Environmental Manipulations as an Effective Alternative Treatment to Reduce Endometriosis Progression

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Environmental enrichment reduced endometriosis vesicle number and size, and dampened stress-related gene expression in vesicles, compared to no enrichment in a rat model.

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The study investigated whether environmental enrichment (EE) alters endometriosis progression and stress-related neuroendocrine signaling in a rat autotransplantation model, comparing enriched versus non-enriched housing conditions before and during growth of surgically induced endometriotic lesions. After 8 weeks and a further 60 days of lesion progression, the authors measured anxiety-like behaviors and vesicle size/number, and assessed corticotropin-releasing hormone (CRH), urocortin-1, CRH receptor (CRHR1/CRHR2), and glucocorticoid receptor (GR) expression by quantitative real-time PCR in vesicles. Endometriosis itself did not change anxiety-like behavior, but EE reduced basal anxiety-like behavior and was associated with fewer (28% reduction) and smaller endometriotic vesicles, alongside dampened CRH and GR increases observed in non-enriched vesicles; urocortin-1 increased in enriched vesicles, indicating different pathway activation. A limitation explicitly implied by the design is that outcomes are based on animal model endpoints without confirming causal relevance to human disease mechanisms beyond these measured markers. This paper is centrally about endometriosis — it tests environmental enrichment as a stress-reducing strategy to reduce endometriosis lesion progression in rats.

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Abstract

Treatments for endometriosis include pharmacological or surgical procedures that produce significant side effects. We aimed to determine how environmental enrichment (EE) could impact the progression of endometriosis using the autotransplantation rat model. Female rats were exposed to EE (endo-EE: toys and nesting materials, 4 rats per cage, larger area enclosure) or no enrichment (endo-NE: 2 rats per cage) starting on postnatal day 21. After 8 weeks, sham surgery or surgical endometriosis was induced by suturing uterine horn tissue next to the intestinal mesentery, then allowed to progress for 60 days during which EE or NE continued. At the time of killing, we measured anxiety behaviors, collected endometriotic vesicles and uterus, and processed for quantitative real-time polymerase chain reaction for corticotropin-releasing hormone (CRH), urocortin-1, CRH receptors type 1 and type 2, and glucocorticoid receptor (GR). Endometriosis did not affect anxiety-like behaviors, yet rats in enriched conditions showed lower basal anxiety behaviors than the nonenriched group. Importantly, the endo-EE group showed a 28% reduction in the number of endometriosis vesicles and the vesicles were significantly smaller compared to the endo-NE group. Endometriosis increased CRH and GR only in the vesicles of endo-NE, and this increase was dampened in the endo-EE. However, urocortin 1 was increased in the vesicles of the endo-EE group, suggesting different pathways of activation of CRH receptors in this group. Our results suggest that the use of multimodal complementary therapies that reduce stress in endometriosis could be an effective and safe treatment alternative, with minimal side effects.
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Abstract

Treatments for endometriosis include pharmacological or surgical procedures that produce significant side effects. We aimed to determine how environmental enrichment (EE) could impact the progression of endometriosis using the autotransplantation rat model. Female rats were exposed to EE (endo-EE: toys and nesting materials, 4 rats per cage, larger area enclosure) or no enrichment (endo-NE: 2 rats per cage) starting on postnatal day 21. After 8 weeks, sham surgery or surgical endometriosis was induced by suturing uterine horn tissue next to the intestinal mesentery, then allowed to progress for 60 days during which EE or NE continued. At the time of killing, we measured anxiety behaviors, collected endometriotic vesicles and uterus, and processed for quantitative real-time polymerase chain reaction for corticotropin-releasing hormone (CRH), urocortin-1, CRH receptors type 1 and type 2, and glucocorticoid receptor (GR). Endometriosis did not affect anxiety-like behaviors, yet rats in enriched conditions showed lower basal anxiety behaviors than the nonenriched group. Importantly, the endo-EE group showed a 28% reduction in the number of endometriosis vesicles and the vesicles were significantly smaller compared to the endo-NE group. Endometriosis increased CRH and GR only in the vesicles of endo-NE, and this increase was dampened in the endo-EE. However, urocortin 1 was increased in the vesicles of the endo-EE group, suggesting different pathways of activation of CRH receptors in this group. Our results suggest that the use of multimodal complementary therapies that reduce stress in endometriosis could be an effective and safe treatment alternative, with minimal side effects. Similar content being viewed by others

