Taking the pregnancy hormone estriol along with their conventional medications helped patients with relapsing-remitting multiple sclerosis (RRMS) avoid relapses, according to results of a Phase II randomized, placebo-controlled study led by UCLA researchers.
The study, published online in Lancet Neurology, was truly translational. The UCLA team took observations from the bedside, tested them in the laboratory and took those findings back again to patients in clinical trials, said the study’s lead author Dr. Rhonda Voskuhl, professor in the UCLA Department of Neurology and director of UCLA’s Multiple Sclerosis Program.
It’s long been observed that during the second half of pregnancy, women with RRMS have reduced relapses, but the reason was unclear. It is also during this period that the fetal placenta produces estriol, increasing the hormone levels in the blood. This protection during pregnancy occurs not only in MS, but also in other autoimmune diseases such as psoriasis and rheumatoid arthritis.
Voskuhl took this information to the lab. She hypothesized that increased estriol in the blood might play a role in suppressing a woman’s immune system so that the fetus is not rejected as being foreign, having half of the father’s proteins. This temporary suppression of the immune system would be good for pregnant mothers with autoimmune diseases. Her team found that treatment with estriol was protective in the MS model. That led to a successful pilot clinical trial in 2002 at UCLA and then the Phase II trial, launched in 2007 at UCLA and 15 other sites across the United States.
“The beauty of estriol is that it is not a shot and can be taken in pill form, and also that it’s not a new drug. It has decades of safety behind it,” said Voskuhl, who holds the Jack H. Skirball Chair for Multiple Sclerosis in the UCLA Department of Neurology. “Also, current MS treatments are very complex to manufacture. These findings hopefully will pave the way for oral, safe treatments that are more widely accessible, since estriol is simple and naturally occurring.”
Multiple sclerosis is an autoimmune disease of the central nervous system where immune cells from the blood attack the tissue surrounding the brain’s nerve fibers. Called myelin, this tissue is like the insulation wrapped around an electrical wire. When the myelin is damaged, it interferes with the ability of the nerves to send signals to and from the brain, resulting in symptoms including cognitive problems, difficulty with walking, poor vision and other disabilities.
In RRMS, there are clear episodes of inflammatory activity, or relapses. During a relapse, there are new or worsening symptoms, accompanied by inflammatory lesions in the brain. A relapse can continue anywhere from several days to months. Relapses are usually followed by remission, or improvement. However, some residual symptoms may remain, and after many years people with RRMS often transition to a progressive form of the disease. During the progressive phase, there are no longer relapses, but instead gradual worsening of permanent disabilities and loss of brain volume or atrophy.
In the lab, Voskuhl and her team discovered that estriol potentially provides a one-two punch against the disease, both reducing the ability of immune cells to attack the brain, while also making brain cells more resistant to damage if any immune cells do make it through. Specifically, they showed that estriol treatment improhved cognition and prevented atrophy of the cognitive region of the brain. It seems that during pregnancy, estriol can both suppress the immune system and protect the brain, for not only is it important to avoid rejection of the fetus as foreign, it is also critical to protect the developing fetal brain. While these two effects may be designed to protect the fetus, they may also be exactly what the doctor ordered for women with MS.
In 2002, Voskuhl completed the pilot study, in which 10 non-pregnant women with MS were given estriol, yielding a greater than 70 percent drop in inflammatory lesions in the brain within only six months of treatment.
In the Phase II study, researchers enrolled 164 patients, with 83 allocated to the estriol group and 81 to the placebo group. Both arms continued their conventional medication, injectable glatiramer acetate. The team found that the patients taking estriol had a third to a half as many relapses compared to those taking the placebo, with this improvement occurring over and above that provided by their conventional treatment. In addition, when estriol levels were the highest, there was improved cognitive function and less atrophy of the brain area related to cognition. The treatment was well tolerated during the two years the volunteers took estriol and the only significant side effect was irregular menstruation. To date, there is no FDA approved treatment for MS that improves disabilities.
These two trials are very unique in that neither were funded by a pharmaceutical company. Rather, they were funded by the National Institutes of Health (NIH) and the National Multiple Sclerosis Society, consistent with the new NIH policy that more research should focus on sex differences in disease. Additional major funding was from the Conrad N. Hilton Foundation, whose mission it is to improve the lives of disadvantaged people throughout the world. Synthetic Biologics, Inc., provided estriol and placebo for the multicenter trial and has licensed certain rights from UCLA.
Going forward, Voskuhl hopes to see a Phase III trial conducted to replicate these findings, since this is necessary for FDA approval of estriol for MS. She continues to seek support to advance this as well as other MS research projects.
