A rational approach on the use of sex steroids in multiple sclerosis

Recent Patents on CNS Drug Discovery

Volumn 3, Issue 1, 2008, Pages 34-39

  Antonio, Martocchia ^a,b   Patrizia, Frugoni ^a   Ilaria, Indiano ^a   Paolo, Falaschi ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Androgen; Estrogen; Multiple sclerosis; Progesterone; Sexual dimorphism

Indexed keywords

CYANOCOBALAMIN; DESOGESTREL; ESTRADIOL; ESTRIOL; ESTROGEN; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; FOLIC ACID; GESTAGEN; GESTODENE; GLATIRAMER; MEDROXYPROGESTERONE; MYELIN; NOMEGESTROL; NOMEGESTROL ACETATE; ORAL CONTRACEPTIVE AGENT; PLACEBO; PROCAINE; PROGESTERONE RECEPTOR; PYRIDOXINE; RALOXIFENE; RIBOFLAVIN; SALICYLATE SODIUM; SELECTIVE ESTROGEN RECEPTOR MODULATOR; SEX HORMONE; TESTOSTERONE; THIAMINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; WAY 138923; ZINC CHLORIDE;

ALLERGIC ENCEPHALOMYELITIS; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CLINICAL TRIAL; DEMYELINATION; DISEASE COURSE; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; HORMONAL THERAPY; HORMONE SUBSTITUTION; HUMAN; HYPERANDROGENISM; HYPOTHALAMUS HYPOPHYSIS GONAD SYSTEM; IMMUNOMODULATION; IMMUNOPATHOGENESIS; INCIDENCE; LOW DRUG DOSE; MULTIPLE SCLEROSIS; NEUROPROTECTION; NONHUMAN; PREVALENCE; PRIORITY JOURNAL; PUERPERIUM; RELAPSE; SEX DIFFERENCE; T LYMPHOCYTE;

ANIMALS; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; HUMANS; MULTIPLE SCLEROSIS; SEX CHARACTERISTICS; STEROIDS;

EID: 38949144388     PISSN: 15748898     EISSN: None     Source Type: Journal    
DOI: 10.2174/157488908783421474     Document Type: Article

References (97)

