{"paper_id":"41b6021f-9d5f-4259-a158-853c8c8e1a4e","body_text":"© 2017 Králíčková Milena and Vetvicka Vaclav. This open acce ss article is distributed under a Creative Commons \nAttribution (CC-BY) 3.0 license. \nAmerican Journal of Immunology \n \n \n \nReview \nConnection between Endometriosis and Vitamin D – True or \nFalse? \n \n1,2,3 Králíčková Milena and 4Vetvicka Vaclav \n \n1Department of Histology and Embryology, Faculty of Medicine, \nCharles University, Karlovarska 48, Plzen, Czech Republic, CZ-301 00,  Czech Republic \n2Department of Obstetrics and Gynecology, University Hospital, \nFaculty of Medicine, Charles University, AlejSvobody 80, Plzen, Czech Republic, CZ-301 66, Czech Republic \n3Biomedical Centre, Faculty of Medicine in Plzen, Charles University, Plzen, Czech Republic \n4Department of Pathology, University of Louisville, 511 S. Floyd, Louisville, KY 40202, USA \n \nArticle history \nReceived: 02-03-2017 \nRevised: 09-03-2017 \nAccepted: 10-03-2017 \n \nCorresponding Author: \nVetvicka Vaclav \nUniversity of Louisville, \nDepartment of Pathology, 511 \nS. Floyd, Louisville, KY \n40202, USA \nEmail: Vaclav.vetvicka@louisville.edu  \nAbstract: Endometriosis is a serious health problem character ized by the \npersistence and growth of vascularized tissue at va rious ectopic sites such \nas ovaries, bowel, or bladder. Despite decades of i ntensive research, we are \nnot making significant progress toward the etiology  or treatment of this \ndisease. The question of risk factor is similarly u nclear, with one possible \nfactor being diet-particularly the intake of vitami n D. In addition, as \nendometriosis has some similarities and clear conne ctions to cancer, where \nvitamin D is heavily studied, this relation started to be a subject of intensive \nresearch in this field, too. The overall aim of thi s study is to review possible \nlinks between vitamin D intake and endometriosis. \n \nKeywords:  Endometriosis, Vitamin D, Receptor, Ovaries, Female \n \nIntroduction \nEndometriosis is a chronic disease with estimated \nprevalence of 10% (Missmer and Cramer, 2003). \nDespite the seriousness and long-term research \ninterests, the etiology of endometriosis is still p oorly \nunderstood. However, immunological aspects are \ngaining more and more attention (Kralickova and \nVetvicka, 2015) and the search for reliable markers  is \nstill ongoing, with few clearly defined markers \n(Kralickova and Vetvicka, 2016). The question of ri sk \nfactor is similarly unclear, with one possible fact or \nbeing diet-particularly the intake of vitamin D.  \nVitamin D \nVitamin D is an essential steroid pro-hormone \nplaying an important role in maintenance of phospha te \nand calcium homeostasis. Despite the “vitamin” name , \nits source is not completely dietary and over 85% i s \ngenerated in the skin following exposure to ultravi olet \nlight. For detailed description of chemistry and \nbiological effects of vitamin D, see an excellent \nreview by Nandi et al. (2016). Besides the principal \nrole in bone homeostasis, vitamin D is involved in \nadditional biological processes such as modulation of \ncell growth, immune functions and reduction of \ninflammation. In addition, vitamin D affects in vitro \ninsulin and follicle-stimulating, hormone-induced \nsecretion of progesterone (Smolikova et al ., 2013). \nVitamin D is also heavily involved in human \nreproduction, from fertility outcome to semen quali ty \n(for review, Anagnostis  et al .,  2013). Proposed roles of \nvitamin D in women’s reproduction are summarized in  a \nreport by Grundmann and von Versen-Hoynck (2011).  \nA clinical study found small and nonsignificant \nincrease in 1,25-hydroxyvitamin D levels in patient s \nwith endometriosis with a slight trend towards high er \nlevels according to the severity of the disease \n(Somigliana et al ., 2007). Later, a prospective cohort \nstudy of 70,556 women with endometriosis, evaluated  \nover the period of 14 years, investigated whether t he \nplasma 1,25-hydroxyvitamin D levels were associated  \nwith the disease. The results suggested that greate r \nplasma levels of vitamin D and higher intake of dai ry \nfoods are clearly associated with decreased risk of  \nendometriosis (Harris et al ., 2013). This study, which \nestimated serum values of 1- α,25-hydroxyvitamin D3 \nand calculated variables such as race, age, physica l \nactivity or alcohol intake, showed inverse