It is estimated that more than 2.1 million people are affected by MS worldwide. Approximately 85 percent of patients are diagnosed at onset with RRMS, the most common form of MS.
“These findings are consistent with the hypothesis that increased concentrations of estriol during pregnancy might mediate, at least in part, the protective effect of pregnancy on relapse rates,” the study states. “A phase III study of estriol in multiple sclerosis is needed to confirm these findings as well as to explore potential effects on disabilities.”
The UCLA Department of Neurology, with over 100 faculty members, encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. The department ranks in the top two among its peers nationwide in National Institutes of Health funding.
This news release from UCLA Health Sciences uses a story-telling approach to inform readers how scientists observed that women with relapsing-remitting multiple sclerosis (RRMS) experienced lower rates of relapses during their third trimester. The story told here is well-written, engaging, and effective. The researchers discovered that these intermission periods coincided with the periods when women had the highest levels of estriol in their blood.
Estriol is a relatively weaker and, it’s assumed, safer female sex hormone. When researchers gave estriol with conventional medication, or placebo and conventional drugs, to 164 MS patients they found a lower rate of relapses among those getting the estriol. The trial is published in the journal Lancet Neurology. It’s a Phase II, randomized and controlled trial that was first presented at a national neurological meeting in April 2014. The release offers important, interesting and substantial detail about the clinical observation that led researchers at UCLA to experiment with estriol but doesn’t explicitly state that it is still too soon for neurologists to recommend estriol therapy. The release also omits some key data concerning the reduction of relapse among the patient volunteers.
There are precious few treatments that have a significant impact on MS relapse rates and none that can reverse or improve cognitive, visual and physical disabilities that occur in most patients over time. The availability of a relatively safe, effective, and likely low-cost hormone therapy that, taken as a pill, can reduce relapses and nerve cell damage due to inflammation would be welcome news. If confirmed in a larger Phase lll trial, estriol might have potential value, as the release points out, for MS as well as other autoimmune disorders.
The release could have used some explicit indication of the potential cost of adding estriol to treatment with injectable glatiramer acetate. The text suggests that the hormone is widely available and thus likely to be simpler and less costly to take.
In the United States estriol is available only as a vaginal cream, not in tablet form. It is mostly used in “bioidentical” hormone replacement products obtained from compounding pharmacies.
The release does a pretty good job of noting the apparent benefits in its narrative, but hard data are notably missing or under-reported. Readers would benefit from knowing, for example:
How many of the women who took estriol along with their conventional medications showed reduced relapse rates, and to what degree, compared to women who took the placebo with conventional drugs? (Telling us that these women had “a third to a half as many relapses” is a relative comparison — we wanted to see absolute numbers.)
If there were extended breaks between relapses, how long were they?
What was the rate of inflammatory lesions in the brain and when did they occur? These numbers should be included for the current study, not the 2002 findings.
Finally, the release could have noted an important reduction-in-the-reduction of relapse rates over time. For example, a Medscape news report on the 2014 presentation noted a 47% reduction in confirmed relapses compared to placebo group in the first year and a 32% relapse rate reduction in the second year.
The release notes that the only significant adverse event for those on estriol was irregular menses. It could have gone into more detail, perhaps, but this passes muster. The point is that estriol is essentially a weak form of estrogen that has been shown in previous studies to be fairly safe, and whatever risks exist are likely outweighed by benefits in women with MS.
It’s noted in the release that the study is a randomized, placebo-controlled trial. This is important since randomized, controlled trials provide a higher quality source of evidence. The reader should come away with the idea that this is another good piece of evidence that estriol can, when combined with other medicines, safely decrease MS relapses. The release could have made clearer the limitations of the findings. Not all patients were helped and the effects decreased over time.
No fear mongering here.
The release goes into significant detail about the funders and their mission. Funders include the National Institutes of Health, the National Multiple Sclerosis Society, and a private foundation. The drugs and placebo used in the study were provided by Synthetic Biologics, the manufacturer. The release also notes, somewhat vaguely, that Synthetic Biologics has licensed some rights from UCLA.
This is a comparison study that measures the results of taking estriol and conventional medications compared to placebo with conventional medications to reduce relapses.
The release makes it clear that estriol is widely available now for other uses and that researchers have yet to complete Phase lll trials and apply for FDA approval for application in MS patients. However, it should be noted that estriol is far more commonly used in topical skin creams and not in tablet form as was the case with this study.
Although the release mentions previous studies by the UCLA investigator dating back to 2002, the timeline for the relevance of some findings is somewhat confusing, and it would have been useful to mention that the current data were substantially presented in 2014.
In the headline the release refers to estriol as a “safe” hormone. We think it would have been better to qualify the hormone as “safer” than others.