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Review

Testosterone and estrogen in multiple sclerosis: from pathophysiology to therapeutics

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Pages 515-522 | Received 06 Mar 2018, Accepted 23 May 2018, Published online: 06 Jun 2018

References

  • Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–1517.
  • Baecher-Allan C, Kaskow BJ, Weiner HL. Multiple sclerosis: mechanisms and immunotherapy. Neuron. 2018;97:742–768.
  • Rolf L, Damoiseaux J, Hupperts R, et al. Network of nuclear receptor ligands in multiple sclerosis: common pathways and interactions of sex-steroids, corticosteroids and vitamin D3-derived molecules. Autoimmun Rev. 2016;15:900–910.
  • Jimenez-Balderas FJ, Tapia-Serrano R, Fonseca ME, et al. High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction. Arthritis Res. 2001;3:362–367.
  • Noonan CW, Kathman SJ, White MC. Prevalence estimates for MS in the United States and evidence of an increasing trend for women. Neurology. 2002;58:136–138.
  • Orton SM, Herrera BM, Yee IM, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006;5:932–936.
  • Schwendimann RN, Alekseeva N. Gender issues in multiple sclerosis. Int Rev Neurobiol. 2007;79:377–392.
  • Pakpoor J, Goldacre R, Schmierer K, et al. Testicular hypofunction and multiple sclerosis: cause or consequence? Reply. Ann Neurol. 2014;76:765–766.
  • Safarinejad MR. Evaluation of endocrine profile, hypothalamic-pituitary-testis axis and semen quality in multiple sclerosis. J Neuroendocrinol. 2008;20:1368–1375.
  • Wei T, Lightman SL. The neuroendocrine axis in patients with multiple sclerosis. Brain. 1997;120(Pt 6):1067–1076.
  • Tomassini V, Onesti E, Mainero C, et al. Sex hormones modulate brain damage in multiple sclerosis: MRI evidence. J Neurol Neurosurg Psychiatry. 2005;76:272–275.
  • Schumacher M, Hussain R, Gago N, et al. Progesterone synthesis in the nervous system: implications for myelination and myelin repair. Front Neurosci. 2012;6:10.
  • Spence RD, Voskuhl RR. Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front Neuroendocrinol. 2012;33:105–115.
  • Vukusic S, Hutchinson M, Hours M, et al. Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. Brain. 2004;127:1353–1360.
  • Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003;126:770–782.
  • Cottrell DA, Kremenchutzky M, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis. Brain. 1999;122(Pt 4):625–639.
  • Hawkins SA, McDonnell GV. Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry. 1999;67:148–152.
  • Parmenter BA, Denney DR, Lynch SG, et al. Cognitive impairment in patients with multiple sclerosis: association with the APOE gene and promoter polymorphisms. Mult Scler. 2007;13:25–32.
  • Savettieri G, Messina D, Andreoli V, et al. Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis. J Neurol. 2004;251:1208–1214.
  • Bove R, Musallam A, Healy BC, et al. Low testosterone is associated with disability in men with multiple sclerosis. Mult Scler. 2014;20:1584–1592.
  • Moore S, Patel R, Hannsun G, et al. Sex chromosome complement influences functional callosal myelination. Neuroscience. 2013;245:166–178.
  • Nieschlag E, Kumar N, Sitruk-Ware R. 7alpha-methyl-19-nortestosterone (MENTR): the population council’s contribution to research on male contraception and treatment of hypogonadism. Contraception. 2013;87:288–295.
  • Bebo BF Jr., Schuster JC, Vandenbark AA, et al. Gender differences in experimental autoimmune encephalomyelitis develop during the induction of the immune response to encephalitogenic peptides. J Neurosci Res. 1998;52:420–426.
  • Dalal M, Kim S, Voskuhl RR. Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response. J Immunol. 1997;159:3–6.
  • Liva SM, Voskuhl RR. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J Immunol. 2001;167:2060–2067.
  • Spritzer MD, Galea LA. Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats. Dev Neurobiol. 2007;67:1321–1333.
  • Lustig RH. Sex hormone modulation of neural development in vitro. Horm Behav. 1994;28:383–395.
