We previously demonstrated the negative impact of stress in an animal model of endometriosis. Although its role is unclear, altered levels of vitamin D (VitD) have been found in patients with this condition. VitD signaling through the VitD receptor (VDR) has anti-proliferative properties and induces an anti-inflammatory phenotype in macrophages. We hypothesized that stress impacts the vitamin D-VDR system, influencing macrophage behavior and the local inflammatory milieu in endometriosis. Endometriosis was surgically induced in female Sprague-Dawley rats, which were then exposed to uncontrollable, controllable, or no stress for 10 days. Sham controls received sutures only. VitD levels were measured by ELISA; cytokine levels by multiplex assay and PCR; and VDR expression and macrophage numbers assessed by immunohistochemistry and immunofluorescence. VDR expression in patient samples was assessed by immunohistochemical staining of a tissue microarray. Serum VitD levels were higher in endometriosis animals compared with sham (p < 0.01) with no significant effect of stress. Uncontrollable stress increased macrophage infiltration (p < 0.01) and VDR expression in vesicles, which were attenuated by controllable stress. Macrophage infiltration correlated with vesicle area (p < 0.05), and peritoneal vitamin D levels correlated with vesicle VDR expression (r = 0.81, p < 0.01). Decreased expression of chemokine ligand 2 (p < 0.05) and TGFβ was observed in endometriosis with uncontrollable stress, whereas IL12 increased with controllable stress. Differential expression of VDR was observed in patient tissues. Stress exacerbates development of cysts in endometriosis through mechanisms that include macrophage recruitment, cytokine changes, and a potentially perturbed VitD:VDR axis, suggesting an impact on the local inflammatory environment.
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Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor FN, Vigano P. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9.
Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–9.
Fourquet J, Gao X, Zavala D, Orengo JC, Abac S, Ruiz A, et al. Patients’ report on how endometriosis affects health, work, and daily life. Fertil Steril. 2010;93(7):2424–8.
Fourquet J, Báez 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):107–12.
Nnoham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco Nardone F, de Cicco Nardone C, et al. World Endometriosis Research Foundation Global Study of Women’s Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96(2):366–73.
Barnack JL, Chrisler JC. The experience of chronic illness in women: a comparison between women with chronic migraine headaches. Women Health. 2007;46(1):115–33.
Facchin F, Barbara G, Dridi D, Alberico D, Buggio L, Somigliana E, et al. Mental health in women with endometriosis: searching for predictors of psychological distress. Hum Reprod. 2017;32(9):1855–61.
Pope CJ, Sharma V, Sharma S, Mazmanian D. A systematic review of the association between psychiatric disturbances and endometriosis. J Obstet Gynaecol Can. 2015;37:1006–15.
Chen L-C, Hsu J-W, Huang K-L, Bai YM, Su TP, Li CT, et al. Risk of developing major depression and anxiety disorders among women with endometriosis: a longitudinal follow-up study. J Affect Disord. 2016;190:282–5.
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):851–62.
Appleyard CB, Cruz ML, Hernández S, Thompson KJ, Bayona M, Flores I. Stress management affects outcomes in the pathophysiology of an endometriosis model. Reprod Sci. 2015;22(4):431–41. https://doi.org/10.1177/1933719114542022.
Cuevas M, Cruz ML, Ramirez AE, Flores I, Thompson KJ, Bayona M, et al. Stress during development of experimental endometriosis influences nerve growth and disease progression. Reprod Sci. 2018;25(3):347–57.
Casaletto KB, Staffaroni AM, Elahi F, Fox E, Crittenden PA, You M, et al. Perceived stress is associated with accelerated monocyte/macrophage aging trajectories in clinically normal adults. Am J Geriatr Psychiatry. 2018;26(9):952–63.
Tariverdian N, Theoharides TC, Siendentopf F, Gutierrez G, Jeschke U, Rabinovich GA, et al. Neuroendocrine-immune disequilibrium and endometriosis: an interdisciplinary approach. Semin Immunopathol. 2007;29(2):193–210 Review.
Raiter-Tenenbaum A, Baranao RI, Etchepareborda JJ, Meresman GF, Rumi LS. Functional and phenotypic alterations in peritoneal macrophages from patients with early and advanced endometriosis. Arch Gynecol Obstet. 1998;261:147–57.
