title: Increase in multiple sclerosis activity after assisted reproduction technology.
abstract: OBJECTIVE
  Our objective was to evaluate risk of exacerbations in multiple sclerosis (MS) patients undergoing assisted reproduction technology (ART) infertility treatment.
  
  
  METHODS
  Sixteen patients with relapsing-remitting MS subjected to 26 ART treatment cycles receiving gonadotropin-releasing hormone (GnRH) agonists and recombinant follicle-stimulating hormone were studied prospectively. The baseline study period encompassed 12 months prior to the first cycle and 9 months after final ART cycle. Neurological examinations, brain magnetic resonance imaging (MRI), and immunology testing were conducted every 3 months. Anti-myelin-oligodendrocyte glycoprotein (MOG) antibody production, interleukin (IL)-4, IL-8, IL-10, IL-12, IL-17, interferon (IFN)-γ, and transforming growth factor (TGF)-β secretion by myelin basic protein- and MOG-peptide-specific T cells, as well as ex vivo isolated peripheral blood mononuclear cells (PBMCs), were studied using enzyme-linked immunospot. vascular endothelial growth factor (VEGF) production by PBMCs was assessed using enzyme-linked immunosorbent assay.
  
  
  RESULTS
  ART was associated with a 7-fold increase in risk of MS exacerbation, and a 9-fold increase in risk of enhanced disease activity on MRI. Worsening was associated with higher number of cells producing IL-8, IL-12, IFN-γ, and TGF-β, as well as increased VEGF production by CD4(+) T cells and CXCL-12 plasma levels, all GnRH-mediated effects. A rise in 17-β estradiol production associated with ART increased anti-MOG antibody titers, as well as B-cell survival factor BAFF (B-cell activating factor) and antiapoptotic molecule Bcl-2 levels from purified CD19(+) B cells. Finally, ART facilitated PBMC transmigration across an in vitro blood-brain barrier model, an effect mediated by IL-8, VEGF, and CXCL-12.
  
  
  CONCLUSIONS
  Results indicate a significant increase in MS disease activity in patients receiving ART, a risk that neurologists should be aware of. Reproductive hormones appear to exert an important role in regulating immune responses during the course of autoimmune diseases.
authors.affiliation: Department of Neurology, Institute for Neurological Research Dr Raúl Carrea, Foundation Against Neurological Disease in childhood (FLENI), Buenos Aires, Argentina. jcorreale@fleni.org.ar
authors.forename: Jorge
authors.initials: J
authors.lastname: Correale
authors.forename: Mauricio F
authors.initials: MF
authors.lastname: Farez
authors.forename: María C
authors.initials: MC
authors.lastname: Ysrraelit
mesh_terms: D000328:Adult; D000906:Antibodies / Q000627:therapeutic use; D053264:B-Cell Activating Factor / Q000378:metabolism; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004185:Disability Evaluation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005640:Follicle Stimulating Hormone / Q000009:adverse effects; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007246:Infertility / Q000150:complications / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D009103:Multiple Sclerosis / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012008:Recurrence; D027724:Reproductive Techniques, Assisted / Q000009:adverse effects*; D012189:Retrospective Studies; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000906:Antibodies; D053264:B-Cell Activating Factor; D016207:Cytokines; D007166:Immunosuppressive Agents; C499048:MBP protein, human; D004676:Myelin Basic Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C505719:TNFSF13B protein, human; D042461:Vascular Endothelial Growth Factor A; D007987:Gonadotropin-Releasing Hormone; D005640:Follicle Stimulating Hormone