associat ion \nbetween 1- α,25-hydroxyvitamin D3 values and \nendometriosis and women with the highest levels had  \n\nKrálíčková Milena and Vetvicka Vaclav / American Journa l of Immunology 2017, 13 (2): 127.130 \nDOI: 10.3844/ajisp.2017.127.130  \n \n128 \n24% lower risk of endometriosis (Harris et al ., 2013). \nOn the other hand, a recent study found 1- α,25-\nhydroxyvitamin D3 levels significantly lower in ser um \nof patients with severe endometriosis (Miyashita et al ., \n2016), further confusing the question of whether vi tamin \nD levels are important. \nThe importance of 1- α,25-hydroxyvitamin D3 levels \nwas confirmed using experimental model of rats with  \nendometriotic implants. Animals with 1- α,25-\nhydroxyvitamin D3 showed significantly lesser \nsymptoms, leading to the conclusion that this molec ule \nresulted in regression via altering implant levels of \nVEGF, TIMP-2 and MMP-9 (Yildirim  et al ., 2014). \nHuman clinical trials will be needed to confirm the  \npossibility of treatment. An interesting observatio n by \nAgic  et al.  (2007) of very high metabolism of vitamin D \nin the endometrium suggested possible paracrine act ion \nof vitamin D. This hypothesis was supported by find ings \nthat Elocalcitol, a vitamin D receptor agonist, can  \nreverse endometriotic implants in animal models \n(Mariani  et al ., 2012). \nAn in vitro study focusing on the possible effects of \n1-α,25-hydroxyvitamin D3 on human endometriotic \nstromal cells isolated from ovarian endometrioma \ndemonstrated that the addition of 1- α,25-\nhydroxyvitamin D3 resulted in reduction of IL-1 β- \nand TNF- α-induced inflammatory responses and \nreduction of numbers of viable stromal cells \n(Miyashita et al ., 2016). If these results are \nconfirmed, supplementation with vitamin D might \nrepresent a novel strategy. Another hypothesis \nsuggested that endometriosis is an autoimmune \ndisease. With the known autocrine/paracrine action of \nvitamin D and established relation between \nautoimmune diseases and vitamin D, Peterlik and \nCross (2005) focused their attention on vitamin D a s \nan immunomodulator. The problems with any clear \nrelations result from the fact that endometriosis i s \nassociated with normal or elevated levels of 1- α,25-\nhydroxyvitamin D3 and not with any deficiency. The \nonly possibility would be local effects, which woul d be \nmissed on fluid evaluation such as serum. Additiona l \nhypotheses about vitamin D and endometriosis are \nsummarized in a recent review (Sayegh et al., 2014). \nVitamin D-Binding Protein \nVitamin D-binding protein (also called Gc-globulin \nor DBP) is a multifunctional protein deeply involve d in \ntransport of vitamin D sterols and in modulation of  \ninflammation and defense reactions. Due to the \nsuspected role of inflammation and several immune \naspects in the development of endometriosis, this \nprotein was also evaluated in women with \nendometriosis. However, the levels of this protein both \nin serum and in peritoneum were not significantly \ndifferent between control and endometriosis groups \n(Borkowski et al ., 2008). \n2-D electrophoresis was used for evaluation of DBP \nlevels in peritoneal fluid and plasma. One isoform \n(DBPE) showed lower levels in sampled peritoneal fl uid, \nbut when the patients were treated with oral \ncontraceptive, the levels of DBPE returned to norma l \n(Ferrero et al ., 2005), making the possibility of DBP \ninvolvement even more confusing. \nUsing proteomics, elevated levels of vitamin D-\nbinding protein were found in urine of women with \nendometriosis (Cho et al ., 2012), suggesting that urine \nsamples might be utilized in further investigations  and \nthat this protein might play a role in endometriosi s. A \ndifferent experimental approach, combining 2-DE gel  \nelectrophoresis with mass spectrometry, was later \nused to compare endometrial protein in ectopic \nendometrial tissue and normal endometrial tissue. \nAmong fifteen other proteins, levels of vitamin D-\nbinding protein were found to be significantly incr eased \nin ectopic endometrium, suggesting that this protei n can \nhave a direct role in the progression of this disea se \n(Hwang et al ., 2013). \nHuman cycling endometrium has been shown to \nexpress vitamin D receptor (Vigano et al ., 2006). This \nreceptor is a nuclear ligand-inducible transcriptio n factor \nand in complex with vitamin D, it regulates express ion \nof more