  • Ogata T, Nakamura Y, Tsuji K, et al. Steroid hormones protect spinal cord neurons from glutamate toxicity. Neuroscience. 1993;55:445–449.
  • Chisu V, Manca P, Zedda M, et al. Effects of testosterone on differentiation and oxidative stress resistance in C1300 neuroblastoma cells. Neuro Endocrinol Lett. 2006;27:807–812.
  • Chisu V, Manca P, Lepore G, et al. Testosterone induces neuroprotection from oxidative stress. Effects on catalase activity and 3-nitro-L-tyrosine incorporation into alpha-tubulin in a mouse neuroblastoma cell line. Arch Ital Biol. 2006;144:63–73.
  • Ziehn MO, Avedisian AA, Dervin SM, et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012;32:12312–12324.
  • Golden LC, Voskuhl R. The importance of studying sex differences in disease: the example of multiple sclerosis. J Neurosci Res. 2017;95:633–643.
  • Celotti F, Melcangi RC, Negri-Cesi P, et al. Testosterone metabolism in brain cells and membranes. J Steroid Biochem Mol Biol. 1991;40:673–678.
  • Patel R, Moore S, Crawford DK, et al. Attenuation of corpus callosum axon myelination and remyelination in the absence of circulating sex hormones. Brain Pathol. 2013;23:462–475.
  • Hussain R, Ghoumari AM, Bielecki B, et al. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination. Brain. 2013;136:132–146.
  • Bielecki B, Mattern C, Ghoumari AM, et al. Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin. Proc Natl Acad Sci U S A. 2016;113:14829–14834.
  • Sicotte NL, Giesser BS, Tandon V, et al. Testosterone treatment in multiple sclerosis: a pilot study. Arch Neurol. 2007;64:683–688.
  • Gold SM, Chalifoux S, Giesser BS, et al. Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone. J Neuroinflammation. 2008;5:32.
  • Kurth F, Luders E, Sicotte NL, et al. Neuroprotective effects of testosterone treatment in men with multiple sclerosis. Neuroimage Clin. 2014;4:454–460.
  • Caruso D, D’Intino G, Giatti S, et al. Sex-dimorphic changes in neuroactive steroid levels after chronic experimental autoimmune encephalomyelitis. J Neurochem. 2010;114:921–932.
  • Giatti S, D’Intino G, Maschi O, et al. Acute experimental autoimmune encephalomyelitis induces sex dimorphic changes in neuroactive steroid levels. Neurochem Int. 2010;56:118–127.
  • Massella A, D’Intino G, Fernandez M, et al. Gender effect on neurodegeneration and myelin markers in an animal model for multiple sclerosis. BMC Neurosci. 2012;13:12.
  • Tiwari-Woodruff S, Morales LB, Lee R, et al. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A. 2007;104:14813–14818.
  • Kim RY, Mangu D, Hoffman AS, et al. Oestrogen receptor β ligand acts on CD11c± cells to mediate protection in experimental autoimmune encephalomyelitis. Brain. 2018;141:132–147.
  • Ziehn MO, Avedisian AA, Dervin SM, et al. Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease. Lab Invest. 2012;92:1234–1245.
  • Lelu K, Delpy L, Robert V, et al. Endogenous estrogens, through estrogen receptor alpha, constrain autoimmune inflammation in female mice by limiting CD4+ T-cell homing into the CNS. Eur J Immunol. 2010;40:3489–3498.
  • Spence RD, Wisdom AJ, Cao Y, et al. Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERalpha signaling on astrocytes but not through ERbeta signaling on astrocytes or neurons. J Neurosci. 2013;33:10924–10933.
  • Javadian A, Salehi E, Bidad K, et al. Effect of estrogen on Th1, Th2 and Th17 cytokines production by proteolipid protein and PHA activated peripheral blood mononuclear cells isolated from multiple sclerosis patients. Arch Med Res. 2014;45:177–182.
  • Luchetti S, van Eden CG, Schuurman K, et al. Gender differences in multiple sclerosis: induction of estrogen signaling in male and progesterone signaling in female lesions. J Neuropathol Exp Neurol. 2014;73:123–135.
  • Christianson MS, Mensah VA, Shen W. Multiple sclerosis at menopause: potential neuroprotective effects of estrogen. Maturitas. 2015;80:133–139.