1. Whitacre CC. Sex differences in autoimmune disease. Nature Immunol 2001; 2: 777-780.
2. Duquette P, Pleines J, Girard M, Charest L, Senecal-Quevillon M, Masse C. The increased susceptibility of women to multiple sclerosis. Can J Neurol Sci 1992; 19: 466-471.
3. The Interferon-B multiple sclerosis study group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis I. Clinical results of a multicenter, randomized, double- blind, placebo-controlled trial. Neurology 1993; 43: 655-661.
4. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995; 45: 1277-1285.
5. Jacobs LD, Cookfair DL, Rudick RA, et al. For the Multiple Sclerosis Collaborative Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39: 285-294.
6. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double -blind placebo-controlled trial. The copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45: 1268-1276.
7. Taniguchi T, Ohno S, Fujii-Kuriyama Y, Muramatsu M. The nucleotide sequence of human fibroblast interferon cDNA. Gene 1980; 10: 11-15.
8. Alam, J., Rogge, M., Goetz, S.: WO99062542 (1999).
9. Fiers, W.C.: EP0041313 (1981).
10. Itoh, S., Nishi, T., Mizukami, T., Matsumoto, T., Oka, T., Taniguchi, T., Sugano, H.: EP0083069 (1983).
11. Itoh, S., Nishi, T., Mizukami, T., Matsumoto, T., Oka, T., Taniguchi, T., Sugano, H.: US4686191 (1987).
12. Reiser, W., Joester, K.E., Wolf, W.: EP0287075 (1988).
13. Siklosi, T., Joester, K.E., Hofer, H.: EP0529300 (1993).
14. Pedersen, A.H., Andersen, K.V., Bornaes, C., Rasmussen, P.B.: US20077238344 (2007).
15. Yong, W.V., Chabot S.: US2005014694 (2005).
16. Shah A, Eggenberger E, Zivadinov R, Stüve O, Frohman EM. Corticosteroids for multiple sclerosis: II. Application for disease-modifying effects. Neurotherapeutics 2007; 4: 627-32.
17. Zorgdrager A, De Keyser J. Menstrually related worsening of symptoms in multiple sclerosis. J Neurol Sci 1997; 149: 95-97.
18. Zorgdrager A, De Keyser J. The premenstrual period and exacerbations in multiple sclerosis. Eur Neurol 2002; 48: 204-206.
19. Smith H, Studd JWW. A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J Royal Soc Med 1992; 85: 612-613.
20. Holmqvist P, Wallberg M, Hammar M, Landthlom AM, Brynhildsen J. Symptoms of multiple sclerosis in women in relation to sex steroid exposure. Maturitas 2006; 54:149-153.
21. Confavreux C, Hutchinson M, Hours M, Cortinovis-Tourniaire P, Grimaud J, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998; 339:285-291.
22. Vukusic S, Hutchinson K Hours M, et al. The Pregnancy In Multiple Sclerosis Group; Pregnancy In Multiple Sclerosis Group. Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of postpartum relapse. Brain 2004; 127:1353-1360.
23. Vukusic S, Confavreux C. Multiple sclerosis and pregnancy. Rev Neurol (Paris) 2006; 162:299-309.
24. Duquette P, Girard M. Hormonal factors in susceptibility to multiple sclerosis. Curr Opin Neurol Neurosurg 1993; 6:195-201.
25. Whitacre CC, Reingold SC, O'Looney PA and the Task Force on Gender, Multiple sclerosis and autoimmunity. A gender gap in autoimmunity. Science 1999; 283:1277-1278.
26. Wynn DR, Rodriquez M, O'Fallon WM, Kurland LT. A reappraisal of the epidemiology of multiple sclerosis in Olmsted County, Minnesota. Neurol 1990; 40:780-786.
27. van Walderveen MAA, Barkhof F, Polman CH, Frequin STFM, Hommes OR, Valk J. Magnetic resonance evaluation of disease activity during pregnancy in multiple sclerosis. Neurology 1994; 44:327-329.
28. Pozzilli C, Tomassini V, Marinelli F, Paolillo A, Gasperini C, Bastianello S. "Gender gap" in multiple sclerosis: magnetic resonance imaging evidence. Eur J Neurol 2003; 10:95-97.
29. van Walderveen MA, Lycklama A, Nijeholt GJ, et al. Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis. Arch Neurol 2001; 58:76-81.
30. Pozzilli C, Falaschi P, Maniero C, et al. MRI in multiple sclerosis during the menstrual cycle: relationship with sex hormone patterns. Neurology 1999; 53:622-624.
31. Falaschi P, Martocchia A, Proietti. A, D'Urso R, Antonimi G, Pozzilli C. The modulatory role of the sex steroid balance on the disease activity in female patients with multiple sclerosis. in: Focus on Multiple Sclerosis Research. Columbus F, Editor. Nova Science Publishers, Inc. 2004; 199-215.
32. Grinsted L, Heltberg A, Hagen C, Djursing H. Serum sex hormone and gonadotropin concentrations in premenopausal women with multiple sclerosis. J Int Med 1989; 226:241-246.
33. Falaschi P, Martocchia A, Proietti A, D'Urso R, Antonini G. High incidence of hyperandrogenism-related clinical signs in patients with multiple sclerosis. Neuroendocrinol Lett 2001; 22:248-250.
34. Tomassini V, Onesti E, Mainero C, et al. Sex hormones modulate brain damage in multiple sclerosis: MRI evidence. J Neurol Neursurg Psychiatry 2005; 76:272-275.
