Estrogen–vitamin D interaction in multiple sclerosis

Abstract

To the Editor:We read with interest the recently published article showing that women who had been using combined oral contraceptives and/or had given birth before the onset of multiple sclerosis (MS) had a higher mean age of onset of the disease (1Holmqvist P, Hammar M, Landtblom AM, Brynhildsen J. Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosis. Fertil Steril 2010. DOI:10.1016/j.fertnstert.2010.06.045.Google Scholar). The authors speculate that estrogen (E) levels are likely to influence MS onset through an effect on the immune system. A number of potential mechanisms may be involved. In chronic inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis, studies have shown that E effects are likely to be mediated by the E receptors α and β, which are expressed in a wide range of immune cells involved in both the innate and adaptive immune response (2Cutolo M. Brizzolara R. Atzeni F. Capellino S. Straub R.H. Puttini P.C. The immunomodulatory effects of estrogens: clinical relevance in immune-mediated rheumatic diseases.Ann N Y Acad Sci. 2010; 1193: 36-42Crossref PubMed Scopus (62) Google Scholar).However, we feel that at least part of the protective effect exerted by Es in MS may be mediated by vitamin D. High serum 25-hydroxyvitamin D (25-OH-D, the circulating form of vitamin D) levels are associated with a lower risk of MS, and relapsing remitting MS patients have low 25-OH-D serum levels, particularly before the onset of relapses (3Ascherio A. Munger K.L. Simon K.C. Vitamin D and multiple sclerosis.Lancet Neurol. 2010; 9: 599-612Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar). Interestingly, E treatment has been shown to increase the levels of both bound and free calcitriol (1,25-OH-D, the active form of vitamin D) and of vitamin-binding protein (4Marcus R. Villa M.L. Cheema M. Cheema C. Newhall K. Holloway L. Effects of conjugated estrogen on the calcitriol response to parathyroid hormone in postmenopausal women.J Clin Endocrinol Metab. 1992; 74: 413-418Crossref PubMed Scopus (12) Google Scholar, 5Cheema C. Grant B.F. Marcus R. Effects of estrogen on circulating “free” and total 1,25-dihydroxyvitamin D and on the parathyroid-vitamin D axis in postmenopausal women.J Clin Invest. 1989; 83: 537-542Crossref PubMed Scopus (143) Google Scholar). Additionally, Es are able to restore vitamin D–mediated resistance to experimental autoimmune encephalomyelitis (the animal model of MS) in preovariectomized mice by increasing the expression of the vitamin D receptor gene and decreasing the expression of Cyp24a1, the enzyme that inactivates 1,25-OH-D (6Nashold F.E. Spach K.M. Spanier J.A. Hayes C.E. Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression.J Immunol. 2009; 183: 3672-3681Crossref PubMed Scopus (125) Google Scholar).Intriguingly, Es and vitamin D seem to be characterized by a mutual relationship, because vitamin D also influences E metabolism. Indeed, several studies have shown that calcitriol regulates the expression of Cyp19 (aromatase, the enzyme that catalyzes E synthesis) (7Barrera D. Avila E. Hernandez G. Halhali A. Biruete B. Larrea F. et al.Estradiol and progesterone synthesis in human placenta is stimulated by calcitriol.J Steroid Biochem Mol Biol. 2007; 103: 529-532Crossref PubMed Scopus (147) Google Scholar, 8Krishnan A.V. Swami S. Peng L. Wang J. Moreno J. Feldman D. Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy.Endocrinology. 2010; 151: 32-42Crossref PubMed Scopus (162) Google Scholar, 9Yague J.G. Garcia-Segura L.M. Azcoitia I. Selective transcriptional regulation of aromatase gene by vitamin D, dexamethasone, and mifepristone in human glioma cells.Endocrine. 2009; 35: 252-261Crossref PubMed Scopus (41) Google Scholar). Moreover, a recent study evaluated the effect of vitamin D supplementation on hormone levels in young women. Both progesterone and to a lesser extent E levels were decreased after 4 weeks of treatment (10Knight J.A. Wong J. Blackmore K.M. Raboud J.M. Vieth R. Vitamin D association with estradiol and progesterone in young women.Cancer Causes Control. 