When women are afflicted by migraine attacks, it often happens shortly before or during menstruation. A research team from the Charité – Universitätsmedizin Berlin has now found a possible explanation for this. According to the study published in the journal Neurology*, affected women produce particularly large amounts of CGRP during menstruation. This messenger substance is known to play a decisive role in the development of migraines.
Women are affected by migraines three times more often than men. They experience particularly numerous and severe attacks around menstruation, but also at the onset of menopause. In contrast, the symptoms improve in many cases during pregnancy, and migraine attacks also become less frequent at the end of the menopause. It has therefore been known for a long time that hormonal fluctuations are associated with migraine. How exactly they do this, on the other hand, is still largely unclear.
“From the animal model, we have evidence that fluctuations in female hormones – especially oestrogen – lead to an increased release of the inflammatory messenger CGRP in the brain,” explains Dr Bianca Raffaelli from the Headache Centre of the Department of Neurology with Experimental Neurology at Charité Campus Mitte, who led the study. “CGRP stands for ‘Calcitonin Gene-Related Peptide’ and is an endogenous substance that is increasingly released during migraines and strongly dilates the blood vessels in the brain. This causes an inflammatory reaction, which could be one of the reasons for the severe headaches in migraines.”
Increased CGRP levels during menstruation
Using a total of 180 women, the Charité research group now tested whether the connection between female hormones and the release of CGRP also exists in humans. For this purpose, the researchers determined the CGRP level in migraine patients twice during the course of the cycle, namely during menstruation and at the time of ovulation. A comparison with women without migraine showed: During menstruation, the concentration of CGRP is significantly higher in migraine sufferers than in the healthy test subjects. “So when the oestrogen level drops at the onset of the period, migraine sufferers secrete more CGRP,” says Dr Raffaelli, who is also a fellow of the Clinician Scientist Programme, which Charité runs together with the Berlin Institute of Health at Charité (BIH). “This could explain why the affected women experience migraine attacks more frequently shortly before and during menstruation.”
In women who take the pill, there are hardly any fluctuations in the oestrogen level. As the researchers demonstrated in the current study, the CGRP concentration also does not change in the course of the “artificial cycle” and is comparable in migraine patients to that of healthy women. The scientists observed similar results in women who had completed the menopause.
“Even if these data still need to be confirmed by larger studies: they suggest that in humans the release of CGRP is dependent on the hormonal state,” Dr Raffaelli sums up. “Indeed, taking the pill and the end of the menopause can provide relief for some migraine sufferers. But as our study shows, there are women who get migraines even without hormonal fluctuations. We suspect that other processes in the body play a role in the development of an attack. Because CGRP is not the only inflammatory peptide that can trigger migraines.”
Possible relevance for migraine medication
Because of the central function of CGRP in the development of migraine, new drugs have been developed in recent years that are directed against the messenger substance – so-called CGRP inhibitors. Dr. Raffaelli: “Based on our study, the question now arises: Do CGRP inhibitors have a different effect in different hormonal conditions? Would it therefore make sense, for example, to administer these drugs depending on the cycle? That’s what further studies now need to show.”
In the future, the research team will investigate which other physical processes are influenced by the menstrual cycle and could contribute to the development of migraine attacks – for example, the function of the blood vessels or the excitability of the brain. The researchers also plan to take a closer look at CGRP levels in men of different 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
Headache Research Group of the Department of Neurology with Experimental Neurology