Stress During Development of Experimental Endometriosis Influences Nerve Growth and Disease Progression

Purpose We have previously shown that stress prior to induction worsens clinical presentation and inflammatory parameters in a rat model of endometriosis. This study was designed to examine whether stress during the development of endometriosis can affect the growth of endometriotic implants through nerve growth and immune alterations.

Endometriosis was surgically induced in female Sprague-Dawley rats by suturing uterine horn implants onto the small intestine mesentery. Two weeks later, one group of rats (endo-stress) was subjected to a 10-day swim stress protocol. Controls had no stress (endo-no stress) or sutures only and stress (sham-stress). On day 60, all rats were killed and examined for the presence of endometriotic vesicles. The size of each vesicle was measured. The uterus and colon were removed and assessed for damage, cell infiltration, and expression of nerve growth factor (NGF), its receptors (p75 and Tropomyosin receptor kinase A (Trk-A)/pTrk-A), and calcitonin gene-related peptide, a sensory fiber marker. A differential analysis of peritoneal fluid white blood cell count was performed.

Stress significantly increased endometriotic vesicle size but not colonic damage and increased infiltration of mast cells. Significantly increased expression of NGF and its receptors was found in the uterus of animals with endometriosis receiving stress.

Stress stimulates the development of ectopic endometrial vesicles in an animal model of endometriosis and increases inflammatory cell recruitment to the peritoneum. In addition, stress promotes nerve fiber growth in the uterus. Similar content being viewed by others