35. Foster SC, Daniels C, Bourdette DN, Bebo BF. Dysregulation of the hypothalamic-pituitary-gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis: J. Neuroimmunol 2003; 140:78-87.
36. Wei T, Lightman SL. The neuroendocrine axis in patients with multiple scierosis. Brain 1997; 120:1067-1076.
37. De Andres C, Rodriguez-Sainz MC, Munoz-Fernandez MA, et al. Short-term sequential analysis of sex hormones and helper T cells type 1 (Th1) and helper T cells type 2 (Th2) cytokines during and after multiple sclerosis relapse. Eur Cytokine Netw 2004; 15:197-202.
38. Poser S, Raun NE, Wikstrom J, Poser W. Pregnancy, oral contraceptives and multiple sclerosis. Acta Neurol Scand 1979; 59:108-118.
39. Alonso A, Jick SS, Otek MJ, Ascherio A, Jick H, Hernan MA. Recent use of oral contraceptives and the risk of multiple sclerosis. Arch Neurol 2005; 62:1362-1365.
40. Villard-Mackintosh M, Vessey MP. Oral contraceptives and reproductive factors in multiple sclerosis incidence. Contraception 1993; 47:161-168.
41. Thorogood M, Hannaford PC. The influence of oral contraceptives on the risk of multiple sclerosis. Br J Obstet Gynaecol 1998; 105:1296-1299.
42. Hernan MA, Hohol MJ, Olek MJ, Spiegolman D, Ascherio A. Oral contraceptives and the incidence of multiple sclerosis. Neurology 2000; 55:848-854.
43. Dwosh E, Guimond C, Sadovnick AD. Reproductive counselling in MS: a guide for healthcare professionals Int MS J 2003; 10:67.
44. Tsai M, O'Malley BM. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Ann Rev Biochem 1994; 63:451-486.
45. Simoncini T, Genazzani AR. Non-genomic actions of sex steroid hormones. Eur J Endocrinol 2003; 148:281-292.
46. Weusten U, Blankenstein MA, Gmelig-Meyling FH, Schuurmann HJ, Kater L, Thijssen JH. Presence of oestrogen receptors in human blood mononuclear cels and thymocytes, Acta Endocrinol (Copenh) 1986; 112:409-414.
47. Danel L, Souweine G, Monier JC, Saez S. Soecific estrogen binding sites in human lymphoid cells and thymic cells. J Steroid Biochem 1983; 18:559-563.
48. Cohen JH, Danel L, Cordier G, Saez S, Revillard JP. Sex steroid receptors in peripheral T cells: absence of androgen receptors and restriction of estrogen receptors to OKT8-positive cells. J Immunol 1983; 131:2767-2771.
49. Danel L, Menouni M, Cohen JH, et al. Distribution of androgen and estrogen receptors among lymphoid and haemopoietic cell lines. Leuk Res 1985; 9:1373-1378.
50. Kovacs WJ, Olsen NJ. Androgen recetors in human thymocytes. J Immunol 1987; 139:490-493.
51. Stimson WH. Oestrogen and human T lymphocytes: presence of specific receptors in the T-suppressor/cytotoxic subset Scand J Immunol 1988; 28:345-350.
52. Gulshan S, McCruden AB, Stimson WH. Oestrogen receptors in macrophages. Scand J Immunol 1990; 31:691-697.
53. Viselli SM, Olsen NJ, Shults K, Steizer G, Kovacs WJ. Immunochemical and flow cytometric analysis of androgen receptor expression in thymocytes. Mol Cell Endocrinol 1995; 109:19-26.
54. Butts CL, Shukair SA, Duncan KM, Harris CW, Belyavskaya E, Sternberg EM. Evaluation of steroid hormone receptor protein expression in intact cells using flow cytometry. Nucl Recept Signal 2007,5:e007.
55. Srivastava MD, Anderson DJ. Progesterone receptor expression by human leukocyte cell lines: molecular mechanisms of cytokine suppression. Clin Exp Obstet Gynecol 2007; 34:14-24.
56. Jung-Testas I, Renoir JM, Gasc JM, Baulieu EE. Estrogen-inducible progesterone receptor in primary cultures of rat glial cells. ExpCell Res 1991; 193:12-19.
57. Benten WP, Lieberherr M, Giese G, Wunderlich F. Estradiol binding to cell surface raises cytosolic free calcium in T cells. FEBS Lett 1998; 422:349-353.
58. Benten WP, Lieberhen M, Giese G, Wrehlke C, Stamm O, Sekeris CE. Functional testosterone receptors in plasma membranes on T cell. FASEB J 1999; 13:123-133.
59. Butler NS, Monick MM, Yarovinsky TO, Powers-LS, Hunninghake GW. Altered IL-4 mRNA stability correlates with Th1 and Th2 bias and susceptibility to hypersensitivity pneumonitis in two inbred strains of mice. J Immunol 2002; 169:3700-3709.
60. Raine CS, Cannella B, Duijvestijn AM, Cross AH. Homing to central nervous system vasculature by antigen-specific lymphocytes: II. Lymphocyte/endothelial cell adhesion during the initial stages of autoimmune demyelination. Lab Invest 1990; 63:476-489.
61. Keith AB. Sex differences in Lewis rats in the incidence of recurrent experimental allerig encephalomyelitis. Nature 1978; 272:824-825.
62. Bebo BF, Schuster JC, Vandenbark AA, Offner H. Gender differences in experimental autoinumme encephalomyelitis develop during the induction of the immune response to encephalitogenic peptide. J Neurosci Sci 1998; 52:420-426.
63. Papenfuss TL, Rogers CJ, Gienapp I, et al. Sex differences in experimental autoimmune encephalomyelitis in multiple murine strains. J Neuroimmunol 2004; 150:59-69.