2010; 21: 479-483Crossref PubMed Scopus (40) Google Scholar).One of the most enigmatic features of MS epidemiology is the striking change in the sex ratio of the disease over time. Canadian studies have shown that the female/male ratio has been increasing for at least 50 years and now exceeds 3:1 (11Orton S.M. Herrera B.M. Yee I.M. Valdar W. Ramagopalan S.V. Sadovnick A.D. et al.Sex ratio of multiple sclerosis in Canada: a longitudinal study.Lancet Neurol. 2006; 5: 932-936Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar). Moreover, the same trend has been found among immigrants to Canada, suggesting the presence of some environmental factor responsible for this observation (12Orton S.M. Ramagopalan S.V. Brocklebank D. Herrera B.M. Dyment D.A. Yee I.M. et al.Effect of immigration on multiple sclerosis sex ratio in Canada: the Canadian Collaborative Study.J Neurol Neurosurg Psychiatry. 2010; 81: 31-36Crossref PubMed Scopus (45) Google Scholar). The functional mutual synergy between vitamin D and E, together with the wide-scale vitamin D deficiency present in populations residing in temperate climes (13Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10452) Google Scholar), suggests that a vitamin D–E interaction may well play a role in determining this epidemiologic observation. This hypothesis is further supported by studies showing that the female to male sex ratio of MS is correlated with latitude (14Taylor BV, Pearson JF, Clarke G, Mason DF, Abernethy DA, Willoughby E, et al. MS prevalence in New Zealand, an ethnically and latitudinally diverse country. Mult Scler 2010. DOI:10.1177/1352458510379614.Google Scholar).Thus, we believe it would be of interest to further investigate how E and vitamin D levels influence each other in both the general population and the MS population and to assess the prevalence of hormonal disorders in female MS patients. A better understanding of these mechanisms could ultimately lead to future strategies for disease prevention. To the Editor: We read with interest the recently published article showing that women who had been using combined oral contraceptives and/or had given birth before the onset of multiple sclerosis (MS) had a higher mean age of onset of the disease (1Holmqvist P, Hammar M, Landtblom AM, Brynhildsen J. Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosis. Fertil Steril 2010. DOI:10.1016/j.fertnstert.2010.06.045.Google Scholar). The authors speculate that estrogen (E) levels are likely to influence MS onset through an effect on the immune system. A number of potential mechanisms may be involved. In chronic inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis, studies have shown that E effects are likely to be mediated by the E receptors α and β, which are expressed in a wide range of immune cells involved in both the innate and adaptive immune response (2Cutolo M. Brizzolara R. Atzeni F. Capellino S. Straub R.H. Puttini P.C. The immunomodulatory effects of estrogens: clinical relevance in immune-mediated rheumatic diseases.Ann N Y Acad Sci. 2010; 1193: 36-42Crossref PubMed Scopus (62) Google Scholar). However, we feel that at least part of the protective effect exerted by Es in MS may be mediated by vitamin D. High serum 25-hydroxyvitamin D (25-OH-D, the circulating form of vitamin D) levels are associated with a lower risk of MS, and relapsing remitting MS patients have low 25-OH-D serum levels, particularly before the onset of relapses (3Ascherio A. Munger K.L. Simon K.C. Vitamin D and multiple sclerosis.Lancet Neurol. 2010; 9: 599-612Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar). Interestingly, E treatment has been shown to increase the levels of both bound and free calcitriol (1,25-OH-D, the active form of vitamin D) and of vitamin-binding protein (4Marcus R. Villa M.L. Cheema M. Cheema C. Newhall K. Holloway L. Effects of conjugated estrogen on the calcitriol response to parathyroid hormone in postmenopausal women.J Clin Endocrinol Metab. 1992; 74: 413-418Crossref PubMed Scopus (12) Google Scholar, 5Cheema C. Grant B.F. Marcus R. Effects of estrogen on circulating “free” and total 1,25-dihydroxyvitamin D and on the parathyroid-vitamin D axis in postmenopausal women.J Clin Invest. 