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At the ACTRIMS Forum 2021, Rhonda Voskuhl, MD, a neurology professor at the University of California Los Angeles (UCLA), called for a Phase 2 clinical trial to examine the effects, notably to the brain, of estrogen treatment in people with multiple sclerosis (MS) who are going through menopause.
Her talk — during a presentation at this year’s virtual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) — was titled “Menopause and Hormonal Effects.”
Menopause is when a woman’s menstrual periods cease, typically in the fourth or fifth decade of life. During menopause, levels of certain hormones are known to decrease. Most notable is the drop in a woman’s estrogen levels.
Estrogen can have substantial impacts on many bodily systems, including the brain. However, the effect of decreased estrogen during menopause on brain health — and the associated implications for MS — are not well understood.
In the presentation, Voskuhl provided an overview on the available data concerning menopause, brain function, and MS, with a particular focus toward possible therapeutic interventions.
“Cognitive difficulties clearly occur in healthy women [during menopause], and they’re extremely frequent,” said Voskuhl, director of the UCLA MS program.
“They’re so frequent during menopause that it’s got a name in layman’s terms: it’s called ‘brain fog,'” Voskuhl said.
The cognitive impact of menopause has been thoroughly validated using objective cognitive tests. Of note, however, global or overall cognition does not change during menopause in healthy women. Instead, specific aspects of cognition are impacted, such as verbal memory, or the ability to remember words, and processing speed, which is how quickly a person can take in new information.
Also of note, cognitive problems do not just occur during age-related menopause, research shows. Younger women who have their ovaries removed surgically, called an ovariectomy, also experience similar cognitive difficulties. Plus, women who have their ovaries removed earlier in life tend to have worse cognitive problems later on.
Consistently, imaging studies have shown that certain parts of the brain have smaller volumes (brain atrophy) following menopause.
These observations imply that reduced estrogen levels during menopause contribute to brain abnormalities and, consequently, cognitive problems.
Voskuhl highlighted data from a clinical trial called KEEPS (NCT00154180), in which 662 women — all without MS — were given estrogen-based treatments starting about 1.4 years after the onset of menopause.
Results from this KEEPS study showed that estrogen treatment did not affect global cognition or whole brain atrophy; however, there were effects on specific brain regions. Specifically, treatment with a form of estrogen called estradiol led to less atrophy of the prefrontal cortex, a part of the brain that is involved in high-level cognition and decision-making.
Other studies also have indicated that estradiol treatment can lessen the decline in prefrontal cortex function following menopause. Thus, according to Voskuhl, the available evidence indicates that estradiol treatment near menopause could improve the health of this brain region.
Voskuhl then discussed menopause in the context of MS, though she cautioned that there is generally less available data for this specific group of patients.
She highlighted subjective data indicating that some people with MS experience a worsening of symptoms following menopause. Objective data also have indicated that people with MS tend to experience worsening disability following menopause, though the effect of menopause on relapse rates is less clear.
Combined with data from people without MS, these findings indicate that estrogen-replacing therapies may provide some benefit to people with MS undergoing menopause.
“What’s known about hormone treatments in MS women with menopause? Almost nothing,” said Voskuhl. She noted only one small ongoing study testing the effects of estrogen treatment to reduce hot flashes in women with menopause.
Voskuhl also noted some data on estrogen treatment in MS individuals who have not yet undergone menopause. These studies have shown that estrogen-based treatments can reduce relapse rates, lessen brain damage, and improve cognition.
New data from a study in which premenopausal MS patients were treated with estriol — another type of estrogen — or a placebo also were discussed. After a year of treatment, participants given estriol had significantly lower levels of serum neurofilament light chain (NfL), a marker of damage to the nervous system. Meanwhile, NfL levels did not change in those given a placebo.
Collectively, Voskuhl said, the data available so far support further testing of estrogen therapies in MS. She noted the importance of measuring appropriate outcomes in such trials. For example, according to her, it would make more sense to measure specific cognitive aspects like verbal memory, rather than global cognition.
The neurologist also noted that lessons learned about estrogen treatments in people without MS — such as the timing and dose of treatment and the type of estrogen used — could help to inform the design of such trials in women with MS.
“I will make a call to action, as I conclude, and that is to design a Phase 2 trial of estriol treatment in menopausal MS women,” Voskuhl concluded. According to her, such a trial would focus on brain aging and factors that are preventable, such as the dramatic loss of estrogen when women enter menopause.
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