64. Amason BG, Richman DP. Effect of oral contraceptives on experimental demyelinating disease. Arch Neurol 1969; 21:103-108.
65. Trooster WJ, Teelken AW, Kampinga J, Loof JG, Nieuwenhuis P, Minderhoud JM. Suppression of acute experimental allergic encephalomyelitis by the synthetic sex hormone 17-α-ethinylestradiol: an immunological study in the Lewis rat. Int Arch Allergy Immunol 1993; 102:133-140.
66. Jansson L, Olsson T, Holmdahl R. Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. J Neuroimmunol 1994; 53:203-207.
67. Gilmore W, Weiner LP, Correale J. Effect of estradol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 1997; 158:446-451.
68. Martin R, McFarland HF. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit Rev Clin Lab Sci 1995; 32:121-182.
69. Steinman L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 1996; 85:299-302.
70. Matejuk A, Dwyer J, Zamora A, Vandenbark AA, Offner H, Evaluation of the effects of 17ß-estradiol (17ß-E2) on gene expression in experimental autoimmune encephalomyelitis using DNA microarray Endocrinology Vol. 143; 1:313-319.
71. Polancyzk MJ, Hopke C, Vanderbark AA, Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res 2006; 84:370-378.
72. Bebo BF, Fyfe-Johnson A, Adlard Y, Beam AG, Vandenbark AA, Offner H. Low-Dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J Immunol 2001; 166:2080-2089.
73. Jansson L, Olsson T, Holmdahl R. Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. J Neuroimmunol, 1994; 53:203-207.
74. Offner H, Polanczyk M. A potential role for estrogen in experimental autoimmune encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci 2006; 1089:343-372.
75. Polanczyk M, Zamora A, Subramahian S, et al. The protective effect of 17(beta)-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-{alpha}. Am J Pathol 2003; 163:1599-1605.
76. Mattila KM, Luomala M, Lehtimaki T, Laippala P, Koivula T, Elovaara I. Interaction between ESR1 and HLA-DR2 may contribute to the development of MS in women. Neurology 2001; 56:1246-1247.
77. Elloso MM, Phiel K, Henderson RA, Harris HA, Adelman SJ. Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands. J Endocrinol 2005; 185:243-252.
78. Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)α and EPβ ligand treatment. Proc Natl Acad Sci USA 2007; 104:14813-14818.
79. StitesDP, Siiteri PK. Steroids as immunosuppressants in pregnancy. Immunol. Rev 1983; 75:117-138.
80. Piccini W, Giudizi MG, Biagiotti R, et al. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both RA production and membrane CD30 expression in established Th1 cell clones. J Inummol 1995; 155:128-133.
81. Correale J, Arias M, Gilmore W. Steroid hormone regulation of cytokme secretion by proteolipid protem-specific CD4+T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 1998; 161:3365-3374.
82. Szekeres-Bartho J, Autran B, Debre P, Andreu G, Denver L, Chaouat G. Immunoregulatory effects of a suppressor factor from healthy pregnant women's lymphocytes after progesterone induction. Cell Inummol 1989; 122:281-294.
83. Dalal M, Kim S, Voskuhl RR. Testesterone therapy ameliorates experimental automimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response. J Immunol 1997; 159:3-6.
84. Fillmore PD, Blankenhorn EP, Zachary JF, Teuscher C. Adult gonadal hormones selectiveiy regulate sexually dimorphic quantitative traits observed in experimental allergic encephalomyelitis. Am J Pathol 2004; 164:1167-175.
85. Sicotte NL, Giesser BS, Tandon V, et al. Testosterone treatment in multiple sclerosis: a pilot study. Arch Neurol 2007; 64:683-688.
86. Sicotte NL, Liva SM, Klutch R, et al. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol 2002; 52:421-428.
87. Soldan SS, Retuerto AIA, Sicotte NL, Voskuhl RR. Immune modulation in multiple sclerosis patients vested with the pregnancy hormone estriol. J Immunol 2003; 171:6267-6274.
88. Voskhul, R.R.: WO02085374 (2002).
89. Voskuhl, R.R.: WO07038636 (2007).
90. Hristov, I.D.: WO02034199 (2002).
91. Merrill, J.E., Funes, S., Petko, W., Wirtz-Brugger, F., Chandross, K.: US20070225330 (2007).
92. Ellose, M.,M., Mitchell, R., Hamish, D.C., Adelman, S.J.: WO04062653 ( 2004).
93. Prossnitz, E.R., Tkatchenko, S.E., Revankar, C.M., et al.: WO07019180 (2007).
94. El-Etra M, Vukusic S, Gignoux L, et al. Steroid hormones in multiple sclerosis. J Neurol Sci 233; 2005:49-54.
95. Popartmus. A European multicenter trial of postpartum progestin and estriol in multiple sclerosis. www.edmus.org/src/proj/ studiespopart.html
96. Ferguson, S.W.: US20070167418 (2007).
97. Coyle PK,Christie S, Fodor P, et al. Multiple sclerosis gender issues: clinical practices of women neurologists. Multiple Scler 2004; 10:582-588.