1989; 83: 537-542Crossref PubMed Scopus (143) Google Scholar). Additionally, Es are able to restore vitamin D–mediated resistance to experimental autoimmune encephalomyelitis (the animal model of MS) in preovariectomized mice by increasing the expression of the vitamin D receptor gene and decreasing the expression of Cyp24a1, the enzyme that inactivates 1,25-OH-D (6Nashold F.E. Spach K.M. Spanier J.A. Hayes C.E. Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression.J Immunol. 2009; 183: 3672-3681Crossref PubMed Scopus (125) Google Scholar). Intriguingly, Es and vitamin D seem to be characterized by a mutual relationship, because vitamin D also influences E metabolism. Indeed, several studies have shown that calcitriol regulates the expression of Cyp19 (aromatase, the enzyme that catalyzes E synthesis) (7Barrera D. Avila E. Hernandez G. Halhali A. Biruete B. Larrea F. et al.Estradiol and progesterone synthesis in human placenta is stimulated by calcitriol.J Steroid Biochem Mol Biol. 2007; 103: 529-532Crossref PubMed Scopus (147) Google Scholar, 8Krishnan A.V. Swami S. Peng L. Wang J. Moreno J. Feldman D. Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy.Endocrinology. 2010; 151: 32-42Crossref PubMed Scopus (162) Google Scholar, 9Yague J.G. Garcia-Segura L.M. Azcoitia I. Selective transcriptional regulation of aromatase gene by vitamin D, dexamethasone, and mifepristone in human glioma cells.Endocrine. 2009; 35: 252-261Crossref PubMed Scopus (41) Google Scholar). Moreover, a recent study evaluated the effect of vitamin D supplementation on hormone levels in young women. Both progesterone and to a lesser extent E levels were decreased after 4 weeks of treatment (10Knight J.A. Wong J. Blackmore K.M. Raboud J.M. Vieth R. Vitamin D association with estradiol and progesterone in young women.Cancer Causes Control. 2010; 21: 479-483Crossref PubMed Scopus (40) Google Scholar). One of the most enigmatic features of MS epidemiology is the striking change in the sex ratio of the disease over time. Canadian studies have shown that the female/male ratio has been increasing for at least 50 years and now exceeds 3:1 (11Orton S.M. Herrera B.M. Yee I.M. Valdar W. Ramagopalan S.V. Sadovnick A.D. et al.Sex ratio of multiple sclerosis in Canada: a longitudinal study.Lancet Neurol. 2006; 5: 932-936Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar). Moreover, the same trend has been found among immigrants to Canada, suggesting the presence of some environmental factor responsible for this observation (12Orton S.M. Ramagopalan S.V. Brocklebank D. Herrera B.M. Dyment D.A. Yee I.M. et al.Effect of immigration on multiple sclerosis sex ratio in Canada: the Canadian Collaborative Study.J Neurol Neurosurg Psychiatry. 2010; 81: 31-36Crossref PubMed Scopus (45) Google Scholar). The functional mutual synergy between vitamin D and E, together with the wide-scale vitamin D deficiency present in populations residing in temperate climes (13Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10452) Google Scholar), suggests that a vitamin D–E interaction may well play a role in determining this epidemiologic observation. This hypothesis is further supported by studies showing that the female to male sex ratio of MS is correlated with latitude (14Taylor BV, Pearson JF, Clarke G, Mason DF, Abernethy DA, Willoughby E, et al. MS prevalence in New Zealand, an ethnically and latitudinally diverse country. Mult Scler 2010. DOI:10.1177/1352458510379614.Google Scholar). Thus, we believe it would be of interest to further investigate how E and vitamin D levels influence each other in both the general population and the MS population and to assess the prevalence of hormonal disorders in female MS patients. A better understanding of these mechanisms could ultimately lead to future strategies for disease prevention. Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosisFertility and SterilityVol. 94Issue 7PreviewThe aim of this study was to evaluate whether age of onset of multiple sclerosis is related to use of combined oral contraceptives and/or timing of childbirth. The results showed that use of combined oral contraceptives and childbirth before the first multiple sclerosis symptom was correlated to a higher mean age at the onset of the disease. Full-Text PDF Reply of the AuthorsFertility and SterilityVol. 95Issue 1PreviewWe 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. Full-Text PDF