Halme J, White C, Kauma S, Eates J, Haskill S. Peritoneal macrophages from patients with endometriosis release growth factor activity in vitro. J Clin Endocrinol Metab. 1988;66:1044–9.
Shi YL, Luo XZ, Zhu XY, Li DJ. Combination of 17 beta-estradiol with the environmental pollutant TCDD is involved in pathogenesis of endometriosis via up-regulating the chemokine I-309-CCR8. Fertil Steril. 2007;88:317–25.
Yu J, Wang Y, Zhou WH, Wang L, He YY, Li DJ. Combination of estrogen and dioxin is involved in the pathogenesis of endometriosis by promoting chemokine secretion and invasion of endometrial stromal cells. Hum Reprod. 2008;23:1614–26.
Mariani M, Viganò P, Gentilini D, Camisa B, Caporizzo E, di Lucia P, et al. The selective vitamin D receptor agonist, elocalcitol, reduces endometriosis development in a mouse model by inhibiting peritoneal inflammation. Hum Reprod. 2012;27(7):2010–9.
Song L, Papaioannou G, Zhao H, Luderer HF, Miller C, Dall’Osso C, et al. The vitamin D receptor regulates tissue resident macrophage response to injury. Endocrinology. 2016;157(10):4066–75.
Ding C, Wilding JP, Bing C. 1,25-dihydroxyvitamin D3 protects against macrophage-induced activation of NFκB and MAPK signalling and chemokine release in human adipocytes. PLoS One. 2013;8(4):e61707. https://doi.org/10.1371/journal.pone.0061707.
Hidalgo AA, Trump DL, Johnson CS. Glucocorticoid regulation of the vitamin D receptor. J Steroid Biochem Mol Biol. 2010;121(1–2):372–5.
Colón-Díaz M, Báez-Vega P, García M, Ruiz A, Monteiro JB, Fourquet J, et al. HDAC1 and HDAC2 are Differentially expressed in endometriosis. Reprod Sci. 2012;19(5):483–92.
Colón-Caraballo M, Monteiro JB, Flores I. H3K27me3 is an epigenetic mark of relevance in endometriosis. Reprod Sci. 2015;22(9):1134–42.
Segura-Jimenez V, Romero-Zurita A, Carbonell-Baeza A, Aparicio VA, Ruiz JR, Delgado-Fernandez M. Effectiveness of Tai-Chi for decreasing acute pain in fibromyalgia patients. Int J Sports Med. 2014;35:418–23.
Shariff F, Carter J, Dow C, Polley MJ, Salinas M, Ridge D. Mind and body management strategies for chronic pain and rheumatoid arthritis. Qual Health Res. 2009;19:1037–49.
Sayegh L, Fuleihan G-H, Nassar AH. Vitamin D in endometriosis: a causative or confounding factor? Metabolism. 2014;63(1):32–41.
Giampaolino P, Della Corte L, Foreste V, Bifulco G. Is there a relationship between vitamin D and endometriosis? An overview of literature. Curr Pharm Des. 2019;25(22):2421–7.
Cermisoni GC, Alteri A, Corti L, Rabellotti E, Papaleo E, Vigano P, et al. Vitamin D and endometrium: a systematic review of a neglected area of research. Int J Mol Sci. 2018;19(8):2320.
Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA. Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013;177(5):420–30.
Abbas MA, Taha MO, Disi AM, Shomaf M. Regression of endometrial implants treated with vitamin D3 in a rat model of endometriosis. Eur J Pharmacol. 2013;715(1–3):72–5.
Yildirim B, Guler T, Akbulut M, Oztekin O, Sariiz G. 1-α,25-dihydroxyvitamin D3 regresses endometriotic implants in rats by inhibiting neovascularization and altering regulation of matrix metalloproteinase. Postgrad Med. 2014;126:104–10.
Kalaitzopoulos DR, Lempesis IG, Athanasaki F, Schizas D, Samartzis EP, Kolibianakis EM, et al. Association between Vitamin D and endometriosis: a systemic Review. Hormones (Athens). 2019;19:109–21. https://doi.org/10.1007/s42000-019-00166-w.
Miyashita M, Koga K, Izumi G, Sue F, Makabe T, Taguchi A, et al. Effects of 1,25-dihydroxy vitamin D3 on endometriosis. J Clin Endocrinol Metab. 2016;101(6):2371–9.
