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.
Background and objectives: Sex hormones may modulate CGRP release in the trigeminovascular system. We studied CGRP concentrations in plasma and tear fluid in female participants with episodic migraine (EM) and a regular menstrual cycle (RMC), female participants with EM and combined oral contraception (COC), and female participants with EM in the postmenopause. For control, we analyzed three corresponding groups of age-matched female participants without EM.
Methods: Participants with a RMC had two visits: during menstruation on menstrual cycle day 2 ± 2 and in the periovulatory period on day 13 ± 2. Participants with COC were examined at day 4 ± 2 of the hormone-free interval (HFI) and between days 7-14 of hormone intake (HI). Postmenopausal participants were assessed once at a random time point. Plasma and tear fluid samples were collected at each visit for determination of CGRP levels with an enzyme-linked immunosorbent assay.
Results: A total of 180 female participants (n=30 per group) completed the study. Participants with migraine and a RMC showed statistically significantly higher CGRP concentrations in plasma and tear fluid during menstruation compared to female participants without migraine [plasma: 5.95 pg/ml (IQR 4.37 - 10.44) vs. 4.61 pg/ml (IQR 2.83 - 6.92), p=0.020 (Mann-Whitney U test); tear fluid: 1.20 ng/ml (IQR 0.36 - 2.52) vs. 0.4 ng/ml (IQR 0.14 - 1.22), p=0.005 (Mann-Whitney U test)]. In contrast, female participants with COC and in the postmenopause had similar CGRP levels in the migraine and the control groups. In migraine participants with a RMC, tear fluid but not plasma CGRP concentrations during menstruation were statistically significantly higher compared to migraine participants under COC (p=0.015 vs. HFI and p=0.029 vs. HI, Mann-Whitney U test).
Discussion: Different sex hormone profiles may influence CGRP concentrations in people, with current or past capacity to menstruate, with migraine. Measurement of CGRP in tear fluid was feasible and warrants further investigation.
Bianca Raffaelli, Elisabeth Storch, Lucas Hendrik Overeem, Maria Terhart, Mira Pauline Fitzek, Kristin Sophie Lange, Uwe Reuter. Sex Hormones and Calcitonin Gene-Related Peptide in Women With Migraine: A Cross-sectional, Matched Cohort Study. Neurology . 2023 Feb 22;10.1212/WNL.0000000000207114. doi: 10.1212/WNL.0000000000207114. Online ahead of print.
Content created March 2023