Estriol may ease MS

January 8, 2008

http://www.neurologyreviews.com/nov02/nr_nov02_estriol.html ESTRIOL MAY EASE RELAPSING-REMITTING MS IN WOMEN BALTIMORE—Administration of oral estriol, the predominant estrogen of pregnancy, to nonpregnant women with relapsing-remitting multiple sclerosis increased protective immune responses and decreased the number and volume of gadolinium-enhancing lesions on monthly cerebral magnetic resonance imagings (MRIs), a phase I study has shown. “To our knowledge, this is the first time a pregnancy hormone has been given at a pregnancy dose to [patients] in an attempt to ameliorate a putative Th1-mediated autoimmune disease by using highly sensitive subclinical markers of disease activity as an indicator,” reported Rhonda Voskuhl, MD, and colleagues in the October ls of Neurology. Dr. Voskuhl is Associate Professor of Neurology at the Geffen School of Medicine at the University of California, Los Angeles (UCLA). “This novel treatment strategy of using pregnancy doses of estriol in multiple sclerosis has relevance to other autoimmune diseases that also improve during pregnancy,” the authors noted, including rheumatoid arthritis, uveitis, thyroiditis, and a number of other arthritides. HORMONES AND MS Two widely accepted clinical observations implicate hormones in multiple sclerosis. First, “women are clearly more susceptible than men to multiple sclerosis; second, women with multiple sclerosis improve transiently during pregnancy,” particularly during the last trimester, said Dr. Voskuhl at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Estriol, produced by the fetal placental unit, is not detectable at appreciable amounts until pregnancy, when it progressively increases. Previous studies have found that estriol administered to mice with experimental autoimmune encephalomyelitis resulted in amelioration of multiple sclerosis, with a favorable shift in immune response similar to that seen

during pregnancy. Dr. Voskuhl, who is also a research scientist at UCLA’s Brain Research and Neuropsychiatric Institutes, explained that estriol at pregnancy doses has been given in Europe and Asia in the form of hormone replacement therapy for symptoms of menopause, “which means we didn’t have to reinvent the wheel on assessing toxicity. It was very well known how this estriol preparation would be tolerated. Therefore, we could go straight to a phase I clinical trial focusing on multiple sclerosis–related disease measures.” Noting that all currently available anti-inflammatory therapies for multiple sclerosis are injections, Dr. Voskuhl reported that the purpose of the trial “was to test a noninjectable, oral anti-inflammatory hormonal treatment” in an attempt “to recapitulate the beneficial effect of pregnancy.” The study included a

six-month baseline pretreatment period, six months of treatment with oral estriol 8 mg/d, and a six-month posttreatment evaluation period. Patients with relapsing-remitting multiple sclerosis received an additional four months’ retreatment with oral estriol 8 mg/d with progesterone, she added. Twelve women with clinically definite multiple sclerosis were included in the study; six with relapsing-remitting and six with secondary progressive disease. Patients were excluded if they had been taking interferon-beta or glatiramer acetate for six months or steroid therapy for three months prior to enrollment. “We did an MRI every month throughout—we followed them in the clinic every three months,” Dr. Voskuhl said. A delayed-type hypersensitivity (DTH) response to tetanus and candida was performed, once in the pretreatment period and once in the

treatment period, as was Paced Auditory Serial Additional Task (PASAT) cognitive testing. All six patients with relapsing-remitting multiple sclerosis and four with secondary progressive multiple sclerosis completed the study. One patient was disqualified because of concurrent steroid treatment “and the other did not wish to go untreated in the posttreatment period,” the investigators noted. Mean age of those who completed the study was 44 years (range, 28 to 50). For all patients, mean Expanded Disability Status Scale score was 3.3 (range, 1.0 to 6.5); for those with relapsing-remitting disease it was 2.2 and for secondary progressive, 5.0. ENHANCING RESULTS Compared with the six-month pretreatment baseline period, the total volume and

number of enhancing lesions for all 10 patients decreased during the treatment period, the investigators found, with cognitive improvement seen entirely in the relapsing-remitting group. In this group, median total enhancing lesion volumes decreased by 79% and number of lesions by 82% within the first three months. Over the next three months, lesion volumes decreased by 82% and numbers by 82%. During the six-month posttreatment period, “median total enhancing lesion volumes and numbers became variable in the first three months off treatment, before returning to near-baseline levels in the last three months,” the researchers remarked. Patients retreated over four months had a decrease in enhancing lesion volumes of 88% and in numbers of 48% compared with original baseline scores. “Changes in median new enhancing lesion volumes and numbers

followed similar patterns as median total lesion numbers and volumes,” they observed. For the entire group, median T2 lesions were 15.3 cm3 (range, 6.1 to 33.8); no significant differences were seen between the two subgroups. In the relapsing-remitting group, median T2 lesion volumes showed no change during the six-month treatment period, a 7.4% increase during the six-month posttreatment period, and a 2.0% decrease in the four-month retreatment period. After six months of estriol treatment, patients’ DTH responses to tetanus decreased significantly compared with month 3 (pretreatment baseline), whereas responses to candida “were decreased less drastically and more variably,” the researchers found. In relapsing-remitting patients, interferon-gamma levels were significantly decreased after six months of treatment compared with baseline. No

decrease was seen in the patients with secondary progressive disease. Similarly, in the relapsing-remitting group, PASAT cognitive testing scores improved significantly and no change was seen in the secondary progressive group. During treatment and retreatment, serum estriol levels approximated “those observed in women who were six months pregnant but were lower than those who were 8.5 months pregnant,” the authors wrote. Few relapses were observed during the study, and the estriol was found to be well tolerated. Since the study was submitted for publication, Dr. Voskuhl reported that additional immunologic studies performed on the six patients with relapsing-remitting disease showed an increase in IL-5 and a decrease in TNF with estriol treatment. A double-blind placebo-controlled study is now being planned in patients with relapsing

remitting multiple sclerosis only, with the goal “to reproduce what we did in the pilot—that is, to get a decrease in gadolinium-enhancing lesions, a favorable shift toward cytokine production, and an improvement in PASAT,” Dr. Voskuhl concluded. NR

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January 8, 2008