References

Abu Hashim H. Gonadotrophin-releasing hormone analogues and endometriosis: current strategies and new insights. Gynecol Endocrinol. 2012;28(4):314–321. Raffi F, Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2012;97(9):3146–3154. Schrager S, Falleroni J, Edgoose J. Evaluation and treatment of endometriosis. Am Fam Physician. 2013;87(2):107–113. Fourquet J, Baez L, Figueroa M, Iriarte RI, Flores I. Quantification of the impact of endometriosis symptoms on health-related quality of life and work productivity. Fertil Steril. 2011;96(1):107–112. De Graaff AA, D’Hooghe TM, Dunselman GAJ, Dirksen CD, Hummelshoj L, Simoens S. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013;28(10):2677–2685. Tariverdian N, Theoharides TC, Siedentopf F, et al. Neuroendocrine- immune disequilibrium and endometriosis: an interdisciplinary approach. Semin Immunopathol. 2007;29(2):193–210. Kong S, Zhang YH, Liu CF, et al. The complementary and alternative medicine for endometriosis: a review of utilization and mechanism. Evid Based Complement Alternat Med. 2014;2014:146383. doi:10.1155/2014/146383 Goncalves AV, Barros NF, Bahamondes L. The practice of hatha yoga for the treatment of pain associated with endometriosis. J Altern Complement Med. 2017;23(1):45–52. Lemaire GS. More than just menstrual cramps: symptoms and uncertainty among women with endometriosis. J Obstet Gynecol Neonatal Nurs. 2004;33(1):71–79. Toth B. Stress, inflammation and endometriosis: are patients stuck between a rock and a hard place? J Mol Med (Berl). 2010;88(3):223–225. 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. Hernandez S, Cruz M, Torres-Reveron A, Appleyard C. Impact of physical activity on pain perception in an animal model of endometriosis. J endometr. 2015;7(3):100–108. Quinones M, Urrutia R, Torres-Reveron A, Vincent K, Flores I. Anxiety, coping skills and hypothalamus-pituitary-adrenal (HPA) axis in patients with endometriosis. J Reprod Biol Health. 2015;3(2). doi:10.7243/2054-0841-3-2 Petrelluzzi KFS, Garcia MC, Petta CA, Grassi-Kassisse DM, Spadari-Bratfisch RC. Salivary cortisol concentrations, stress and quality of life in women with endometriosis and chronic pelvic pain. Stress. 2008;11(5):390–397. Davidson RJ, McEwen BS. Social influences on neuroplasticity: stress and interventions to promote well-being. Nat Neurosci. 2012;15(5):689–695. Du X, Leang L, Mustafa T, Renoir T, Pang TY, Hannan AJ. Environmental enrichment rescues female-specific hyperactivity of the hypothalamic-pituitary-adrenal axis in a model of Huntington’s disease. Transl Psychiatry. 2012;2:e133. doi:10.1038/tp.2012.58 Renoir T, Pang TYC, Mo C, et al. Differential effects of early environmental enrichment on emotionality related behaviours in Huntington’s disease transgenic mice. J Physiol. 2013;591(1):41–55. Gimenez-Llort L, Mate I, Manassra R, Vida C, De la Fuente M. Peripheral immune system and neuroimmune communication impairment in a mouse model of Alzheimer’s disease. Ann N Y Acad Sci. 2012;1262:74–84. Hutchinson KM, McLaughlin KJ, Wright RL, et al. Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity. Neurobiol Learn Mem. 2012;97(2):250–260. Simpson J, Kelly JP. The impact of environmental enrichment in laboratory rats—behavioural and neurochemical aspects. Behav Brain Res. 2011;222(1):246–264. Rosenzweig MR, Bennett EL, Hebert M, Morimoto H. Social grouping cannot account for cerebral effects of enriched environments. Brain Res. 1978;153(3):563–576. Schoultz M, Atherton I, Watson A. Mindfulness-based cognitive therapy for inflammatory bowel disease patients: findings from an exploratory pilot randomised controlled trial. Trials. 2015;16:379. doi:10.1186/s13063-015-0909-5 McAllister SL, Dmitrieva N, Berkley KJ. Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis. PLoS One. 2012; 7(2):e31758. doi:10.1371/journal.pone.0031758 Sharpe-Timms KL. Using rats as a research model for the study of endometriosis. Ann N Y Acad Sci. 2002;955:318–327. 312-318-406. http://www.ncbi.nlm.nih.gov/pubmed/11949958. Torres-Reveron A, Palermo K, Hernandez-Lopez A, et al. Endometriosis is associated with a shift in MU opioid and NMDA receptor expression in the brain periaqueductal gray. Reprod Sci. 2016;23(9):1158–1167. Vernon MW. Experimental endometriosis in laboratory animals as a research model. Prog Clin Biol Res. 1990;323:49–60. http://www.ncbi.nlm.nih.gov/pubmed/2406756. Vernon MW, Wilson EA. Studies on the surgical induction of endometriosis in the rat. Fertil Steril. 