Tariverdian N, Rucke M, Szekeres-Bartho J, et al. Neuroendocrine circuitry and endometriosis: progesterone derivative dampens corticotropin-releasing hormone-induced inflammation by peritoneal cells in vitro. J Mol Med. 2010;88(3):267–278. Toth B. Stress, inflammation and endometriosis: are patients stuck between a rock and a hard place? J Mol Med. 2010;88(3): 223–225. Huntington A, Gilmour JA. A life shaped by pain: women and endometriosis. J Clin Nurs. 2005;14(9):1124–1132. Barnack JL, Chrisler JC. The experience of chronic illness in women: a comparison between women with endometriosis and women with chronic migraine headaches. Women Health. 2007;46(1):115–133. Cousineau TM, Green TC, Corsini E, Seibring A, et al. Online psychoeducational support for infertile women: a randomized controlled trial. Hum Reprod. 2008;23(3):554–566. Harrison V, Rowan K, Mathias J. Stress reactivity and family relationships in the development and treatment of endometriosis. Fertil Steril. 2005;83(4):857–864. Cuevas M, Flores I, Thompson KJ, Ramos-Ortolaza DL, Torres-Reveron A, Appleyard CB. Stress exacerbates endometriosis manifestations and inflammatory parameters in an animal model Reprod Sci. 2012;19(8):851–862. Epub 2012 Apr 23. Appleyard CB, Cruz ML, Hernandez S, Thompson KJ, Bayona M, Flores I. Stress management affects outcomes in the patho-physiology of an endometriosis model. Reprod Sci. 2015;22(4): 431–441. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–2398. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endo-metriosis. Fertile Steril. 2001;75(1):1–10. Padgett DA, Glaser R. How stress influences the immune response. Trends Immunol. 2003;24(8):444–448. Matsuzaki S, Canis M, Darcha C, Fukaya T, Yajima A, Bruhat MA. Increased mast cell density in peritoneal endometriosis compared with eutopic endometrium with endometriosis. Am J Reprod Immunol. 1998;40(4):291–294. Anaf V, Chapron C, Nakadi IE, De Moor V, Simonart T, Noel J-C. Pain, mast cells, and nerves in peritoneal, ovarian and deep infiltrating endometriosis. Fertil Steril. 2006;86(5):1336–1343. Bienenstock J, Tomioka M, Matsuda H, et al. The role of mast cells in inflammatory processes: evidence for nerve/mast cell interactions. Int Arch Allergy Appl Immunol. 1987;82(3-4): 238–243. Dines KC, Powell HC. Mast cell interactions with the nervous system: relationship to mechanisms of disease. J Neuropathol Exp Neurol. 1997;56(6):627–640. Marshall JS, Gomi K, Blennerhassett MG, Bienenstock J. Nerve growth factor modifies the expression of inflammatory cytokines by mast cells via a prostanoid-dependent mechanism. J Immunol. 1999;162(7):4271–4276. Berkley KJ, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci USA. 2004;101(30):11094–11098. Epub 2004 Jul 15. McAllister SL, Dmitrieva N, Berkley KJ. Sprouted innervation into uterine transplants contributes to the development of hyper-algesia in a rat model of endometriosis. PLoS One. 2012;7(2): e31758. Epub 2012 Feb 21. D’Hooghe T, Hummelshoj L. Multi-disciplinary centres/networks of excellence for endometriosis management and research: a proposal. Hum Reprod. 2006;21(11):2743–2748. Epub 2006 Sep 18. Vernon MW, Wilson EA. Studies on the surgical induction of endometriosis in the rat. Fertil Steril. 1985;44(5):684–694. Appleyard CB, Cruz ML, Rivera E, Hernandez GA, Flores I. Experimental endometriosis in the rat is correlated with colonic motor function alterations but not with bacterial load. Reprod Sci. 2007;14(8):815–824. Maillot C, Million M, Wei JY, Gauthier A, Tache Y. Peripheral corticotropin-releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats. Gastroenterology. 2000;119(6):1569–1579. Ingelmo MR, Quereda F, Acien P. Intraperitoneal and subcutaneous treatment of experimental endometriosis with recombinant human interferon-a-2b in a murine model. Fertil Steril. 1999;71(5):907–911. Boughton-Smith NK, Wallace JL, Whittle BJ. Relationship between arachidonic acid metabolism, myeloperoxidase activity and leukocyte infiltration in a rat model of inflammatory bowel disease. Agents Actions. 1998;25(1-2):115–123. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Derm. 1982;78(3):206–209. Venkova K, Johnson AC, Myers B, Greenwood-Van Meerveld B. Exposure of the amygdala to elevated levels of corticosterone alters colonic motility in response to acute psychological stress. Neuropharmacology. 2010;58(7):1161–1167. Hernandez S, Cruz ML, Seguinot II, Torres-Reveron A, Appleyard CB. Impact of psychological stress on pain perception in an animal model of endometriosis. Reprod Sci. 2017;24(10): 1371–1381. Cramer DW, Missmer SA. The epidemiology of endometriosis. Ann N YAcad Sci. 2002;955:11–22;discussion 34-6, 396-406. Fenster L, Waller K, Chen J, et al. Psychological stress in the workplace and menstrual function. Am J Epidemiol. 1999;149(2):127–134. Kyama CM, Debrock S, Mwenda JM, D’Hooghe TM. Potential involvement of immune system in the development of endometriosis. Reprod Biol Endocrinol. 2003;1:123. Sugamata M, Ihara T, Uchiide I. Increase of activated mast cells in human endometriosis. Am J Reprod Immunol. 2005;53(3): 120–125. Cairns JA, Walls AF. Mast cell tryptase stimulates the synthesis of type 1 collagen in human lung fibroblasts. J Clin Invest. 1997;99(6):1313–1321. Hart A, Kamm MA. Review article: mechanisms of initiation and perpetuation of gut inflammation by stress. Aliment Pharmacol Therap. 2002;16(12):2017–2028. Mawdsley JE, Rampton DS. Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut. 2005;54(10):1481–1491. Tache Y, Perdue MH. Role of peripheral CRF signaling pathways in stress-related alterations of gut motility and mucosal function. Neurogastroenterol Motil. 2004;16(suppl 1):137–142. Review. O’Sullivan M, Clayton N, Breslin NP, et al. Increased mast cell in the irritable bowel syndrome. Neurogastroenterol Motil. 2000;12(5):449–457. Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cell in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004;126(3): 693–702. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science. 2005;308(5728):1587–1589. Anaf V, Simon P, El Nakadi I, et al. Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis. Hum Reprod. 2002;17(7):1895–1900. Kajitani T, Maruyama T, Asada H, et al. Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis. Endocr J. 2013;60(10):1155–1564. Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci. 2006;29:507–538. Kaplan DR, Martin-Zanaca D, Parada LF. Tyrosine phosphorylation and tyrosine kinase activity of the Trk proto-oncogene product induced by NGF. Nature. 1991;350(6314):158–160. Rueff A, Mendell LM. Nerve growth factor NT-5 induce increased thermal sensitivity of cutaneous nociceptors in vitro. J Neurophysiol. 1996;76(5):3593–3596. Zhang G, Dmitrieva N, Liu Y, McGinty KA, Berkley KJ. Endometriosis as a neurovascular condition: estrous variations in innervation, vascularization, and growth factor content of ectopic endometrial cysts in the rat. Am J Physiol Regul Integr Comp Physiol. 2008;294(1):R162-R171. Barcena de Arellano ML, Arnold J, Lang H, et al. Evidence of neurotropic events due to peritoneal endometriotic lesions. Cytokine. 2013;62(2):253–261. Alvarez P, Levine JD. Screening the role of pronociceptive molecules in a rodent model of endometriosis pain. JPain. 2014;15(7): 726–733. Kaplan DR, Miller FD. Signal transduction by the neurotrophin receptors. Curr Opin Cell Biol 1997;9(2):213–221. Wang G, Tokushige N, Russell P, Dubinovsky S, Markham R, Fraser IS. Hyperinnervation in intestinal deep infiltrating endometriosis. J Minim Invasive Gynecol. 2009;16(6):713–719. Anaf V, El Nakadi I, De Moor V, Chapron C, Pistofidis G, Noel JC. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Invest. 2011;71(2):112–117. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Cuevas, M., Cruz, M.L., Ramirez, A.E. et al. Stress During Development of Experimental Endometriosis Influences Nerve Growth and Disease Progression. Reprod. Sci. 25, 347–357 (2018). https://doi.org/10.1177/1933719117737846 Published: Version of record: Issue date: DOI: https://doi.org/10.1177/1933719117737846