Reply of the Authors

Abstract

We thank Disanto and coworkers for their interest in our article. Our study shows a statistically significant correlation between use of combined oral contraceptives (COC) before multiple sclerosis (MS) debut and mean age at the first MS symptom, but it does not show which effect the use of COC has on the pathophysiology of MS, although the results indicate a protective effect of COC. We share the opinion that vitamin D may mediate some of the effects of estrogens (Es). Vitamin D and Es might be closely related to each other, but we would like to point out that Es may also have a direct effect on the immune system and the central nervous system and thereby on the mechanisms involved in the pathophysiology of MS. The different cells of the immune system and CNS that are involved in the development and progression of MS have E receptors (ERs) and are capable of responding directly to Es binding to the receptors (1Tornwall J. Carey A.B. Fox R.I. Fox H.S. Estrogen in autoimmunity: expression of estrogen receptors in thymic and autoimmune T cells.J Gend Specif Med. 1999; 2: 33-40PubMed Google Scholar, 2Tai P. Wang J. Jin H. Song X. Yan J. Kang Y. et al.Induction of regulatory T cells by physiological level estrogen.J Cell Physiol. 2008; 214: 456-464Crossref PubMed Scopus (250) Google Scholar, 3Curran E.M. Berghaus L.J. Vernetti N.J. Saporita A.J. Lubahn D.B. Estes D.M. Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway.Cell Immunol. 2001; 214: 12-20Crossref PubMed Scopus (98) Google Scholar, 4Phiel K.L. Henderson R.A. Adelman S.J. Elloso M.M. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations.Immunol Lett. 2005; 97: 107-113Crossref PubMed Scopus (233) Google Scholar, 5Benten W.P. Stephan C. Wunderlich F. B cells express intracellular but not surface receptors for testosterone and estradiol.Steroids. 2002; 67: 647-654Crossref PubMed Scopus (56) Google Scholar, 6Zhao L. Wu T.W. Brinton R.D. Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons.Brain Res. 2004; 1010: 22-34Crossref PubMed Scopus (213) Google Scholar, 7Zaitsu M. Narita S. Lambert K.C. Grady J.J. Estes D.M. Curran E.M. et al.Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx.Mol Immunol. 2007; 44: 1977-1985Crossref PubMed Scopus (183) Google Scholar, 8Lambert K.C. Curran E.M. Judy B.M. Milligan G.N. Lubahn D.B. Estes D.M. Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation.J Immunol. 2005; 175: 5716-5723PubMed Google Scholar, 9Garcia-Ovejero D. Veiga S. Garcia-Segura L.M. Doncarlos L.L. Glial expression of estrogen and androgen receptors after rat brain injury.J Comp Neurol. 2002; 450: 256-271Crossref PubMed Scopus (223) Google Scholar, 10Arvanitis D.N. Wang H. Bagshaw R.D. Callahan J.W. Boggs J.M. Membrane-associated estrogen receptor and caveolin-1 are present in central nervous system myelin and oligodendrocyte plasma membranes.J Neurosci Res. 2004; 75: 603-613Crossref PubMed Scopus (75) Google Scholar, 11Simerly R.B. Chang C. Muramatsu M. Swanson L.W. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study.J Comp Neurol. 1990; 294: 76-95Crossref PubMed Scopus (1829) Google Scholar). Studies of experimental autoimmune encephalomyelitis (EAE), the dominant animal model for MS, have shown that the protective role of Es is, at least in part, mediated directly via ERs. 17β-Estradiol has an inhibitory effect on the development of EAE, and this effect has been shown to be dependent on ERα (12Polanczyk M. Zamora A. Subramanian S. Matejuk A. Hess D.L. Blankenhorn E.P. et al.The protective effect of 17beta-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-alpha.Am J Pathol. 2003; 163: 1599-1605Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). This has also been shown with ERα-selective ligands (13Elloso M.M. Phiel K. Henderson R.A. Harris H.A. Adelman S.J. Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands.J Endocrinol. 2005; 185: 243-252Crossref PubMed Scopus (93) Google Scholar, 14Tiwari-Woodruff S. Voskuhl R.R. Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice.J Neurol Sci. 2009; 286: 81-85Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). Estrogen receptor-α ligands may also ameliorate both clinical disease and inflammatory and neurodegenerative changes in mice who already have EAE (15Morales L.B. Loo K.K. Liu H.B. Peterson C. Tiwari-Woodruff S. Voskuhl R.R. Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis.J Neurosci. 2006; 26: 6823-6833Crossref PubMed Scopus (130) Google Scholar), whereas ERβ ligands only have neuroprotective effects (14Tiwari-Woodruff S. Voskuhl R.R. Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice.J Neurol Sci. 2009; 286: 81-85Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 16Tiwari-Woodruff S. Morales L.B. Lee R. Voskuhl R.R. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment.Proc Natl Acad Sci U S A. 2007; 104: 14813-14818Crossref PubMed Scopus (191) Google Scholar). Thus there is evidence for direct effects of Es as well as for effects that are mediated by vitamin D. Further research will hopefully show us how these effects can be used in both prevention and treatment of MS. We thank Disanto and coworkers for their interest in our article. Our study shows a statistically significant correlation between use of combined oral contraceptives (COC) before multiple sclerosis (MS) debut and mean age at the first MS symptom, but it does not show which effect the use of COC has on the pathophysiology of MS, although the results indicate a protective effect of COC. We share the opinion that vitamin D may mediate some of the effects of estrogens (Es). Vitamin D and Es might be closely related to each other, but we would like to point out that Es may also have a direct effect on the immune system and the central nervous system and thereby on the mechanisms involved in the pathophysiology of MS. The different cells of the immune system and CNS that are involved in the development and progression of MS have E receptors (ERs) and are capable of responding directly to Es binding to the receptors (1Tornwall J. Carey A.B. Fox R.I. Fox H.S. Estrogen in autoimmunity: expression of estrogen receptors in thymic and autoimmune T cells.J Gend Specif Med. 1999; 2: 33-40PubMed Google Scholar, 2Tai P. Wang J. Jin H. Song X. Yan J. Kang Y. et al.Induction of regulatory T cells by physiological level estrogen.J Cell Physiol. 2008; 214: 456-464Crossref PubMed Scopus (250) Google Scholar, 3Curran E.M. Berghaus L.J. Vernetti N.J. Saporita A.J. Lubahn D.B. Estes D.M. Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway.Cell Immunol. 2001; 214: 12-20Crossref PubMed Scopus (98) Google Scholar, 4Phiel K.L. Henderson R.A. Adelman S.J. Elloso M.M. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations.Immunol Lett. 2005; 97: 107-113Crossref PubMed Scopus (233) Google Scholar, 5Benten W.P. Stephan C. Wunderlich F. B cells express intracellular but not surface receptors for testosterone and estradiol.Steroids. 2002; 67: 647-654Crossref PubMed Scopus (56) Google Scholar, 6Zhao L. Wu T.W. Brinton R.D. Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons.Brain Res. 2004; 1010: 22-34Crossref PubMed Scopus (213) Google Scholar, 7Zaitsu M. Narita S. Lambert K.C. Grady J.J. Estes D.M. Curran E.M. et al.Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx.Mol Immunol. 2007; 44: 1977-1985Crossref PubMed Scopus (183) Google Scholar, 8Lambert K.C. Curran E.M. Judy B.M. Milligan G.N. Lubahn D.B. Estes D.M. Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation.J Immunol. 2005; 175: 5716-5723PubMed Google Scholar, 9Garcia-Ovejero D. Veiga S. Garcia-Segura L.M. Doncarlos L.L. Glial expression of estrogen and androgen receptors after rat brain injury.J Comp Neurol. 2002; 450: 256-271Crossref PubMed Scopus (223) Google Scholar, 10Arvanitis D.N. Wang H. Bagshaw R.D. Callahan J.W. Boggs J.M. Membrane-associated estrogen receptor and caveolin-1 are present in central nervous system myelin and oligodendrocyte plasma membranes.J Neurosci Res. 2004; 75: 603-613Crossref PubMed Scopus (75) Google Scholar, 11Simerly R.B. Chang C. Muramatsu M. Swanson L.W. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study.J Comp Neurol. 1990; 294: 76-95Crossref PubMed Scopus (1829) Google Scholar). Studies of experimental autoimmune encephalomyelitis (EAE), the dominant animal model for MS, have shown that the protective role of Es is, at least in part, mediated directly via ERs. 17β-Estradiol has an inhibitory effect on the development of EAE, and this effect has been shown to be dependent on ERα (12Polanczyk M. Zamora A. Subramanian S. Matejuk A. Hess D.L. Blankenhorn E.P. et al.The protective effect of 17beta-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-alpha.Am J Pathol. 2003; 163: 1599-1605Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). This has also been shown with ERα-selective ligands (13Elloso M.M. Phiel K. Henderson R.A. Harris H.A. Adelman S.J. Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands.J Endocrinol. 2005; 185: 243-252Crossref PubMed Scopus (93) Google Scholar, 14Tiwari-Woodruff S. Voskuhl R.R. Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice.J Neurol Sci. 2009; 286: 81-85Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). Estrogen receptor-α ligands may also ameliorate both clinical disease and inflammatory and neurodegenerative changes in mice who already have EAE (15Morales L.B. Loo K.K. Liu H.B. Peterson C. Tiwari-Woodruff S. Voskuhl R.R. Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis.J Neurosci. 2006; 26: 6823-6833Crossref PubMed Scopus (130) Google Scholar), whereas ERβ ligands only have neuroprotective effects (14Tiwari-Woodruff S. Voskuhl R.R. Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice.J Neurol Sci. 2009; 286: 81-85Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 16Tiwari-Woodruff S. Morales L.B. Lee R. Voskuhl R.R. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment.Proc Natl Acad Sci U S A. 2007; 104: 14813-14818Crossref PubMed Scopus (191) Google Scholar). Thus there is evidence for direct effects of Es as well as for effects that are mediated by vitamin D. Further research will hopefully show us how these effects can be used in both prevention and treatment of MS. Estrogen–vitamin D interaction in multiple sclerosisFertility and SterilityVol. 95Issue 1PreviewTo the Editor: Full-Text PDF