Migraine headaches are approximately three times more common in women than in men, but the prevalence of migraine in women decreases after menopause, suggesting a role for sex hormones in migraine development, wrote Bianca Raffaelli, MD, of Charité-Universitätsmedizin Berlin, Germany, and colleagues. In their new study, based on data of 180 individuals, they found that menstruating women had significantly higher levels of calcitonin gene-related peptide (CGRP), a protein associated with migraine pain and the target of recently developed medications for migraine prevention and treatment.

Study Methods

In the study, published in Neurology, the team examined CGRP concentrations in plasma and tear fluid of women with and without migraine under three hormonal conditions. The study population included women with:

  • episodic migraine with a regular menstrual cycle (RMC)
  • women with episodic migraine who were taking combined oral contraceptives (COC)
  • postmenopausal (PM) women with episodic migraine

Episodic migraine was defined as at least 3 days with migraine in the 4 weeks prior to screening. Three groups of age-matched women without episodic migraine under the same three hormonal conditions served as controls.

Findings in Women with Migraine

Overall, CGRP levels were significantly higher in the tear fluid of women with migraine compared to those without migraine who served as controls (0.67 ng/mL vs. 0.41 ng/mL, P=0.013); CRPG in plasma was similar between the groups.

Among women with a regular menstrual cycle, CGRP concentrations were significantly higher in both the plasma and the tear fluid of women with migraines during the menstrual cycle compared to controls (5.95 pg/mL vs. 4.61 pg/mL for plasma, P=0.020; 1.20 ng/ml vs. 0.4 ng/ml for tear fluid, P=0.005).

During menstruation, women with migraine and a RMC had significantly higher CGRP in tear fluid, compared to women with migraines on COC, Dr. Raffaelli’s et al noted.

“A higher CGRP release during menstruation could help to explain the biological predisposition for more frequent, severe, and long-lasting migraine attacks in this period,” they wrote in their discussion.

The findings were limited by several factors including the lack of continuous hormone measure, and also the exclusion of women with purely menstrual migraine, who might have experienced greater hormonal fluctuations, the researchers noted. An additional limitation was the use of a shorter definition of a migraine-free period (the interictal state) compared to other studies, they said.

However, the results suggest that the elevated release of CGRP following hormonal fluctuations might contribute to an increased susceptibility for migraine among menstruating women, the researchers wrote. In addition, the lower concentrations of CGRP in the tear fluid of women on COC merit further study, as they could be associated with altered susceptibility to migraine under the influence of hormonal therapy, they concluded.

The sex differences in migraine are well-known based on previous epidemiologic studies showing a higher prevalence of migraine in women compared to men, said Nu Cindy Chai, MD, a neurologist and pain management physician at the University of California, San Francisco. “However, how exactly sex hormones influence migraine pain has not been elucidated fully,” she said. The current study, “which linked changes in menstrual cycles as well as changes in hormone status (hormonal contraceptive use and postmenopausal state) with CGRP levels in those with episodic migraine (EM) and controls, provides further evidence that sex hormones may influence menstrually related migraine through changes in CGRP concentrations in certain migraineur populations,” she said.

Dr. Chai said she was not surprised by the findings. “Given prior studies suggesting the estrogen withdrawal theory in migraine, I was not surprised to find that CGRP levels are higher during menstruation (low estrogen level) in migraineurs in this study. However, the fact that CGRP levels are higher during menstruation in migraineurs compared to non-migraineurs is of interest,” she said. “This demonstrates that while sex hormones may play a role in migraine pain via CGRP concentrations, this influence is not universal,” she noted. “In other words, non-migraineurs are expected to experience similar fluctuations in sex hormones as migraineurs through their menstrual cycle, but their CGRP concentrations are lower compared to those of migraineurs.”

Practical Takeaways

The key message of the current study, according to Dr. Chai, is that female sex hormone fluctuations may influence CGRP concentrations in those with migraine. “This association is more pronounced in migraineurs with menstrual-related headaches compared to non-migraineurs,” she added.

As for further research, “Studies of specific sex hormone levels and CGRP concentrations in the ictal state (during migraine attack) may further help clarify the relationship between sex hormones and CGRP,” Dr. Chai said. “Additional studies of treatments with CGRP antagonists and sex hormone levels would also be of interest. Finally, longitudinal studies of migraineurs’ hormone levels as well as CGRP levels on and off hormonal contraceptive medications would also help further elucidate the relationship between CGRP and sex hormones,” she said.

  • Raffaelli B, Storch E, Overeem LH, et al. Sex hormones and calcitonin gene-related peptide in women with migraine: A cross-sectional, matched cohort study. Neurology. 2023;100(17):e1825-e1835.