than 900 different genes (Carlberg, 2003). \nA comparative histological study showed strong \nstaining for vitamin D receptor in endometriosis an d \nendometrial cancer, with the strongest staining in \nepithelial cells. In addition, these samples also s howed \nstronger expression of vitamin D 1 α-hydroxylase    \n(Agic et al ., 2007). The authors hypothesized that \nvitamin D might affect local action of immune cells  \nand/or secretion of cytokines involved in developme nt \nof endometriosis. \nElocalcitol, a selective vitamin D receptor agonist , \nreduced endometriosis development in mouse model vi a \ninhibition of peritoneal inflammation (Mariani et al ., \n2012), demonstrated by inhibition of macrophage inf lux \nand inhibition of secretion of inflammatory cytokines. \nGenetic alterations in the Vitamin D Receptor \n(VDR) gene might lead to biologically relevant \ndefects in gene activation with subsequent changes in \nimmune functions. Detailed analysis of vitamin D \nreceptor gene polymorphism in women suffering from \nendometriosis revealed no changes between patients \nand controls, strongly demonstrating that VDR \npolymorphism is not involved in endometriosis    \n(Lima Vilarino et al ., 2011). \nProteolytic analysis of serum found 3x higher level of \nvitamin D-binding protein in patients with \n\nKrálíčková Milena and Vetvicka Vaclav / American Journa l of Immunology 2017, 13 (2): 127.130 \nDOI: 10.3844/ajisp.2017.127.130  \n \n129 \nendometriosis. Subsequent analysis of specific alle le \nproducts showed that the most commonly expressed \nprotein is GC*2 allele product. As this product is not \nconverted to a macrophage-stimulating factor, the \nauthors hypothesize that the inability to stimulate  \nmacrophages to optimally phagocytose-invading \nmaterial results in allowing the endometriotic tiss ue to \nseed the peritoneal cavity (Faserl et al ., 2011). \nGene Level \nEndometrium is a target of 1- α,25-hydroxyvitamin \nD3 actions via regulation of specific genes, most \nprobably HOXA10 gene expression. This gene is \ncyclically expressed in adult endometrium in respon se to \nestrogens. 1- α,25-hydroxyvitamin D3 can induce \nHOXA10 transcription through VDR binding to its \nresponsive elements in the HOXA10 gene 5 region, \nwhich might subsequently induce differentiation of \nendometrial cells to decidual cells (Du et al ., 2005). \nLower expression of this gene was found in the euto pic \nand ectopic endometrium of endometriosis (Deng et al ., \n2011). However, a study evaluating VDR \npolymorphism found no association between this \npolymorphism and endometriosis or infertility \n(Villarino  et al ., 2011). Another vitamin D-regulated \ngene is osteopontin gene, with higher expression in  \neutopic endometrium (Cho et al ., 2009). \nThe 1 α-hydroxylase (enzyme necessary to catalyze \nthe synthesis of 1- α,25-hydroxyvitamin D3) mRNA is \nexpressed in ectopic endometrium and its levels are  \nincreased in proliferative phase cultures derived f rom \nwomen with endometriosis. These data suggested that  \ncycling endometrium might be included among the \nextrarenal sites able to synthesize vitamin D    \n(Vigano et al ., 2006). \nConclusion \nEndometriosis was first described more than 150 \nyears ago (Von Rokitansky, 1860), but the causes an d \ntreatments remain enigmatic and the search for \nresponsible molecules is still ongoing. Numerous \nstudies suggest some kind of vitamin D involvement \nin the pathogenesis of endometriosis, but direct pr oof \nis still elusive. Several studies have found altere d \nlevels of vitamin D in patients suffering from \nendometriosis; however, no clear benefits from \nsupplementation with vitamin D have been \nestablished. On the other hand, despite intensive \nresearch, we are not closer to understanding the \npathogenesis of endometriosis than we were decades \nago and there is still a need to fully confirm or d isprove \nthe functional role of the vitamin D system at the \nendometrial level. The hopes that vitamin D will \nrepresent the Golden Fleece seem to be unsubstantiated.  \nFinancial Support and Sponsorship \nNil. \nAuthor’s Contributions \nMilena Kralickova:  Designed the article, wrote the \nmanuscript. \nVaclav Vetvicka:  Designed the article, wrote the \nmanuscript. \nConflicts of Interest \nThere are no conflicts of interest. \nReferences \nAgic, A., H. Xu, C. 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