  • McClain MA, Gatson NN, Powell ND, et al. Pregnancy suppresses experimental autoimmune encephalomyelitis through immunoregulatory cytokine production. J Immunol. 2007;179:8146–8152.
  • Sicotte NL, Liva SM, Klutch R, et al. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol. 2002;52:421–428.
  • Soldan SS, Alvarez Retuerto AI, Sicotte NL, et al. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol. 2003;171:6267–6274.
  • Voskuhl RR, Wang H, Wu TC, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:35–46.
  • Vukusic S, Ionescu I, El-Etr M, et al. The prevention of post-partum relapses with progestin and estradiol in multiple sclerosis (POPART’MUS) trial: rationale, objectives and state of advancement. J Neurol Sci. 2009;286:114–118.
  • Spanier JA, Nashold FE, Mayne CG, et al. Vitamin D and estrogen synergy in Vdr-expressing CD4(+) T cells is essential to induce helios(+)FoxP3(+) T cells and prevent autoimmune demyelinating disease. J Neuroimmunol. 2015;286:48–58.
  • Etemadifar M, Janghorbani M. Efficacy of high-dose vitamin D3 supplementation in vitamin D deficient pregnant women with multiple sclerosis: preliminary findings of a randomized-controlled trial. Iran J Neurol. 2015;14:67–73.
  • Pozzilli C, De Giglio L, Barletta VT, et al. Oral contraceptives combined with interferon beta in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2015;2:e120.
  • Talmage GD, Coppes OJM, Javed A, et al. Natalizumab stabilizes physical, cognitive, MRI, and OCT markers of disease activity: a prospective, non-randomized pilot study. PLoS One. 2017;12:e0173299.
  • Bergsland N, Zivadinov R, Dwyer MG, et al. Localized atrophy of the thalamus and slowed cognitive processing speed in MS patients. Mult Scler. 2016;22:1327–1336.
  • Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol. 2006;5:158–170.
  • Koini M, Filippi M, Rocca MA, et al. Correlates of executive functions in multiple sclerosis based on structural and functional MR imaging: insights from a multicenter study. Radiology. 2016;280:869–879.
  • Houtchens MK, Benedict RH, Killiany R, et al. Thalamic atrophy and cognition in multiple sclerosis. Neurology. 2007;69:1213–1223.
  • Motl RW, Zivadinov R, Bergsland N, et al. Thalamus volume and ambulation in multiple sclerosis: a cross-sectional study. Neurodegener Dis Manag. 2016;6:23–29.
  • Ciampi E, Pareto D, Sastre-Garriga J, et al. Grey matter atrophy is associated with disability increase in natalizumab-treated patients. Mult Scler. 2017;23:556–566.
  • Wilting J, Rolfsnes HO, Zimmermann H, et al. Structural correlates for fatigue in early relapsing remitting multiple sclerosis. Eur Radiol. 2016;26:515–523.
  • Klawiter EC, Schmidt RE, Trinkaus K, et al. Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords. Neuroimage. 2011;55:1454–1460.
  • Song SK, Yoshino J, Le TQ, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage. 2005;26:132–140.
  • Budde MD, Xie M, Cross AH, et al. Axial diffusivity is the primary correlate of axonal injury in the experimental autoimmune encephalomyelitis spinal cord: a quantitative pixelwise analysis. J Neurosci. 2009;29:2805–2813.
  • Chen JT, Easley K, Schneider C, et al. Clinically feasible MTR is sensitive to cortical demyelination in MS. Neurology. 2013;80:246–252.
  • Fjaer S, Bo L, Lundervold A, et al. Deep gray matter demyelination detected by magnetization transfer ratio in the cuprizone model. PLoS One. 2013;8:e84162.
  • Schmierer K, Scaravilli F, Altmann DR, et al. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol. 2004;56:407–415.
  • Filippi M, Rocca MA. MR imaging of multiple sclerosis. Radiology. 2011;259:659–681.
  • Ontaneda D, Fox RJ. Imaging as an outcome measure in multiple sclerosis. Neurotherapeutics. 2017;14:24–34.
  • Laule C, Vavasour IM, Kolind SH, et al. Magnetic resonance imaging of myelin. Neurotherapeutics. 2007;4:460–484.
  • Fox RJ, Cronin T, Lin J, et al. Measuring myelin repair and axonal loss with diffusion tensor imaging. AJNR Am J Neuroradiol. 2011;32:85–91.

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