated to semaphorin 3C and 3F expression. Mol Neurobiol. 2017; 54(7): 5131-5141. doi:10.1007/s12035-016-0058-1 - 92Liang Y, Wang W, Huang J, et al. Potential role of semaphorin 3A and its receptors in regulating aberrant sympathetic innervation in peritoneal and deep infiltrating endometriosis. PLoS ONE. 2015; 10(12):e0146027. doi:10.1371/journal.pone.0146027 - 93De Blasio FM, Love S, Barry RJ, et al. Frontocentral delta-beta amplitude coupling in endometriosis-related chronic pelvic pain. Clin Neurophysiol. 2023; 149: 146-156. doi:10.1016/j.clinph.2023.02.173 - 94Knyazev GG. EEG delta oscillations as a correlate of basic homeostatic and motivational processes. Neurosci Biobehav Rev. 2012; 36(1): 677-695. doi:10.1016/j.neubiorev.2011.10.002 - 95Szentirmai É, Kapás L. Brown adipose tissue plays a central role in systemic inflammation-induced sleep responses. PLoS ONE. 2018; 13(5):e0197409. doi:10.1371/journal.pone.0197409 - 96Morrison SF, Madden CJ. Central nervous system regulation of brown adipose tissue. Compr Physiol. 2014; 4(4): 1677-1713. doi:10.1002/cphy.c140013 - 97Cero C, Lea HJ, Zhu KY, Shamsi F, Tseng YH, Cypess AM. β3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis. JCI Insight. 2021; 6(11). doi:10.1172/jci.insight.139160 - 98Ferdek MA, Oosterman JM, Adamczyk AK, et al. Effective connectivity of beta oscillations in endometriosis-related chronic pain during rest and pain-related mental imagery. J Pain. 2019; 20(12): 1446-1458. doi:10.1016/j.jpain.2019.05.011 - 99Sherman MA, Lee S, Law R, et al. Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice. Proc Natl Acad Sci U S A. 2016; 113(33): E4885-E4894. doi:10.1073/pnas.1604135113 - 100Furman AJ, Prokhorenko M, Keaser ML, et al. Sensorimotor peak alpha frequency is a reliable biomarker of prolonged pain sensitivity. Cereb Cortex. 2020; 30(12): 6069-6082. doi:10.1093/cercor/bhaa124 - 101De Pascalis V, Cacace I. Pain perception, obstructive imagery and phase-ordered gamma oscillations. Int J Psychophysiol. 2005; 56(2): 157-169. doi:10.1016/j.ijpsycho.2004.11.004 - 102Li T, Mamillapalli R, Ding S, et al. Endometriosis alters brain electrophysiology, gene expression and increases pain sensitization, anxiety, and depression in female mice. Biol Reprod. 2018; 99(2): 349-359. doi:10.1093/biolre/ioy035 - 103Mamillapalli R, Dang T, Habata S, Gao XB, Taylor HS. Activation of hypocretin neurons in endometriosis. Reprod Sci. 2022; 29(1): 243-249. doi:10.1007/s43032-021-00682-4 - 104As-Sanie S, Kim J, Schmidt-Wilcke T, et al. Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain. J Pain. 2016; 17(1): 1-13. doi:10.1016/j.jpain.2015.09.008 - 105Maulitz L, Stickeler E, Stickel S, Habel U, Tchaikovski SN, Chechko N. Endometriosis, psychiatric comorbidities and neuroimaging: estimating the odds of an endometriosis brain. Front Neuroendocrinol. 2022; 65:100988. doi:10.1016/j.yfrne.2022.100988 Citing Literature Article Metrics Total unique accesses to an article’s full text in HTML or PDF/ePDF format.More metric information Scite metrics Explore this article's citation statements on scite.ai Share QR Code Generating QR code QR code copied to clipboard! Something went wrong while generating your QR code. Please try again in a moment. If the issue persists, refresh the page or contact support. Export citation Unable to load citation data. Please try again in a moment. How to cite Elkins, L. J., & Spiegelman, M. (2021). pyUserCalc: A revised Jupyter notebook calculator for uranium-series disequilibria in basalts. Earth and Space Science, 8, e2020EA001619. https://doi.org/10.1029/2020EA001619 Download Citation If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click on download. This feature enables you to download the bibliographic information (also called citation data, header data, or metadata) for the articles on our site. Citation manager file format Use the dropdown list to choose how to format the bibliographic data you're harvesting. Several citation manager formats are available, including EndNote and BibTex. You can then copy the formatted citation (as displayed) or download it as file, to your device. If the RefWorks format is chosen, the 'Download' button will be replaced with an option to directly export to RefWorks