Female Sex Hormones and Migraines

Migraines as another potential result of fluctuating female sex hormones

Migraines are another potential result of fluctuating female sex hormones.

Female sex hormones and calcitonin gene-related peptide (CGRP) appear to be responsible for the onset of migraines. Calcitonin gene-related peptide (CGRP) is a molecule responsible for the onset of migraines.¹ 

Fluctuating sex hormone levels, particularly those of estrogen, may promote the activity of CGRP and thus trigger migraines. 

Compared to women without migraines, women who experienced migraines had higher amounts of CGRP in their blood and tear fluid during their periods, which further supports this relationship.²

A simplified explanation of the biology of migraines

The mechanisms leading to migraine are complex and still not fully understood.

The trigeminal nerve is responsible for sensory experiences in the face,³ and releases CGRP to expand the blood vessels in the head.¹

The trigeminal system also releases CGRP during migraine episodes, and drugs blocking the activity of CGRP can provide relief.¹

An interplay between the menstrual cycle and CGRP

Migraines are most frequent and severe before menstruation and peri-menopause when estrogen levels are low.²

Thus, the estrogen withdrawal hypothesis states that plummeting estrogen levels lead to the onset of a migraine. Birth control drugs that stabilize female sex hormone levels can suppress migraines for some people but exacerbate them for others.²

But how does this happen?

Some evidence suggests that low levels of estrogen promote the release of CGRP, leading to migraines.

People experiencing migraines presented with higher levels of CGRP in their tear fluid. This further establishes the role of the trigeminal system.⁴

These findings prompted the investigation of CGRP levels throughout different stages of the menstrual cycle in women.²

The study

A group of researchers sought to characterize CGRP levels and female sex hormone changes in women with and without migraines.²

In each group, the participants were further segregated into the following subgroups:

• Fertile women with regular menstruation.
• Women on hormonal contraceptives.
• Post menopausal women.

Results among women with a regular menstrual cycle

Roughly during the times of ovulation and before menstruation, women with migraines had higher levels of CGRP in their tears and blood than women without migraines.²

In addition, the women with migraines had lower levels of estrogen than the women without migraines around the time of ovulation. Levels of other female sex hormones were similar among both groups at both time points.²

Results among the women on hormonal contraceptives

Concentrations of CGRP were similar between the women with and without migraines, during both the hormone-free and hormone-intake intervals.²

Women without migraines experienced lower levels of estrogen and other hormones during both intervals, while testosterone levels were similar during both intervals.²

The stabilization of female sex hormones in women with migraines was associated with lower levels of CGRP in tears.²

Results among post-menopausal women

Between the women with and without migraines, hormone levels were similar, and CGRP levels were not significantly different.²

Interpreting the findings

The women with migraines had higher levels of CGRP than the women without migraines; this was not the case for those who were post-menopausal or using hormonal contraception.

In addition, the change in hormone levels rather than their absolute amounts seemed to have a relationship with CGRP levels.²

In sync with the estrogen withdrawal hypothesis and related studies, the elevated amounts of CGRP were associated with the decrease in estrogen that occurs before menstruation.

These phenomena may explain why migraines are so frequent and severe in the peri-menstrual phase.² Despite these findings, elevated CGRP levels have also been found in parts of the body unrelated to the trigeminal nerve in pregnant and post-menopausal women.² 

In the case of pregnancy, estrogen levels are also elevated,² suggesting other mechanisms are at play.

Further characterizing the relationship between trigeminal-sourced CGRP in tear fluid and migraines will add valuable insight into the matter of female sex hormones and migraines.

References

1. Edvinsson L. CGRP and migraine: from bench to bedside. Rev Neurol (Paris). Sep 2021;177(7):785-790. doi:10.1016/j.neurol.2021.06.003

2. 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. Apr 25 2023;100(17):e1825-e1835. doi:10.1212/wnl.0000000000207114

3. Clinic C. Trigeminal Nerve. Accessed May 25, 2023. https://my.clevelandclinic.org/health/body/21581-trigeminal-nerve#:~:text=The%20trigeminal%20nerve%20is%20the,help%20you%20chew%20and%20swallow.

4. Kamm K, Straube A, Ruscheweyh R. Calcitonin gene-related peptide levels in tear fluid are elevated in migraine patients compared to healthy controls. Cephalalgia. Oct 2019;39(12):1535-1543. doi:10.1177/0333102419856640