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| ID | Type | Description | Link |
|---|---|---|---|
| R01NS051591 | U.S. NIH Grant/Contract | View source | |
| RG3915 | Other Grant/Funding Number | NMSS |
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| Name | Class |
|---|---|
| Washington University School of Medicine | OTHER |
| University of Texas Southwestern Medical Center | OTHER |
| Ohio State University | OTHER |
| University of Medicine and Dentistry of New Jersey |
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This is a double-blinded, placebo controlled study of estriol pills versus placebo pills in relapsing remitting multiple sclerosis. The study treatment will be an added on to Copaxone injections in all subjects. The primary outcome measure is a reduction in relapses.
Multiple sclerosis (MS) relapses are known to be significantly decreased during pregnancy. This proposal will establish whether oral treatment with estriol, the major estrogen of pregnancy, induces a decrease in relapses in relapsing remitting multiple sclerosis (RRMS) subjects when used in combination with injectable Copaxone. Previously, in a pilot study, it has been demonstrated that treatment of RRMS subjects with oral estriol for six months resulted in a significant reduction in gadolinium enhancing lesions on serial brain MRIs (Annals of Neurology, 2002; 52:421-428) and caused a favorable shift in immune responses (Journal of Immunology, 2003; 171:6267-6274). This is an add-on study aiming to extend these previous findings by treating longer and focusing on clinical outcomes. The combination of Copaxone injection plus estriol pill (8 mg per day) will be compared to Copaxone injection plus placebo pill in a double blind trial. The duration of treatment will be two years and the primary outcome measure will be relapse rate. Other outcomes will include disability measures and brain MRI outcomes. Safety measures (blood tests and gynecologic evaluations) will also be followed and correlations will be made between serum estriol levels with efficacy and safety. The overall goal of this study will be the development of a new oral treatment, estriol, for RRMS.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Estriol plus Copaxone injections QD | Active Comparator | Estriol Capsules (daily) plus Copaxone injections (daily). Progestin capsules given for 2 weeks every 3 months to avoid unopposed estrogens. |
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| Placebo plus Copaxone injections QD | Placebo Comparator | Placebo Capsules (daily) plus Copaxone injections (daily). A second placebo capsule given for 2 weeks every 3 months. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Estriol | Drug | Estriol 8 mg capsule, once per day, duration of treatment is 2 years |
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| Measure | Description | Time Frame |
|---|---|---|
| Confirmed Relapse, Annualized Relapse Rate | A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection. | 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| Relapse Event, Annualized Relapse Rate | Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner. | 24 months |
| Confirmed Relapse, Probability of First Relapse |
| Measure | Description | Time Frame |
|---|---|---|
| Confirmed Relapse, Annualized Relapse Rate | A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rhonda Voskuhl, M.D. | University of California, Los Angeles (UCLA), Los Angeles, CA | Study Director |
| Anne Cross, M.D. | Washington University, Saint Louis, MO | Principal Investigator |
| Elliot Frohman, M.D. | University of Texas, Southwestern, Dallas, TX | Principal Investigator |
| Suhayl Dhib-Jalbut, M.D. | Robert Wood Johnson Medical School, UMDNJ, New Brunswick, NJ | Principal Investigator |
| Michael Racke, M.D. | Ohio State University | Principal Investigator |
| Anthony Reder, M.D. | University of Chicago | Principal Investigator |
| John Rose, M.D. | Western Institute for Biomedical Research, Salt Lake City, UT | Principal Investigator |
| Barbara Giesser, M.D. | University of California, Los Angeles (UCLA), Los Angeles, CA | Principal Investigator |
| John Ratchford, M.D. | Johns Hopkins, Baltimore, MD |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Scottsdale | Arizona | 85259 | United States | ||
| University of California, Los Angeles |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12325070 | Background | Sicotte NL, Liva SM, Klutch R, Pfeiffer P, Bouvier S, Odesa S, Wu TC, Voskuhl RR. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol. 2002 Oct;52(4):421-8. doi: 10.1002/ana.10301. | |
| 14634144 | Background | Soldan SS, Alvarez Retuerto AI, Sicotte NL, Voskuhl RR. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol. 2003 Dec 1;171(11):6267-74. doi: 10.4049/jimmunol.171.11.6267. |
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Investigators interested in further research using the data should contact Dr. Voskuhl with proposed plans and request.
