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 prior to the onset of multiple sclerosis (MS) had a higher mean age of onset of the disease (1). The authors speculate that estrogen 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 estrogen effects are likely to be mediated by the estrogen receptors α and β, which are expressed in a wide range of immune cells involved in both the innate and adaptive immune response (2).
However, we feel that at least part of the protective effect exerted by estrogens 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 prior to the onset of relapses (3).
Interestingly, estrogen 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 (4-5). Additionally, estrogens are able to restore vitamin D mediated resistance to experimental autoimmune encephalomyelitis (the animal model of MS) in pre-ovariectomized mice by increasing the expression of the vitamin D receptor gene and decreasing the expression of Cyp24a1, the enzyme which inactivates 1,25-OH-D (6).
Intriguingly, estrogens and vitamin D seem to be characterized by a mutual relationship, as vitamin D also influences estrogen metabolism. Indeed, several studies have shown that calcitriol regulates the expression of Cyp19 (aromatase, the enzyme which catalyzes estrogen synthesis) (7-9). Moreover, a recent study evaluated the effect of vitamin D supplementation on hormone levels in young women. Both progesterone and to a lesser extent estrogen levels were decreased after 4 weeks of treatment (10).
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-to-male ratio has been increasing for at least 50 years and now exceeds 3:1 (11). Moreover, the same trend has been found among immigrants to Canada, suggesting the presence of some environmental factor responsible for this observation (12). The functional mutual synergy between vitamin D and estrogen, together with the wide scale vitamin D deficiency present in populations residing in temperate climes (13) suggest that a vitamin D-estrogen interaction may well play a role in determining this epidemiological observation. This hypothesis is further supported by studies showing that the female to male sex-ratio of MS is correlated with latitude (14).
Thus, we feel it would be of interest to further investigate how estrogen and vitamin D levels influence each other in both the general and the MS population and to assess the prevalence of hormonal disorders in MS female patients. A better understanding of these mechanisms could ultimately lead to future strategies for disease prevention.
Giulio Disanto, MD a,b
Adam E Handel, BMBCh a,b
Sreeram V Ramagopalan, D.Phil a,b,c
aWellcome Trust Centre for Human Genetics
bDepartment of Clinical Neurology
cNuffield Department of Clinical Medicine
University of Oxford
Oxford, United Kingdom
1. Holmqvist 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 (in press). 2010.
2. Cutolo M, Brizzolara R, Atzeni F, Capellino S, Straub RH, Puttini PC. The immunomodulatory effects of estrogens: clinical relevance in immune-mediated rheumatic diseases. Ann N Y Acad Sci. 2010 Apr;1193(1):36-42.
3. Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. Lancet Neurol. 2010 Jun;9(6):599-612.
4. Marcus R, Villa ML, 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 Feb;74(2):413-8.
5. Cheema C, Grant BF, 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 Feb;83(2):537-42.
6. Nashold FE, Spach KM, Spanier JA, Hayes CE. Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. J Immunol. 2009 Sep 15;183(6):3672-81.
7. Barrera 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 Mar;103(3-5):529-32.
8. Krishnan AV, 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 Jan;151(1):32-42.
9. Yague JG, Garcia-Segura LM, Azcoitia I. Selective transcriptional regulation of aromatase gene by vitamin D, dexamethasone, and mifepristone in human glioma cells. Endocrine. 2009 Apr;35(2):252-61.
10. Knight JA, Wong J, Blackmore KM, Raboud JM, Vieth R. Vitamin D association with estradiol and progesterone in young women. Cancer Causes Control. 2010 Mar;21(3):479-83.
11. Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006 Nov;5(11):932-6.
12. Orton SM, Ramagopalan SV, Brocklebank D, Herrera BM, Dyment DA, Yee IM, et al. Effect of immigration on multiple sclerosis sex ratio in Canada: the Canadian Collaborative Study. J Neurol Neurosurg Psychiatry. 2010 Jan;81(1):31-6.
13. Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.
14. Taylor 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 Sep 2.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.09.047
The Authors Respond:
We thank Disanto and co-workers for their interest in our article. Our study shows a statistical significant correlation between use of COC before 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. Vitamin D and estrogens might be closely related to each other, but we would like to point out that estrogens 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 estrogen receptors (ER) and are capable of responding directly to estrogens binding to the receptors (1-11). Studies of experimental autoimmune encephalomyelitis (EAE), the dominant animal model for MS, have shown that the protective role of estrogens 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 of ERα(12). This has also been shown with ERα-selective ligands(13-14). ERα ligands may also ameliorate both clinical disease and inflammatory and neurodegenerative changes in mice who already have EAE(15) whereas ERβ ligands only have neuroprotective effects (14, 16). Thus there is evidence for direct effects of estrogens 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.
Per Holmqvist, MD a,b
Jan Brynhildsen MD, PhD a
aWomen’s and Children’s Health
Department of Clinical and Experimental Medicine
Faculty of Health Sciences
bClinical Department of Obstetrics & Gynaecology
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Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.09.048