Pregnancy Hormone Benefits MS?

December 04, 2015

Supplementation with the estrogen hormone estriol ― found in high levels during pregnancy ― was associated with fewer relapses in patients with relapsing-remitting multiple sclerosis (RRMS) in a randomized, placebo-controlled study.

The study, published online November 29 in Lancet Neurology, was led by Rhonda Voskuhl, MD, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (UCLA).

"We have shown a beneficial effect on relapse rate, and this was backed up by suggestions of less gray matter atrophy and improved cognition," she commented to Medscape Medical News. "We believe we are seeing both an anti-inflammatory and an independent, direct neuroprotective effect."

However, in an accompanying commentary, Annette Langer-Gould, MD, Kaiser Permanente, Pasadena, California, asserts that the interpretation of Dr Voskuhl and colleagues seems "overly optimistic."

"First, the MRI evidence (which would have been a more suitable outcome) was null or in the opposite direction of the annualized relapse rate, suggesting that the difference in annualized relapse rate could be due to chance," she writes. "Second, the trial had methodological issues that could also explain the difference."

Dr Rhonda Voskuhl

Dr Voskuhl explained that pregnancy is known to be associated with fewer relapses in MS patients, but the reason for this is unclear.

Suspecting that estriol, produced by the placenta in pregnancy, may play a role, the researchers first conducted a pilot crossover study in 10 nonpregnant MS patients, which showed a significant reduction in gadolinium-enhancing lesions during 6 months of treatment with estriol.

In addition, mononuclear cells from the patients' peripheral blood showed increased production of protective cytokines and reduced production of proinflammatory molecules.

Dr Voskuhl and her team followed this with the current phase 2 trial, in which 164 women aged 18 to 50 years with RRMS were randomly assigned to receive either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate (20 mg daily).

The primary endpoint was annualized relapse rate after 24 months. This was reduced from 0.37 in the placebo group to 0.25 in the estriol group (adjusted rate ratio, 0.63; 95% confidence interval, 0.37 - 1.05; P = .077).

The researchers note that because this was a phase 2 trial, they used a significance level of 0.10 for all analyses, which they say "is considered stringent enough to assess the potential for clinical efficacy of a new intervention, while controlling for false positives and avoiding the much higher costs of the larger sample sizes needed to achieve a P value of less than 0.05."

"We found a reduction in relapses of about one third in patients taking estriol. The effect was actually even greater at 12 months ― a 48% reduction," Dr Voskuhl reported.

She noted that gray matter results showed similar findings, with less atrophy in the estriol group than in the placebo group at 12 months, which was not apparent at 24 months.

"This gray matter sparing effect was seen even in patients without enhancing lesions, suggesting a direct neuroprotective effect independent from anti-inflammatory effects," Dr Voskuhl said. Cognitive scores followed the same pattern, increasing in the estriol group at 12 months but not at 24 months.

Dr Voskuhl suggested that the greater effect seen at 12 months may be due to worse compliance in the second year. "This was confirmed by results of blood tests showing the estriol concentration increased and remained high through to 12 months but then decreased, with a significant decrease by 24 months," she noted.

In contrast with the gray matter findings, in patients in the estriol group who had enhancing lesions, there was a greater degree of white matter atrophy compared with the patients in the placebo group. Dr Voskuhl said this was consistent with "pseudoatrophy."

"White matter is where the inflammatory lesions are situated in MS," she said. "As the atrophy effect in the white matter was seen only in those patients with enhancing lesions at baseline, we believe what we are seeing is the anti-inflammatory effect of estriol, which would be consistent with the reduction in relapse rate seen."

"Challenges Plausibility"

But in her commentary, Dr Langer-Gould points out that the increase in T2 lesion volume was higher in the estriol group than in the placebo group, which she says could indicate increased neuroinflammation. And the effect on the number of new or active T2 lesions, a superior surrogate measure for annualized relapse rate to change in T2 volume, was not reported, she adds.

Dr Langer-Gould concludes: "Showing no positive effect on any brain MRI measure of neuroinflammation yet a positive effect on annualized relapse rate is unprecedented in trials of RRMS and challenges plausibility."

She adds that other study limitations included the high dropout rate, the unconventional significance level chosen, and the lack of an unadjusted comparison of the primary endpoint.

Dr Langer-Gould further notes that a previous trial of pregnancy-approximated doses of progesterone (in combination with low-dose estradiol) failed to show a reduction in postpartum MS relapses. She describes both this and the current study as "disappointingly negative."

In terms of safety in the current study, the proportion of patients with serious adverse events did not differ substantially between the estriol group (10%) and the placebo group (13%). Irregular menses were more common in the estriol group than in the placebo group, but vaginal infections were less common.

There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness, as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy.

Despite Dr Langer-Gould's comments, Dr Voskuhl believes her results are "very promising."

Although estriol is used extensively in Europe for treating menopausal symptoms, it is not available in the United States.

"We need a pharmaceutical company to take it on and develop it here," Dr Voskuhl said. She is hoping such a company will come forward to sponsor a large-scale phase 3 trial.

The study was funded by the National Institutes of Health (NIH), the National Multiple Sclerosis Society, the Conrad N. Hilton Foundation, the Jack H. Skirball Foundation, the Sherak Family Foundation, and the California Community Foundation. Dr Voskuhl has received research grants from the NIH and the National Multiple Sclerosis Society, has received personal payment as a consultant from Synthetic Biologics, and is an inventor on a patent for estriol owned by UCLA. Dr Langer-Gould has received grants from the National Multiple Sclerosis Society and the NIH and has been involved in clinical trials for Biogen Idec and Hoffman-LaRoche.

Lancet Neurol. Published online November 29, 2015. Abstract, Commentary

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