When women suffer migraine attacks, it is often just before or during their monthly period. A team of researchers from Charité – Universitätsmedizin Berlin has now identified a possible explanation. According to their study, published in the journal Neurology,* women who experience migraines have higher levels of CGRP during menstruation. CGRP is a neurotransmitter that is known to play an important role in triggering migraines.
Women suffer migraines at triple the rate that men do. The attacks tend to cluster around the time of menstruation, when they are also more severe, and the same is true at the onset of menopause. In many cases, symptoms improve during pregnancy, and the frequency of migraines also declines after menopause. Researchers have long known that there was a connection between hormonal fluctuations and migraines, but how exactly these changes trigger migraine remains largely unclear.
“Animal models suggest that fluctuations in female hormones, especially estrogen, lead to an increased release of CGRP, an inflammatory neurotransmitter, in the brain,” explains study lead Dr. Bianca Raffaelli of the Headache Center at the Department of Neurology with Experimental Neurology at Charité’s Mitte campus. “CGRP’s full name is calcitonin gene-related peptide. It is a naturally occurring substance in the body, and when a person has a migraine attack, increasing levels are released, significantly dilating – or widening – the blood vessels in the brain. This causes an inflammatory response that could be one of the reasons behind the severe headaches people experience with migraine.”
Increased CGRP levels during menstruation
The Charité research group studied a total of 180 women to determine whether the link between female hormones and the release of CGRP also exists in humans. The researchers tested the CGRP levels in migraine patients twice during their cycle, with one measurement taken during menstruation and the other during ovulation. When the data were compared to those of women who do not suffer migraines, it became clear that migraine patients have significantly higher concentrations of CGRP during menstruation than healthy subjects. “This means that when estrogen levels drop immediately before the start of a menstrual period, migraine patients release more CGRP,” says Raffaelli, who is also a fellow with the Clinician Scientist Program jointly operated by Charité and the Berlin Institute of Health (BIH) at Charité. “This could explain why these patients suffer more migraine attacks just before and during their monthly period.”
In women who take oral contraception, by contrast, there are hardly any fluctuations in estrogen levels. As researchers showed in this study, CGRP concentrations are also uniform over the course of the “artificial cycle” caused by oral contraception, with comparable levels seen in both female migraine patients and healthy women. The researchers made a similar observation in postmenopausal women.
“The data will still need to be confirmed by larger studies, but our findings do suggest that the release of CGRP depends on hormonal status in humans, as it does in the animal model,” Raffaelli notes. “Taking birth control pills and the end of menopause do in fact bring relief for some female migraine patients. But as our study also shows, there are women who suffer from migraine even without any hormonal fluctuations. We suspect that other processes in the body play a role in triggering attacks in those patients. After all, CGRP isn’t the only inflammatory peptide that can cause a migraine attack.”
Possible relevance for migraine medications
Since CGRP plays such a pivotal role in migraines, researchers have developed new medications known as CGRP inhibitors to target this neurotransmitter in recent years. Raffaelli comments: “Based on our study, the question now is, Do CGRP inhibitors work differently in differing hormonal states? So might it be a good idea to administer these drugs depending on where a person is in their cycle? Further studies will be needed on these points.”
The team now plans to study what other physical processes are influenced by the menstrual cycle, potentially contributing to migraine – such as the functioning of the blood vessels or brain excitability. The researchers also plan to take a closer look at CGRP levels in men of varying age groups.
*Raffaelli B et al. Sex hormones and Calcitonin Gene-Related Peptide (CGRP) in women with migraine: a cross-sectional, matched cohort study. Neurology 2023 Feb 22. doi: 10.1212/WNL.0000000000207114
Dr. Bianca Raffaelli
Department of Neurology with Experimental Neurology
Campus Charité Mitte
Charité – Universitätsmedizin Berlin
t: +49 30 450 570 400
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