Summary: In a small-scale, early-phase trial of the hormone estriol, a form of estrogen, women with relapsing-remitting MS showed decreases in MRI-detected brain lesion activity and immune responses during treatment, suggesting that additional study of estriol is called for to determine longer-term efficacy and safety.

• Women who have MS and are pregnant often experience fewer MS symptoms and relapses, especially during the second and third trimester. Because the hormone estriol is elevated during later stages of pregnancy, and mice given pregnancy levels of estriol were shown to have fewer symptoms of an MS-like disease, the hormone was considered as a candidate for testing against MS.
• Estriol was well tolerated. Six women with relapsing-remitting MS experienced significant decreases in brain lesion numbers and volume, as well as reductions in levels of immune proteins indicative of inflammation. Women with secondary-progressive MS did not improve significantly during the course of the trial.
• Larger, longer-term trials will be needed to determine whether these preliminary encouraging findings translate into significant reductions in relapse rates and/or disease progression.

Details: In a small-scale, early-phase trial of the hormone estriol, a form of estrogen, women with relapsing-remitting MS showed decreases in brain lesion activity (detected by MRI – magnetic resonance imaging) and immune responses during treatment, suggesting that additional study of estriol is called for to determine longer-term efficacy and safety. Rhonda Voskuhl, MD (University of California at Los Angeles) and colleagues report their findings in the October 2002 issue of Annals of Neurology. The study was funded by the National MS Society, and Dr. Voskuhl and co-author Nancy Sicotte, MD, are Harry Weaver Neuroscience Scholars of the National MS Society. 

Background: Pregnant women who have MS often experience fewer MS symptoms and relapses, especially during the second and third trimesters. Dr. Voskuhl and others have noted that pregnancy also reduces the severity of the MS-like disease EAE in laboratory animals. Because the hormone estriol (a form of estrogen) is elevated during later stages of pregnancy, and mice given pregnancy levels of estriol were shown to have fewer symptoms of EAE, the hormone was considered as a candidate for testing against MS. Estriol is used in Europe to treat symptoms associated with menopause, but it has never been systematically given to women who have MS as a potential MS therapy.

The Study: Dr. Voskuhl and colleagues conducted a pilot trial of estriol treatment in women with MS to determine if the treatment is safe and to evaluate if more definitive, larger-scale studies were warranted. Twelve women with relapsing-remitting (characterized by partial or total recovery after acute attacks) or secondary-progressive MS (steadily progressive disease that often occurs after the relapsing course) were enrolled. None were receiving the disease-altering drugs then available (Avonex, Betaseron or Copaxone). The women were monitored for six months prior to treatment for evidence of relapse, progression and disease activity, and with monthly MRI scans. Laboratory studies and skin tests were used to measure immune responses. All 12 volunteers received active treatment with 8 mg estriol by pill, once a day for six months. They were given monthly MRI scans and clinical and immunologic tests every three months. After the treatment phase, MRI scans continued monthly and clinical exams were done every three months for a period of six months, to assess any longer term, post-treatment beneficial or harmful effects of the estriol. Because estrogen use has been reported to improve mental function in other neurologic disorders, participants also underwent pre-treatment and post-treatment testing for cognitive function. After completion of the original trial, women with relapsing-remitting MS were treated for an additional four months based on the initial findings. 

Results: In this short-term trial, estriol was well tolerated, with only menstrual cycle abnormalities. The six participants with relapsing-remitting MS experienced significant decreases in brain lesion numbers and volume, as well as a reduction in levels of immune proteins indicative of inflammation. When estriol treatment was stopped, lesion numbers returned to pre-treatment levels, and then decreased again when estriol treatment was resumed. During treatment, cognitive function scores improved significantly in women with relapsing-remitting MS. Women with secondary-progressive MS did not improve significantly during the course of the trial.

Conclusions: This small-scale trial of pregnancy levels of the hormone estriol suggests that short-term use of estriol is well tolerated and that further trials are warranted in women with relapsing-remitting MS. Larger, longer-term trials will be needed to determine whether these preliminary, encouraging findings translate into significant reductions in relapse rates and/or disease progression. One such trial is currently in the planning stages. 

A Note on Estriol: In July 2002, media attention was drawn to the premature stopping of a clinical trial of estrogen plus progesterone for treatment of symptoms in otherwise healthy post-menopausal women, because of a higher than expected risk of breast cancer, heart attack and stroke. In further studies of estriol in MS, safety would be closely monitored at all stages to ensure that, should the therapy prove beneficial, it would have an acceptable side-effect profile.