Lauren S. Franklin

Background: Multiple sclerosis (MS) is an autoimmune neurological disorder characterized by demyelination of neurons in the central nervous system and affects an estimated 900,000 individuals in the United States.¹ A notable risk factor for MS is infection with Epstein-Barr virus (EBV), which induces EBV-activated T-cells that cross-react with antigens in the central nervous system (CNS), leading to destruction of myelin sheaths around nerves.² While EBV infection is noted as a prominent risk factor, other factors are also involved in the pathogenesis of  MS. Females are affected by MS at a 3:1 ratio compared to men,³ and rates of relapse of MS decrease significantly in the third trimester of pregnancy, when estrogen levels are at their peak.⁴ Currently, MS treatment is therapeutic, though potential effects of estrogen have been proposed due to the sex-differences in disease prevalence and progression.

Objective: In this narrative review, we explored the mechanisms by which MS progression may be altered by hormonal-based therapies.

Search Methods: An online search of PubMed database was conducted from 2018 to 2024 using the following keywords: “multiple sclerosis”, “estrogen”, “androgens”, “hormones”, and “EBV”.

Results: Studies indicate that EBV infection increases risk of developing MS but is not sufficient to cause MS.⁵ MS prevalence and progression is sex dependent, and estradiol (E2) is known to regulate expression and release of inflammatory and anti-inflammatory cytokines, reducing disease burden.^1,3,6 Female lymphoblastoid cells deprived of estrogen and supplemented with E2 show correlation of estrogen receptor 2 (ESR2) with EBV latency genes EBNA2 and LMP1 as well as EBV copy number, suggesting E2’s role in propagating EBV’s effects on MS progression.⁵ In an experimental autoimmune encephalomyelitis (EAE) model of MS, treatment with highly selective estrogen receptor b ligand choroindazole (IndCl) improved neurological scoring and fine motor skills and reduced IFNg, IL-6, and IL-17,¹ indicative of reduced demyelination and blood-brain barrier alterations. Additionally, IndCl increased CXCL1 and decreased CXCL10,¹ indicating better homeostasis of white matter development and reduced oligodendrocyte progenitor cell death. Similarly, in EAE female mice treated with dihydrotestosterone (DHT), a reduction in known MS-contributing pro-inflammatory markers was observed, most notably Th1, Th17, IFNg, TNF-a, and IL-1b.³ In a lysophosphatidylcholine model of MS, DHT treatment resulted in improvements in myelination possibly explaining the higher incidence of MS in females, as DHT is not naturally produced at high quantities in females.³ Following administration of estriol, EAE mice had improved gray matter atrophy, restoration of cortical layer V neurons, improved dendritic spine quantities, and improved axonal integrity,⁵ suggestive of reduced neurodegeneration with estriol treatment. In human clinical trial with MS patients, treatment with estriol lead to improvements in gray matter atrophy and reduction in neurodegeneration, indicating estriol’s potential to slow disease progression and ameliorate MS symptoms.⁷

Conclusions: Studies have found that treatment with estrogen-based therapies leads to improvement in motor symptoms, reduction of inflammatory and demyelinating signals, restoration of cortical neurons, reduction in gray matter atrophy, and improvement in cognitive function. Consideration of estrogen-based therapies as treatment for MS may lead to development of effective therapeutic agents.

Works Cited:

1. Karim H, Kim SH, Lauderdale K, et al. Analogues of ERβ ligand chloroindazole exert immunomodulatory and remyelinating effects in a mouse model of multiple sclerosis. Sci Rep. 2019;9(1):503. Published 2019 Jan 24. doi:10.1038/s41598-018-37420-x
2. Bar-Or A, Pender MP, Khanna R, et al. Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies [published correction appears in Trends Mol Med. 2021 Apr;27(McGinley):410-411]. Trends Mol Med. 2020;26(4):296-310. doi:10.1016/j.molmed.2019.11.003
3. Zahaf A, Kassoussi A, Hutteau-Hamel T, et al. Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination. Nat Commun. 2023;14(1):1592. Published 2023 Mar 22. doi:10.1038/s41467-023-36846-w
4. Maglione A, Rolla S, Mercanti SF, Cutrupi S, Clerico M. The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View. Cells. 2019;8(10):1280. Published 2019 Oct 19. doi:10.3390/cells8101280
5. Keane JT, Afrasiabi A, Schibeci SD, et al. Gender and the Sex Hormone Estradiol Affect Multiple Sclerosis Risk Gene Expression in Epstein-Barr Virus-Infected B Cells. Front Immunol. 2021;12:732694. Published 2021 Sep 8. doi:10.3389/fimmu.2021.732694
6. Meyer CE, Smith AW, Padilla-Requerey AA, et al. Neuroprotection in Cerebral Cortex Induced by the Pregnancy Hormone Estriol. Lab Invest. 2023;103(8):100189. doi:10.1016/j.labinv.2023.100189
7. MacKenzie-Graham A, Brook J, Kurth F, et al. Estriol-mediated neuroprotection in multiple sclerosis localized by voxel-based morphometry. Brain Behav. 2018;8(9):e01086. doi:10.1002/brb3.1086