Estrogen & Multiple Sclerosis

In a case study by researchers at the Royal Free Hospital in London, a 26-year-old man was hospitalized due to a sudden onset of weakness and fatigue on the right side of his body.[1] When he was first admitted, he was unable to walk by himself, and his right leg dragged behind him. In his later visits, he experienced numbness on the left side of his body and had difficulty moving and speaking. Brain scans showed the degeneration of myelin sheaths, modified cell membranes that protect and insulate the axons of neurons. Doctors concluded that he had multiple sclerosis, also known as MS.[1]

Multiple sclerosis is an autoimmune disease that causes the body to attack myelin sheaths and neurons in the brain and spinal cord.[2] Myelin sheaths protect the axons and facilitate the communication of information between neurons by preventing electrical currents from diffusing out of the axons. Damage to the myelin sheaths causes delay and distortion of brain signals, resulting in a variety of symptoms, such as difficulty with movement, numbness, and problems with the transmission of sensory information to the brain.[2]

In MS, immune cells cause neuroinflammation and neurodegeneration, triggering the destruction of myelin sheaths and axons.[3] Neurodegeneration in MS occurs when B cells of the immune system release proteins called antibodies that bind to the host’s own neural tissues. The binding causes the recruitment of other immune cells, which destroy the antibody-bound tissues. T cells release additional molecules that increase inflammation, contributing to the degeneration of myelin sheaths.[2, 3, 4]

Although there are medications that suppress the immune system, studies have shown that they do not slow down the process of tissue degeneration observed in MS.[5] To combat the degeneration, researchers have to develop a different type of treatment that will promote the health of both neurons’ axons and oligodendrocytes, the support cells that produce myelin sheaths.[5]

In the search for an effective treatment, researchers discovered that estrogen, a steroid hormone that promotes the development and regulation of the female reproductive system, reduces inflammation associated with MS.[5, 6] Researchers started to explore the role of estrogen when they discovered the correlation between pregnancy and reduced severity of MS symptoms in both humans and other animal species in the late stages of pregnancy.[7, 8] Even though pregnancy affects multiple factors besides estrogen production, researchers noticed that an increase specifically in estrogen levels during the third trimester of pregnancy in women with MS coincided with the reduction of the severity of MS symptoms.[9] After giving birth, the women’s estrogen levels decreased and their symptoms relapsed.[8] This, along with its demonstrated neuroprotective effects in other neurological disorders such as Parkinson’s disease and epilepsy, led researchers to further study estrogen’s effect on MS symptoms.[10, 11]

Growing evidence suggests that estrogen binds to a type of neuronal receptor, known as ERβ, and can reduce inflammation as well as protect brain cells from degeneration.[5, 12] Using an experimental animal model for human MS, known as experimental allergic encephalomyelitis (EAE), researchers discovered that estrogen reduced the production of proinflammatory molecules in the nervous system upon estrogen binding.[6, 10] In addition, symptoms such as the progression of paralysis were reduced when estrogen treatment was applied in several strains of mice.[13, 14]

Estrogen binding to ERβ receptors also has neuroprotective effects. Estrogen plays a crucial role in promoting cell survival, regenerative responses, synaptic transmission, and the growth of new neurons.[15] Estrogen binding to ERβ receptors regenerates myelin sheaths and prolongs the survival of damaged cells, reducing the severity of demyelination and axonal damage caused by MS.[15] Estrogen administration also prevents cell death in oligodendrocytes that are targeted for destruction by immune cells[16]. Furthermore, estrogen binding to oligodendrocytes activates the production of BDNF growth factors that stimulate growth, maturation, and differentiation of those cells, which is crucial for myelin sheath regeneration.[17, 6]

However, directly administering estrogen is not a viable treatment, as it would be delivered to receptors throughout the body, not just in the brain.[18] Instead, it would be best to design and administer an estrogen-like ligand, a molecule mimicking the structure of estrogen, that could bind specifically to the ERβ receptor in the nervous system. The administration of such a molecule could be a potential treatment for MS.[6] The treatment could help both men and women with MS because, contrary to popular belief, men also produce estrogen by converting it from testosterone.[19]

The specificity of the ligand is important because there is another type of estrogen receptor, ERɑ, that can elicit negative side effects.[9, 3] ERɑ and ERβ receptors are located not only in the brain but also in the breast and uterus. Estrogen binding to ERɑ receptors in the breast and uterus increases the chance of developing cancer in those areas by stimulating the proliferation of cells in breast tumors.[9, 3, 20] Therefore, creating a molecule that binds only to ERβ receptors can elicit the neuroprotective response to estrogen while avoiding the adverse consequences on the body.

