Research Suggests Connection Between Sex Hormones and CGRP in Migraine Pathophysiology


Females with episodic migraine had higher interictal CGRP concentrations in plasma and the tear fluid during menstruation than females without migraine.

Uwe Reuter, MD, PhD, MBA, managing medical director, Charité Universitätsmedizin, Berlin

Uwe Reuter, MD, PhD, MBA

In a recently published study of females, calcitonin gene-related peptide (CGRP) levels in plasma and tear fluid varied depending on the presence of migraine and hormonal status, suggesting a connection between sex hormones and CGRP in migraine pathophysiology.

"The elevated CGRP release from the trigeminovascular system following hormonal fluctuations could help to explain a higher susceptibility for migraine in female people who menstruate,” senior investigator Uwe Reuter, MD, PhD, MBA, managing medical director, Charité Universitätsmedizin, Berlin, and colleagues, concluded. “The lower CGRP tear fluid concentrations under hormonal contraception in patients with migraine could be associated with an altered migraine susceptibility under hormonal therapy and should be further investigated in a longitudinal design."

Conducted between August 2020 and May 2022, the study featured females with episodic migraine (EM) on a regular menstrual cycle (RMC), females with EM and combined oral contraception (COC), and females with EM in the postmenopause. The trial comprised of 180 females, including 3 corresponding groups of age-matched females without EM. Females with an RMC had 2 study visits, scheduled at day 2 (±2) of the menstrual cycle (during menstruation) and day 13 (±2) of the menstrual cycle, or periovulatory period.

Female participants with COC were assessed twice: at day 4 (±2) of the hormone-free interval (HFI) and days 7-14 of hormone intake (HI). Postmenopausal female participants had only 1 visit at a variable time point, and all visits for those with migraine were performed in the interictal period, which was defined as a state free of any migraine symptoms and free of acute pain medication for 12 hours before and after each visit. Each visit took place between 9AM and 5PM in a nonfasting condition, with blood and fluid samples collected using standardized protocols.

All told, during menstruation, CGRP concentrations in both plasma and tear fluid were statistically significantly higher during menstruation in participants with migraine compared with females without migraine (plasma: 5.95 pg/mL [IQR, 4.37-10.44] vs 4.61 pg/mL [IQR, 2.83-6.92] P = .020; tear: 1.20 ng/mL [IQR, 0.36-2.52] vs 0.4 ng/mL [IQR, 0.14-1.22]; P = .005). In contrast, for females with COC, CGRP concentration in plasma and tear fluid were similar between participants with migraine and controls during both HFI and HI. Similar observations were observed in the postmenopausal period, as no statistically significant difference was identified based on migraine status.

When comparing different hormonal states, females with migraine with an RMC had statistically significantly higher CGRP concentration in tear fluid during menstruation compared with those with migraine under COC (P = .015 vs HFI; P = .029 vs HI). Notably, there was no correlation between the absolute estrogen and progesterone concentrations and the CGRP concentrations in plasma and tear fluid (P >.17 for all analyses).

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When assessing those without migraine, CGRP concentrations of controls with an RMC were lower than those of females under COC treatment and postmenopausal female participants (menstruation vs HI: P = .035; ovulation vs HI: P = .030; menstruation vs postmenopause: P = .015; ovulation vs postmenopause: P = .013). CGRP levels in the tear fluid were similar across groups and all visits of control female participants (P = .622 among all groups).

Reuter et al noted that multiple physiologic and pathologic processed can influence both CGRP and sex hormone concentrations. “Despite careful selection of subjects and standardized visits, we could not control for all possible confounding factors,” the study authors wrote. “This study is intended as a pilot study. It provides evidence of an association between CGRP and different sex hormone profiles in humans and sets the context for further studies with larger sample sizes and adequate power to correct for multiple testing and confounders."

As expected, CGRP levels in tear fluid were statisticially significantly higher between those with and without migraine (migraine groups: 0.67 ng/mL [IQR, 0.17-1.59 ng/mL) vs controls: 0.41 ng/mL [IQR, 0.15-0.80 ng/mL]; P = .013). Plasma concentrations were similar, with 5.22 pg/mL (IQR, 4.03-7.97 pg/mL) in the migraine groups vs 5.95 pg/mL (IQR, 3.73-7.79 pg/mL) in the control groups (P = .965).

1. 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). doi:10.1212/WNL.000000000000207114
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