1985;44(5):684–694. Cason AM, Samuelsen CL, Berkley KJ. Estrous changes in vaginal nociception in a rat model of endometriosis. Horm Behav. 2003;44(2):123–131. Grummer R. Translational animal models to study endometriosis-associated infertility. Semin Reprod Med. 2013;31(2):125–132. Konno R, Fujiwara H, Netsu S, et al. Gene expression profiling of the rat endometriosis model. Am J Reprod Immunol. 2007;58(4):330–343. Fourquet J, Gao X, Zavala D, et al. Patients’ report on how endometriosis affects health, work, and daily life. Fertil Steril. 2010;93(7):2424–2428. Crofton EJ, Zhang Y, Green TA. Inoculation stress hypothesis of environmental enrichment. Neurosci Biobehav Rev. 2015;49:19–31. Appleyard CB, Cruz ML, Hernandez S, Thompson KJ, Bayona M, Flores I. Stress management affects outcomes in the pathophysiology of an endometriosis model. Reprod Sci. 2015;22(4):431–441. Walf AA, Frye CA. Antianxiety and antidepressive behavior produced by physiological estradiol regimen may be modulated by hypothalamic-pituitary-adrenal axis activity. Neuropsychopharmacology. 2005;30(7):1288–1301. 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. Strehl JD, Hackl J, Wachter DL, et al. Correlation of histological and macroscopic findings in peritoneal endometriosis. Int J Clin Exp Pathol. 2014;7(1):152–162. Agarwal N, Subramanian A. Endometriosis—morphology, clinical presentations and molecular pathology. J Lab Physicians. 2010;2(1):1–9. Novembri R, Borges LE, Carrarelli P, et al. Impaired CRH and urocortin expression and function in eutopic endometrium of women with endometriosis. J Clin Endocrinol Metab. 2011;96(4):1145–1150. 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 (Berl). 2010;88(3):267–278. Vergetaki A, Jeschke U, Vrekoussis T, et al. Differential expression of CRH, UCN, CRHR1 and CRHR2 in eutopic and ectopic endometrium of women with endometriosis. PLoS One. 2013;8(4):e62313. doi:10.1371/journal.pone.0062313 McEwen BS. Protective and damaging effects of stress mediators. Semin Med Beth Isr Deaconess Med Cent. 2004;338(3):171–179. McEwen BS. Protective and damaging effects of stress mediators: central role of the brain. Dialogues Clin Neurosci. 2006;8(4):283–297. Ronzoni G, Anton M, Mora F, Segovia G, Del Arco A. Infralimbic cortex controls the activity of the hypothalamus-pituitary-adrenal axis and the formation of aversive memory: effects of environmental enrichment. Behav Brain Res. 2016;297:338–344. Lehmann ML, Herkenham M. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. J Neurosci. 2011;31(16):6159–6173. Brenes JC, Padilla M, Fornaguera J. A detailed analysis of openfield habituation and behavioral and neurochemical antidepressant-like effects in postweaning enriched rats. Behav Brain Res. 2009;197(1):125–137. Mann PE, Gervais KJ. Environmental enrichment delays pupinduced maternal behavior in rats. Dev Psychobiol. 2011;53(4):371–382. Del Arco A, Segovia G, Garrido P, de Blas M, Mora F. Stress, prefrontal cortex and environmental enrichment: studies on dopamine and acetylcholine release and working memory performance in rats. Behav Brain Res. 2007;176(2):267–273. Luisi S, Pinzauti S, Regini C, Petraglia F. Serum markers for the noninvasive diagnosis of endometriosis. Womens Health (Lond). 2015;11(5):603–610. Pena Y, Prunell M, Rotllant D, Armario A, Escorihuela RM. Enduring effects of environmental enrichment from weaning to adulthood on pituitary-adrenal function, pre-pulse inhibition and learning in male and female rats. Psychoneuroendocrinology. 2009;34(9):1390–1404. Girbovan C, Plamondon H. Environmental enrichment in female rodents: considerations in the effects on behavior and biochemical markers. Behav Brain Res. 2013;253:178–190. Brown KJ, Grunberg NE. Effects of housing on male and female rats: crowding stresses male but calm females. Physiol Behav. 1995;58(6):1085–1089. Arnason BG, Berkovich R, Catania A, Lisak RP, Zaidi M. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler. 2013;19(2):130–136. Montero-Melendez T. ACTH: the forgotten therapy. Semin Immunol. 2015;27(3):216–226. Whirledge SD, Oakley RH, Myers PH, Lydon JP, DeMayo F, Cidlowski JA. Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization. Proc Natl Acad Sci U S A. 2015;112(49):15166–15171. Zoumakis E, Margioris AN, Stournaras C, et al. Corticotrophin-releasing hormone (CRH) interacts with inflammatory prostaglandins and interleukins and affects the decidualization of human endometrial stroma. Mol Hum Reprod. 2000;6(4):344–351. Makrigiannakis A, Zoumakis E, Kalantaridou S, et al. Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance. Nat Immunol. 2001;2(11):1018–1024. Fang X, Hong Y, Dai L, et al. CRH promotes human colon cancer cell proliferation via IL-6/JAK2/STAT3 signaling pathway and VEGF-induced tumor angiogenesis. Mol Carcinog. 2017;56(11):2434–2445. Sato N, Takagi K, Suzuki T, et al. Immunolocalization of corticotropin-releasing hormone (CRH) and its receptors (CRHR1 and CRHR2) in human endometrial carcinoma: CRHR1 as a potent prognostic factor. Int J Gynecol Cancer. 2014;24(9):1549–1557. Rodriguez JA, Huerta-Yepez S, Law IKM, et al. Diminished expression of CRHR2 in human colon cancer promotes tumor growth and EMT via persistent IL-6/Stat3 signaling. Cell Mol Gastroenterol Hepatol. 2015;1(6):610–630. Grandi G, Mueller MD, Papadia A, et al. Inflammation influences steroid hormone receptors targeted by progestins in endometrial stromal cells from women with endometriosis. J Reprod Immunol. 2016;117:30–38. Monsivais D, Dyson MT, Yin P, et al. Estrogen receptor beta regulates endometriotic cell survival through serum and glucocorticoid-regulated kinase activation. Fertil Steril. 2016;105(5):1266–1273. Karteris E, Markovic D, Chen J, Hillhouse EW, Grammatopoulos DK. Identification of a novel corticotropin-releasing hormone type 1beta-like receptor variant lacking Exon 13 in human pregnant myometrium regulated by estradiol-17beta and progesterone. Endocrinology. 2010;151(10):4959–4968. Kempuraj D, Papadopoulou N, Stanford EJ, et al. Increased numbers of activated mast cells in endometriosis lesions positive for corticotropin-releasing hormone and urocortin. Am J Reprod Immunol. 2004;52(4):267–275. Florio P, Busacca M, Vignali M, et al. Peritoneal fluid levels of immunoreactive corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP) in healthy and endometriosic women. J Endocrinol Invest. 1998;21(1):37–42. Cao J, Papadopoulou N, Kempuraj D, et al. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol. 2005;174(12):7665–7675. Ulrich RS. Effects of interior design on wellness: theory and recent scientific research. J Health Care Inter Des. 1991;3:97–109. Kaplan R, Kaplan S. The Experience of Nature: A Psychological Perspective. Cambridge University Press, New York, NY; 1989. Birch AM, McGarry NB, Kelly AM. Short-term environmental enrichment, in the absence of exercise, improves memory, and increases NGF concentration, early neuronal survival, and synaptogenesis in the dentate gyrus in a time-dependent manner. Hippocampus. 2013;23(6):437–450. Vachon P, Millecamps M, Low L, et al. Alleviation of chronic neuropathic pain by environmental enrichment in mice well after the establishment of chronic pain. Behav Brain Funct. 2013;9:22. doi:10.1186/1744-9081-9-22 Zheng J, Jiang YY, Xu LC, et al. Adult hippocampal neurogenesis along the dorsoventral axis contributes differentially to environmental enrichment combined with voluntary exercise in alleviating chronic inflammatory pain in mice. J Neurosci. 2017;37(15):4145–4157. Gelfo F, Mandolesi L, Serra L, Sorrentino G, Caltagirone C. The neuroprotective effects of experience on cognitive functions: evidence from animal studies on the neurobiological bases of brain reserve [published online August 4, 2017.]. Neuroscience. 2017. pii:S0306-4522(17)30551-1. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Torres-Reverón, A., Rivera, L.L., Flores, I. et al. Environmental Manipulations as an Effective Alternative Treatment to Reduce Endometriosis Progression. Reprod. Sci. 25, 1336–1348 (2018). https://doi.org/10.1177/1933719117741374 Published: Version of record: Issue date: DOI: https://doi.org/10.1177/1933719117741374

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endometriosis

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Behavior, Animal Endometriosis Environment Housing, Animal Uterus Animals Anxiety Anxiety Anxiety Behavior, Animal Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Disease Models, Animal Disease Progression Endometriosis Endometriosis Endometriosis Female Rats Rats, Sprague-Dawley

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