Although there is currently no cure for MS, researchers over the past fifteen years have gained significant insight into the workings of this autoimmune disease. The discovery of estrogen’s potential effects on alleviating MS symptoms by both reducing inflammation and increasing direct neuroprotection can lead to a new type of treatment. With a better understanding of the mechanisms behind MS, more effective treatments can be designed. The implementation of a treatment that not only decreases the inflammatory response caused by the immune system but also regenerates the myelin sheaths would significantly improve the health and welfare of patients with MS.

References

  1. Fernando K, James M. (2017). Early predictors of rapidly evolving multiple sclerosis: A case report. Journal of Neuroimmunology. 307: 42-46.
  2. Steinman L. (2001). Multiple sclerosis: a two-stage disease. Nature Immunology. 2: 762-764.
  3. Saijo K, Glass C. (2011). An ADIOL-ERβ-CtBP Transrepression Pathway Negatively Regulates Microglia-Mediated Inflammation. Cell. 145: 584-595
  4. Martino G. (2004). How the brain repairs itself: new therapeutic strategies in inflammatory and degenerative CNS disorders. The Lancet. 3: 372-378.
  5. Gold S, Voskuhl R. (2009). Estrogen treatment in multiple sclerosis. Journal of Neurological Sciences. 286: 99-103.
  6. Kim R, Mangu D, Hoffman A, Kovash R, Jung E, Itoh N, Voskuhl. (2017). Oestrogen receptor β ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis. Brain. 141: 132-147.
  7. Williams C, Edvardsson K, Lewandowski S, Strom A, Gustafsson J. (2008). A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells. Oncogene. 27: 1019-1032.
  8. Kim S, Liva S, Dalal M, Verity M, Voskuhl R. (1999). Estriol ameliorates autoimmune demyelinating disease: Implications for multiple sclerosis. Neurology. 6: 52
  9. Moore S, Khalaj A, Kumar S, Winchester Z, Yoon J, Yoo T, Martinez-Torres L, Yasui N, Katzenellenbogen J, Tiwari-Woodruff S. (2014). Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis. PNAS. 111: 1806118066.
  10. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. (1998). Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 339:285-91.
  11. Leranth C, Roth R, Elsworth J, Naftolin F, Horvath T, Redmond E. (2000). Estrogen Is Essential for Maintaining Nigrostriatal Dopamine Neurons in Primates: Implications for Parkinson’s Disease and Memory. Journal of Neuroscience. 20: 8604-8609
  12. Veliskova J, Velisek L, Galanopoulou A, Sperber E. (2000). Neuroprotective Effects of Estrogens on Hippocampal Cells in Adult Female Rats After Status Epilepticus. Epilepsia. 41: S30S35.
  13. Planey S, Kumar R, Arnott J. (2014). Estrogen receptors (ERα versus ERβ): friends or foes in human biology? J Recept Signal Transduct Res. 34: 1-5.
  14. Robinson A, Harp C, Norohna A, Miller S. (2014). The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment. Handb Clin Neurol. 122: 173-189.
  15. Bebo B, Fyfe-Johnson A, Adlard K, Beam A, Vandenbark A, Offner H. (2001). Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains. Journal of Immunology. 166: 2080-2089.
  16. Moorea S, Khalaja A, Kumar S, Winchestera Z, Yoona J, Yooa T, Martinez-Torresa L, Yasuid N, Katzenellenbogend J, and Tiwari-Woodruf S. (2014). Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis. PNAS. 111: 1806118066.
  17. Garcia-Segura L, Azcoitia I, DonCarlos L. (2001). Neuroprotection by estradiol. Prog Neurobiol. 63: 29-30.
  18. Rettberga J, Yaob J, Brinton R. (2014). Estrogen: A master regulator of bioenergetic systems in the brain and body. Frontiers of Neuroendocrinology. 35: 8-30.
  19. Longcope C, Kato T, Horton R. (1969). Conversion of blood androgens to estrogens in normal adult men and women. J Clin Invest. 48: 2191-2201.
  20. Prokai L, Nguyen V, Szarka S, Garg P, Sabnis G, Bimonte-Nelson H, McLaughlin K, Talboom J, Conrad C, Shughrue P, Gould T, Brodie A, Merchenthaler I, Koulen P, Prokai-Tatrai K. (2015). The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders. Sci Transl Med. 7: 297.

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