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| ID | Title | Description |
|---|---|---|
| FG000 | Estriol Capsules Plus Copaxone Injections | Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years |
| FG001 | Placebo Capsules Plus Copaxone Injections | Placebo: Placebo capsule, once per day, treatment duration is 2 years |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| OTHER |
| University of Chicago | OTHER |
| University of Utah | OTHER |
| Johns Hopkins University | OTHER |
| University of Kansas Medical Center | OTHER |
| University of Minnesota | OTHER |
| Mayo Clinic | OTHER |
| University of Colorado, Denver | OTHER |
| University of New Mexico | OTHER |
| University of Pennsylvania | OTHER |
| Dartmouth-Hitchcock Medical Center | OTHER |
| National Multiple Sclerosis Society | OTHER |
| National Institutes of Health (NIH) | NIH |
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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| Placebo | Drug | Placebo capsule, once a day, treatment duration is 2 years |
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| Copaxone | Drug | Injection, once a day, all subjects |
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| 24 months |
| Relapse Event, Probability of First Relapse Event | 24 months |
| 12 months |
| Relapse Event, Annualized Relapse Rate | Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner. | 12 months |
| Sharon Lynch, M.D. | University of Kansas | Principal Investigator |
| Gareth Parry, M.D. | University of Minnesota | Principal Investigator |
| Dean Wingerchuk, M.D. | Mayo Clinic | Principal Investigator |
| John Corboy, M.D. | University of Colorado, Denver | Principal Investigator |
| Corey Ford, M.D. | University of New Mexico, Albuquerque | Principal Investigator |
| Dina Jacobs, M.D. | University of Pennsylvania | Principal Investigator |
| Lloyd Kasper, M.D. | Dartmouth University, Lebanon, NH | Principal Investigator |
| Los Angeles |
| California |
| 90095 |
| United States |
| University of Colorado | Aurora | Colorado | 80045 | United States |
| University of Chicago | Chicago | Illinois | 60637 | United States |
| University of Kansas | Kansas City | Kansas | 66160 | United States |
| Johns Hopkins University | Baltimore | Maryland | 21287-6965 | United States |
| University of Minnesota | Minneapolis | Minnesota | 55455 | United States |
| Washington University | St Louis | Missouri | 63110 | United States |
| Dartmouth Medical School | Lebanon | New Hampshire | 03765 | United States |
| UMDNJ-Robert Wood Johnson Medical Center | New Brunswick | New Jersey | 08901 | United States |
| University of New Mexico | Albuquerque | New Mexico | 87131 | United States |
| Ohio State University | Columbus | Ohio | 43221 | United States |
| University of Pennsylvania | Philadelphia | Pennsylvania | 19104 | United States |
| University of Texas Southwestern | Dallas | Texas | 75390-8575 | United States |
| Western Institute for Biomedical Research | Salt Lake City | Utah | 84158 | United States |
| Montreal Neurological Institute | Montreal | Canada |
| 16793889 | Background | Morales LB, Loo KK, Liu HB, Peterson C, Tiwari-Woodruff S, Voskuhl RR. Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis. J Neurosci. 2006 Jun 21;26(25):6823-33. doi: 10.1523/JNEUROSCI.0453-06.2006. |
| 17785421 | Background | Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14813-8. doi: 10.1073/pnas.0703783104. Epub 2007 Sep 4. |
| 17502467 | Background | Sicotte NL, Giesser BS, Tandon V, Klutch R, Steiner B, Drain AE, Shattuck DW, Hull L, Wang HJ, Elashoff RM, Swerdloff RS, Voskuhl RR. Testosterone treatment in multiple sclerosis: a pilot study. Arch Neurol. 2007 May;64(5):683-8. doi: 10.1001/archneur.64.5.683. |
| 19668239 | Background | Gold SM, Sasidhar MV, Morales LB, Du S, Sicotte NL, Tiwari-Woodruff SK, Voskuhl RR. Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERalpha). Lab Invest. 2009 Oct;89(10):1076-83. doi: 10.1038/labinvest.2009.79. Epub 2009 Aug 10. |
| 22525427 | Background | Ziehn MO, Avedisian AA, Dervin SM, O'Dell TJ, Voskuhl RR. Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease. Lab Invest. 2012 Aug;92(8):1234-45. doi: 10.1038/labinvest.2012.76. Epub 2012 Apr 23. |
| 21555578 | Background | Spence RD, Hamby ME, Umeda E, Itoh N, Du S, Wisdom AJ, Cao Y, Bondar G, Lam J, Ao Y, Sandoval F, Suriany S, Sofroniew MV, Voskuhl RR. Neuroprotection mediated through estrogen receptor-alpha in astrocytes. Proc Natl Acad Sci U S A. 2011 May 24;108(21):8867-72. doi: 10.1073/pnas.1103833108. Epub 2011 May 9. |
| 26621682 | Result | Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, Itoh N, Bardens J, Bernard JT, Corboy JR, Cross AH, Dhib-Jalbut S, Ford CC, Frohman EM, Giesser B, Jacobs D, Kasper LH, Lynch S, Parry G, Racke MK, Reder AT, Rose J, Wingerchuk DM, MacKenzie-Graham AJ, Arnold DL, Tseng CH, Elashoff R. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jan;15(1):35-46. doi: 10.1016/S1474-4422(15)00322-1. Epub 2015 Nov 29. |
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| NOT COMPLETED |
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Relapsing remitting multiple sclerosis women aged 18 to 50 years.
