Estriol Treatment in Multiple Sclerosis (MS): Effect on Cognition

Inclusion Criteria: * Diagnosis of clinically definite or MacDonald criteria relapsing-remitting multiple sclerosis, secondary-progressive multiple sclerosis or primary-progressive multiple sclerosis. * No relapse within 30 days before day of trial enrollment (month 0 visit). If steroids given for relapse, then the month 0 visit must be 30 days after last steroid dose. * Females age 18 to 55, inclusive. * Expanded Disability Status Score (EDSS) = 0.0 to 6.0. * Screening PASAT (3-second) score 25-50, inclusive. * Must be mentally competent enough to comply with study guidelines and give informed consent. * Must be willing and able to travel to the study center at frequencies in the protocol for a total period of 12 months. * Patients must be on no treatment or be on a stable dose of one of the following agents for a minimum of 3 months duration prior to the month 0 visit: Copaxone®, Betaseron® (or Extavia®), Rebif®, Avonex®, PLEGRITY®, Ocrelizumab, Rituximab, Gilenya®, Aubagio®, or Tecfidera®. The time spent in the screening period may serve as part of this 3-month period. * Patients who are currently being treated with ACTH, corticosteroids, intravenous immunoglobulins (IVIG), plasma exchange, Lipitor® or minocycline may be included. * If patients plan to start treatment with Copaxone® or an interferon \[Betaseron® (or Extavia®), Rebif®, Avonex®, PLEGRITY®\], Ocrelizumab, Rituximabor an oral agent \[Gilenya®, Aubagio® or Tecfidera®\] and then they must be on for at least 3 months prior to month 0 (as above). Exclusion Criteria: * Males * Subjects on oral contraceptives (OCP), hormone replacement therapy (HRT) other sex hormones during screening and during the 12-month study period (Mirena® IUD is permitted). * Females who are pregnant or who plan to become pregnant during the 12 months of enrollment, who wish to become pregnant within 3 months following completion of the study, or who will be within 6 months post partum at the day of first enrollment visit (month 0). * Females who plan to breastfeed after first enrollment visit (month 0). * Fertile sexually active women who are unwilling to practice reliable barrier methods of contraception other than oral contraceptives (i.e. condom, diaphragm, IUDs Note: Hormonal IUD \[Mirena®\] is permitted). * Patients with surgical ovariectomy with no hormone replacement for 1 year or more. * Menopause with no hormone replacement for 3 years or more prior to the first enrollment visit. * Patients who smoke at any time during screening or during the 12 month study period. * Patients who have serious pulmonary, renal, gastrointestinal, hepatic, immunologic, infectious, neoplastic, major psychiatric disease (major depression, schizophrenia), endocrine disease (including major diabetes, thyroid disease), or gynecologic disease, including but not limited to those with: Thrombophlebitis or thromboembolic disorders, a past history of deep vein thrombophlebitis or thromboembolic disorders, cerebral vascular or coronary artery disease, migraine with focal aura, known or suspected carcinoma of the breast, carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia, undiagnosed abnormal genital bleeding, polycystic ovary disease, amenorrhea of unknown etiology, cholestatic jaundice of pregnancy or jaundice with prior birth control pill use, acute or chronic hepatocellular disease with abnormal liver function, hepatic adenomas or carcinomas, known or suspected pregnancy, known hypersensitivity to birth control pill Copaxone or Betaseron use. * B12 level \< 200. * Drug abuse within the past five years. * Conditions that would interfere with assessing neurologic functions such as deforming arthritis or a major amputation. * Have at any time been treated with total lymphoid irradiation, monoclonal antibody, T cell vaccination, cladribine, bone marrow transplantation, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, or cyclosporine. * Have been treated with natalizumab (Tysabri®) in the 6 months prior to screening. * Positive titers to HIV in the past. * Previous serious adverse effects with estrogen treatment. * Patients who participated in the previous multi-center estriol trial for RRMS ("A Combination Trial of Copaxone plus Estriol in RRMS").