Pauline Anderson

April 30, 2014

PHILADELPHIA — Adding the sex hormone estriol to glatiramer acetate (Copaxone, Teva Neuroscience), a drug indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS), results in a greater reduction in the 1-year relapse rate, although the difference is not as great after 2 years, a new study shows.

The combination therapy in this phase 2 trial was safe and well tolerated, Rhonda Voskuhl, MD, professor, neurology, and director, MS program, University of California at Los Angeles, reported to delegates attending the American Academy of Neurology (AAN) 66th Annual Meeting here.

However, it's too early for neurologists to advise their female patients with MS to start taking estriol, Dr. Voskuhl later told Medscape Medical News. "We need to wait until a validation trial has been done for efficacy, and then women must weigh the risk/benefit ratio with their personal physician."

Hormones in Pregnancy

Research shows that MS relapse rates decrease during pregnancy at a time when levels of sex hormones are elevated, the researchers point out. Estriol is an estrogen that naturally increases to high levels in serum during the last half of pregnancy.

The new double-blind study included 164 women with RRMS aged 18 to 50 years at 16 sites in the United States who were not pregnant or breastfeeding. Participants had an Expanded Disability Status Scale score of 0.0 to 4.5.

These patients were randomly assigned to glatiramer acetate plus either 8 mg estriol per day or placebo. Those taking estriol also took progesterone, and those in the placebo group took another placebo. All patients began glatiramer acetate injections within 2 months of randomization.

Of the 83 patients in the estriol group, 70 completed the 1-year study and 60 completed the 2-year study. In the placebo group, which initially comprised 81 patients, 63 completed the 1-year study and 56 the 2-year study.

At 12 months, the estriol plus glatiramer acetate group had a 47% reduction in confirmed relapses compared with the placebo plus glatiramer acetate group (P = .0326; after adjustments for baseline characteristics, P = .0306).

Criteria for confirmed relapses included the following: (1) new neurologic symptoms or worsening of preexisting symptoms, (2) symptoms lasting at least 48 hours, (3) stable or improved condition in the previous 30 days, and (4) objective change confirmed by an examining neurologist.

For combined confirmed and unconfirmed relapses, the relapse rate reduction was 45% (P = .0216; adjusted for baseline characteristics, P = .0234).

At 24 months, the relapse rate reduction was 32% in the estriol group compared with the placebo group (P = .1549; adjusted P = .1527).

Dual Approach

Estriol appears to have "a dual approach" in protecting the brain, commented Dr. Voskuhl. She added that estrogens have been shown in the most widely used MS model to be both anti-inflammatory and neuroprotective.

"Anti-inflammatory effects occur in the peripheral immune system, so there are less immune attacks on the brain," she explained to Medscape Medical News. "This immunomodulation, which we and others have observed both in the mouse MS model and in a previous trial of estriol in women with MS, shifts immune responses from a Th1 to a Th2 type, a pattern consistent with immune changes during pregnancy."

The direct neuroprotective effects of estriol "occur since estrogens are capable of passing into the brain even in areas devoid of lesions, such as gray matter, to then bind to cells within the central nervous system to prevent them from being injured," said Dr. Voskuhl.

The study also showed improvement on cognitive test scores in the estriol group. At 12 months, there was about a 5.5% to 6% change on the Paced Auditory Serial Addition Test, which assesses information processing and attention. This change, said Dr. Voskuhl, represents a 3-point increase. Cognitive improvements remained high at 24 months. The placebo group also had cognitive improvements at 24 months.

More than 1 mechanism might underlie the improved cognition associated with estriol treatment, commented Dr. Voskuhl.

For example, some studies have shown that estrogen treatment increases dendrite branching and synapse formation in non-MS conditions and improves cognition function in healthy women in their 30s who have undergone ovariectomy.

"We showed that this also occurs in the MS mouse model with new synapses being formed during estriol treatment that were associated with improved electrophysiologic function in mice with the MS-like disease during estriol treatment," Dr. Voskuhl said. Other studies, she noted, have shown remyelination when estrogen receptor ligands were used in the MS model.

On the whole, estriol was safe and well tolerated. One patient in the glatiramer acetate group died of B cell lymphoma after the study. Some patients were hospitalized because of MS relapse (6 in the glatiramer plus placebo group and 2 in the glatiramer plus estriol group).

Cases of irregular menstrual spotting also occurred (26 in glatiramer acetate plus estriol recipients and 4 in glatiramer acetate plus placebo recipients).

There were no treatment-related differences in uterine fibroids on ultrasonography (8 in both groups), in uterine endometrial thickness greater than 8 mm on ultrasonography (27 patients and 41 examinations in the placebo group vs 24 patients and 32 examinations in the estriol group), in uterine endometrial biopsies, or in fibrocystic breast disease on clinical examination (4 patients in the placebo group and 5 in the estriol group).

Of note, no breast cancer was detected on mammography in either group. Uterine and breast cancer can occur with the high doses of estrogen that are used in birth control pills and hormone replacement therapy said Dr. Voskuhl.

Estriol, she said, is safer than other estrogens, likely because it binds to estrogen receptor (ER)-β more than to ER-α, with ER-α known to mediate these toxicities. Estriol is used safely in Europe and Asia for menopausal symptoms but at a dose of 2 mg per day, which is much lower than the 8 mg used in this study.

Results Encouraging, Preliminary

"While these results are encouraging, the results of this phase 2 study should be considered preliminary as a larger study would be needed to know whether benefits outweigh the risks for persons affected by MS," commented Walter Koroshetz, MD, deputy director, National Institute of Neurological Disorders and Stroke (NINDS), which funded the study, in a statement. "At present, we cannot recommend estrogen as part of standard therapy for MS."

Dr. Koroshetz agreed that patients should talk with their doctors before making any changes to their treatment plans.

The study was funded by NINDS, which is part of the National Institutes of Health, and the National Multiple Sclerosis Society. Dr. Voskuhl is a consultant with Synthetic Biologics. She is an inventor on a use patent for estriol for MS in the United States.

American Academy of Neurology (AAN) 66th Annual Meeting. Abstract 23.003. Presented April 29, 2014.

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