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| ID | Title | Description |
|---|---|---|
| BG000 | Estriol Capsules Plus Copaxone Injections | Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years |
| BG001 | Placebo Capsules Plus Copaxone Injections | Placebo: Placebo capsule, once a day, treatment duration is 2 years |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Confirmed Relapse, Annualized Relapse Rate | A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection. | Included all as intention to treat | Posted | Mean | 95% Confidence Interval | relapses per year | 24 months |
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| Secondary | Relapse Event, Annualized Relapse Rate | Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner. | Included all as intention to treat. | Posted | Mean | 95% Confidence Interval | relapses per year | 24 months |
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| Secondary | Confirmed Relapse, Probability of First Relapse | All included as intention to treat | Posted | Mean | 95% Confidence Interval | probability of relapse at 24 months | 24 months |
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| Secondary | Relapse Event, Probability of First Relapse Event | Included all as intention to treat | Posted | Mean | 95% Confidence Interval | probability of relapse event at 24 mo | 24 months |
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| Other Pre-specified | Confirmed Relapse, Annualized Relapse Rate | A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection. | Posted | Mean | 95% Confidence Interval | relapses per year | 12 months |
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| Other Pre-specified | Relapse Event, Annualized Relapse Rate | Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner. | Posted | Mean | 95% Confidence Interval | relapses per year | 12 months |
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After enrollment, during the 24-month treatment period
An adverse event is any condition that occurs after enrollment, whether or not considered related to study treatment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Estriol Capsules Plus Copaxone Injections | Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years | 8 | 82 | 76 | 82 | ||
| EG001 | Placebo Capsules Plus Copaxone Injections | Placebo: Placebo capsule, once a day, treatment duration is 2 years | 10 | 76 | 67 | 76 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| MS Relapse (hospitalization) | Nervous system disorders | Systematic Assessment |
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| Pregnancy | Pregnancy, puerperium and perinatal conditions | Systematic Assessment |
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| Urinary Tract Infection | Infections and infestations | Systematic Assessment |
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| Migraine headache related eye pain | Eye disorders | Systematic Assessment |
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| Heart Failure/ pace maker implantation | Cardiac disorders | Systematic Assessment |
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| Pyelonephritis | Renal and urinary disorders | Systematic Assessment |
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| Accidentally took other's drug | Investigations | Systematic Assessment |
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| Acute appendicitis | Infections and infestations | Systematic Assessment |
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| B-cell lymphoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
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| car accident related body numbness | Injury, poisoning and procedural complications | Systematic Assessment |
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| Right Knee Replacemebt | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper respiratory Infection | Infections and infestations | Systematic Assessment |
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| GA injection area abnormalities | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Irregular menses/ spotting | Reproductive system and breast disorders | Systematic Assessment |
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| Urinary tract infection | Renal and urinary disorders | Systematic Assessment |
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| Fatigue | General disorders | Systematic Assessment |
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| Depression/ Anxiety | Psychiatric disorders | Systematic Assessment |
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| Menstrual flow amount increased | Reproductive system and breast disorders | Systematic Assessment |
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| Headache | General disorders | Systematic Assessment |
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| Nausea/ vomitting | Gastrointestinal disorders | Systematic Assessment |
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| GA injection systemic reaction (SOB, hot flashes) | General disorders | Systematic Assessment |
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| Sinusitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Arm/ leg numbness, tingling | Nervous system disorders | Systematic Assessment |
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| Gastroenteritis | Gastrointestinal disorders | Systematic Assessment |
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| Dizziness | Nervous system disorders | Systematic Assessment |
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| Vision problem (blurry, double) | Eye disorders | Systematic Assessment |
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| Back Pain | General disorders | Systematic Assessment |
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| Menstrual cramp | Reproductive system and breast disorders | Systematic Assessment |
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| Insomnia | General disorders | Systematic Assessment |
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| Heart palpitation | Cardiac disorders | Systematic Assessment |
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| Shingles | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Vaginal infection | Reproductive system and breast disorders | Systematic Assessment |
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| Uterus, endometrial thickness > 8mm (ultrasound) | Reproductive system and breast disorders | Systematic Assessment |
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| Uterus, endometrial biopsies performed | Reproductive system and breast disorders | Systematic Assessment |
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| Uterus, fibroibds (ultrasound) | Reproductive system and breast disorders | Systematic Assessment |
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| Fibrocystic disease on clinical exam | Reproductive system and breast disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Rhonda Voskuhl | University of California Los Angeles | 310-206-4636 | rvoskuhl@mednet.ucla.edu |
| ID | Term |
|---|---|
| D020529 | Multiple Sclerosis, Relapsing-Remitting |
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D004964 | Estriol |
| D004967 | Estrogens |
| D000073893 | Sugars |
| D000068717 | Glatiramer Acetate |
| ID | Term |
|---|---|
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045505 | Physiological Effects of Drugs |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D002241 | Carbohydrates |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
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| >=65 years |
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| Male |
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