Buggio L, Somigliana E, Pizzi MN, Dridi D, Roncella E, Vercellini P. 25-Hydroxyvitamin D serum levels and endometriosis: results of a case-control study. Reprod Sci. 2019;26(2):172–7.
Agic A, Xu H, Altgassen C, Noack F, Wolfler MM, Diedrich K, et al. Relative expression of 1,25-dihydroxyvitamin D3 receptor, vitamin D 1_-hydroxylase, vitaminD 24-hydroxylase, and vitamin D 25-hydroxylase in endometriosis and gynecologic cancers. Reprod Sci. 2007;14:486–97.
Hartwell D, Rodbro P, Jensen SB, Thomsen K, Christiansen C. Vitamin D metabolites- relation to age, menopause and endometriosis. Scad J Clin Lab Invest. 1990;50(2):115–21.
Somigliana E, Panina-Bordignon P, Murone S, Di Lucia P, Vercellini P, Vigano P. Vitamin D reserve is higher in women with endometriosis. Hum Reprod. 2007;22(8):2273–8.
Trabert B, Peters U, De Roos AJ, Holt VL. Diet and risk of endometriosis in a population-based case-control study. Br J Nutr. 2011;105(3):459–67.
Parazzini F, Viganò P, Candiani M, Fedele L. Diet and endometriosis risk: a literature review. Reprod BioMed Online. 2013;26(4):323–36.
Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44(3):450–62.
Beste MT, Pfaffle-Doyle N, Prentice EA, Morris SN, Lauffenburger DA, Isaacson KB, et al. Endometriosis: molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation. Sci Transl Med. 2014;6(222):222ra16.
Pike JW, Meyer MB. The vitamin D receptor: new paradigms for the regulation of gene expression 1,25-dihydroxyvitamin D3. Endocrinol Metab Clin N Am. 2010;39(2):255–69.
Luderer HF, Nazarian RM, Zhu ED, Demay MB. Ligand-dependent actions of the vitamin D receptor are required for activation of TGF-b signaling during the inflammatory response to cutaneous injury. Endocrinology. 2013;154(1):16–24.
Al-Azhri J, Zhang Y, Bshara W, Zirpoli G, McCann SE, Khoury T, et al. Tumor expression of vitamin D receptor and breast cancer histopathological characteristics and prognosis. Clin Cancer Res. 2017;23(1):97–103.
Lee S-K, Choi H-S, Song M-R, Lee M-O, Lee JW. Estrogen receptor, a common interaction partner for a subset of nuclear receptors, Mol Endocrinol 1998, 12 (8) August 1184–1192.
Gilad LA, Schwartz B. Association of estrogen receptor beta with plasma-membrane caveola components: implication in control of vitamin D receptor. J Mol Endocrinol. 2007;38(6):603–18.
Gilad LA, Bresler T, Gnainsky J, Smirnoff P, Schwartz B. Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells. J Endocrinol. 2005;185(3):577–92.
The authors would like to acknowledge the technical support of Inevy Seguinot and Yadmarie Rivera. Also, thanks to Alcira Benítez for histological preparation and analysis. The endometriosis TMA was constructed with funds from U56CA126379 and we would like to acknowledge the assistance of the staff in the H. Lee Moffitt Cancer Center imaging core.
These studies were supported in part by R15AT006373 (CBA), R25 GM096955 (AL), R25GM082406 (SH & RAI), and G12MD007579-12 (Behavioral Core Laboratory) from the National Institutes of Health (NIH).
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committee at Ponce Health Sciences University (Animal Welfare Assurance D16-00352).
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Electronic Supplementary Material
Tissue samples included in Tissue Micro Array (PPTX 51 kb)
Vitamin D receptor correlates with estrogen receptor expression. A significant negative correlation between VDR and estrogen receptor (ER) alpha was found in endometrium glands of both (A) controls (p < 0.01) and (B) patients (p < 0.01). A significant negative correlation with ER beta (p < 0.05) was only found in (D) patients, and not in (C) controls. No significant correlations with progesterone receptor (PR) were found in the glands of either controls (E) or patients (F) (PPTX 387 kb)
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Lopez, A., Cruz, M.L., Chompre, G. et al. Influence of Stress on the Vitamin D-Vitamin D Receptor System, Macrophages, and the Local Inflammatory Milieu in Endometriosis. Reprod. Sci. 27, 2175–2186 (2020). https://doi.org/10.1007/s43032-020-00235-1
- Vitamin D
- Vitamin D receptor